Revisiting the Role of Serotonin in Attention-Deficit Hyperactivity Disorder: New Insights from Preclinical and Clinical Studies

Matia B Solomon; Brittney Yegla; Jeffrey H Newcorn; Vladimir Maletic; Jonathan Rubin; Trevor W Robbins

doi:10.1007/s40261-025-01473-4

. 2025 Sep 3;45(10):701–742. doi: 10.1007/s40261-025-01473-4

Revisiting the Role of Serotonin in Attention-Deficit Hyperactivity Disorder: New Insights from Preclinical and Clinical Studies

Matia B Solomon ^1,^#, Brittney Yegla ^2,^✉,^#, Jeffrey H Newcorn ³, Vladimir Maletic ⁴, Jonathan Rubin ², Trevor W Robbins ^5,⁶

PMCID: PMC12476428 PMID: 40903701

Abstract

Attention-deficit hyperactivity disorder (ADHD) is characterized by core symptoms of inattention, hyperactivity, and impulsivity. Aberrant dopaminergic and noradrenergic neurotransmission are often implicated in the pathogenesis of these symptoms because ADHD treatments increase synaptic levels of these neurotransmitters in brain regions associated with attention and impulse control. However, some ADHD treatments also enhance serotonergic neurotransmission in these regions, which could contribute to their efficacy. Here, we review preclinical and clinical data highlighting functional interactions between the serotonergic and catecholaminergic systems in mediating ADHD phenotypes and responses to treatment. The potential utility of serotonergic compounds for treating distinct behavioral features and psychiatric comorbidities (e.g., depression) is also discussed. Overall, preclinical and clinical studies underscore important neuromodulatory effects of serotonin on the catecholaminergic system in mediating distinct ADHD behavioral phenotypes, notably hyperactivity–impulsivity and emotional dysregulation. Incorporating a basic understanding of dynamic monoaminergic interactions and their contributions to ADHD symptoms may identify new targets for treatment. Beyond ADHD core symptoms, emotional dysregulation, which is closely linked to serotonergic dysfunction, is common in ADHD and significantly contributes to negative outcomes across the lifespan. Therefore, an expanded conceptualization of ADHD that includes emotional dysregulation may facilitate insight into ADHD pathology and treatment.

Key Points

Impulsivity and emotional dysregulation, which are linked to serotonin (5-HT) deficiency, may be improved with distinct 5-HT receptor-targeting agents.

Corticostriatal 5-HT and its interactions with catecholamines modulate attention-deficit hyperactivity disorder (ADHD) behaviors and responses to standard treatments.

Some standard ADHD treatments increase 5-HT in ADHD-relevant brain networks.

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Introduction

Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, with reported prevalence rates of 10% in children (6–11 years), 13% in adolescents (12–17 years) [1], and 5% in adults [2]. At its core, ADHD is defined by excessive levels of inattention, hyperactivity, and impulsivity in multiple environments (e.g., school, work, home). These behavioral phenotypes are largely attributed to structural and functional abnormalities in cortico-striatal-limbic circuits and hindbrain regions subserving attention, cognitive and motor inhibition, and emotional regulation. Specifically, these brain regions include the dorsolateral prefrontal cortex (PFC) [3, 4], medial prefrontal cortex (mPFC) [5–7], orbitofrontal cortex [8, 9], anterior cingulate [10–14], striatum (i.e., caudate, putamen, globus pallidus) [12–15], amygdala [16], and cerebellum [17–19] (Fig. 1). While the emergence of ADHD symptoms typically occurs during childhood, for many people it is a life-long condition [20] that often includes impairment in a variety of associated domains, such as executive dysfunction [21], emotional dysregulation [22, 23], and comorbid conditions, such as mood [2, 24–26], anxiety [2, 27], and substance use disorders [28, 29]. Notably, it has been proposed that timely and successful treatment of ADHD may prevent the onset of some of these comorbidities [30, 31]. The toll of untreated ADHD cannot be overstated, as it is linked with a sixfold increased risk for mortality, particularly before the age of 30 years [32, 33].

Fig. 1 — Brain regions implicated in attention deficit/hyperactivity disorder. Bs brain stem, Cb cerebellum, CC cingulate cortex, *HPC* hippocampus, *NAc* nucleus accumbens, *OFC* orbitofrontal cortex, *PFC* prefrontal cortex, *Str* striatum. Created with BioRender.com

The etiology of ADHD has yet to be fully elucidated; however, both genetic and environmental risk factors are implicated [34–38]. In addition to these risk factors, aberrant signaling in inflammatory pathways [39–41] and multiple neurotransmitter systems [42–44] are noted as key factors. The catecholamines dopamine (DA) and norepinephrine (NE) are the most well-studied neurotransmitters implicated in ADHD pathogenesis, primarily because effective ADHD treatments (both stimulants and nonstimulants) increase these neurotransmitters in brain regions such as the PFC and striatum, which are critical for impulse control, attention, and emotional regulation [45, 46]. In addition to the supportive evidence provided by the efficacy of these compounds, the centrality of the catecholamine systems in ADHD has also been established through brain imaging studies in patients with ADHD that consistently show DA and NE system disruptions, and preclinical experiments using genetic and pharmacological manipulations [47–49]. While the subject of several theoretical and systematic reviews [50–52], the role of serotonin (5-HT) in ADHD has been overshadowed by research centering on DA and NE. This largely results from the well-documented actions of approved treatments on catecholaminergic systems, while selective serotonin reuptake inhibitors (SSRIs) are reportedly ineffective for ADHD [53, 54]. Yet, there is considerable evidence from preclinical and some clinical studies indicating a role for 5-HT in certain ADHD behavioral phenotypes (e.g., behavioral inhibition) and stimulant-mediated effects. Given the ubiquity of monoamines (DA, NE, and 5-HT) and their importance in central nervous system function, understanding their dynamic interplay may be critical for advancing our understanding of the etiology, manifestations, and treatment of ADHD. Therefore, a reexamination of the role of 5-HT in ADHD is warranted.

We review evidence from preclinical and clinical studies investigating potential links between the serotonergic system and ADHD phenotypes. We discuss the necessity and sufficiency of serotonergic neurotransmission based on studies involving tryptophan modulation, genetic manipulations (i.e., knockout [KO] rodents), and drugs with known serotonergic activity on ADHD behavioral phenotypes. Serotonergic effects on brain function and behavior are vast and include interactions with multiple neurotransmitter systems and neuropeptides across brain networks. For this review, we focus on its intricate connection and functional interactions with the catecholaminergic systems in ADHD behavioral phenotypes and stimulant-mediated effects in preclinical species and patients with ADHD. Although 5-HT is broadly linked with some ADHD phenotypes, the potential role of 5-HT receptor subtypes in mediating clinical effects is unclear. Thus, we describe preclinical studies, highlighting their effects in key cortico-striatal-limbic regions (i.e., PFC, orbitofrontal cortex, and nucleus accumbens). Given the renewed interest in emotional dysregulation (i.e., emotional impulsivity and reactive aggression) as an inherent feature in ADHD [22, 23] and its link to the serotonergic system [55–57], we also discuss 5-HT within the context of emotional dysregulation. As our conceptualization of ADHD evolves so does our understanding of the putative role of 5-HT as an important component in its etiology and treatment.

To identify appropriate articles for the review, PubMed and GoogleScholar were utilized in a non-time-restricted fashion, with search terms focused on 5-HT, 5-HT receptor subtypes, 5-HT genes, and ADHD-relevant terms, such as impulsivity, attention, hyperactivity, emotional dysregulation, and aggression in both preclinical and clinical publications. A variety of preclinical techniques, including but not limited to microdialysis, optogenetics, electrophysiology, behavioral assays, pharmacological agents, toxins, viral vectors, and genetically modified rodents, were included in the search with the purpose of identifying interactions between 5-HT and other monoamines for neurochemical interactions and behavioral effects.

Serotonin (5-HT)

The rate-limiting step in 5-HT synthesis is conversion of tryptophan to 5-hydroxytryptamine (5-HTP) by tryptophan hydroxylase (TPH), which has two isoforms, TPH1 and TPH2 [58, 59]; however, TPH2 is the only isoform produced by serotonergic neurons in the brain [59]. In addition to its rate of synthesis, 5-HT concentrations in the brain are regulated by (1) 5-HT transporters (SERT) [60]; (2) 5-HT autoreceptors (i.e., 5-HT1A and 5-HT1B receptors located on the presynaptic membrane) [61–67], both of which decrease its concentration in the synapse; as well as (3) monoamine oxidase [68], an enzyme that causes cytosolic degradation of all monoamines. Broadly, 5-HT regulates a variety of behaviors, including emotion [69], cognition [70], motor output [71], feeding [72], and sleep [73]. Serotonergic efferents from the dorsal and median raphe nuclei widely project to cortico-striatal-limbic regions associated with many of these behaviors, including the cingulate cortex, mPFC, basal ganglia, amygdala, and hippocampus [74–76] (Fig. 2).

Fig. 2 — Monoaminergic signaling in the human brain. The monoaminergic systems highly overlap across brain regions implicated in ADHD, especially the cortex, midbrain, and brainstem. DA dopamine, NE norepinephrine, *5-HT* serotonin. Created with BioRender.com

Proper serotonergic signaling is critical for prefrontal and somatosensory cortical development and function [77–80]. These brain regions are associated with delayed maturation or reduced gray matter in individuals with ADHD [81–84]. The integral role for 5-HT in the development and function of these brain regions is noteworthy, given the well-documented involvement of the PFC in executive function, including behavioral inhibition and emotional regulation, as well as sensory dysregulation issues that are apparent in some individuals with ADHD [85]. Disruption in serotonergic neurotransmission during development also impacts the catecholaminergic systems and their projections to the PFC [86]. Together, these findings highlight a critical role for 5-HT in the development and function of ADHD-relevant brain networks, including interconnections with the catecholaminergic systems (Fig. 2), through which it may influence the onset of ADHD symptoms and perhaps other closely related psychiatric comorbidities.

The diverse effects of 5-HT in the brain are due to the diversity of presynaptic and postsynaptic 5-HT receptors in multiple brain regions, their expression on multiple cell types, their dimerization with other serotonergic receptors, and their diverse secondary messenger signaling. Serotonin also functions as a neuromodulator that can regulate the activity of other neurotransmitters, including DA, NE [87, 88], and the principal inhibitory (γ-aminobutyric acid, GABA) and excitatory (glutamate) neurotransmitters in the brain [89]. Serotonin mediates its biological effects through at least 14 different receptor subtypes: 5-HT1 (1A_, 1B, 1D, 1F), 5-HT2 (2A, 2B, 2C), 5-HT3, 5-HT4, 5-HT5 (5A, 5B), 5-HT6, and 5-HT7 (Table 1). Apart from the 5-HT3 receptor, which functions as a ligand-gated ion channel, most 5-HT receptor subtypes are classified as metabotropic (G-protein coupled) receptors that activate distinct second messenger systems to mediate either excitatory or inhibitory neurotransmission [90]. Delineating the role of these distinct receptor subtypes is critical to understanding the role for 5-HT in brain function and behavior; however, for this review we primarily highlight select receptor subtypes, including 5-HT1A_, 5-HT1B, 5-HT2A, 5-HT2C, and 5-HT3, which have been implicated in the core behavioral features of ADHD, emotional dysregulation, and stimulant-mediated efficacy.

Table 1.

Impact of agonism of select serotonin receptor subtypes on the dopaminergic system across multiple brain regions

Agonism	Effect on dopamine	Brain Regions Impacted
5-HT1A	Increase	Prefrontal cortex, substantia nigra (locally)
5-HT1A	Decrease	Striatum, nucleus accumbens
5-HT1B	Increase	Striatum, nucleus accumbens, substantia nigra (locally)
5-HT1D	Unclear	Selective agonists have not been examined for effects on dopamine
5-HT1F	Unclear	Selective agonists have not been examined for effects on dopamine
5-HT2A	Increase	Prefrontal cortex, striatum, nucleus accumbens
5-HT2B	Increase	Nucleus accumbens
5-HT2B	Decrease	Prefrontal cortex
5-HT2C	Decrease	Prefrontal cortex, striatum, nucleus accumbens
5-HT3	Increase	Prefrontal cortex, striatum, nucleus accumbens
5-HT4	Increase	Striatum
5-HT5	Unknown, no selective agonists confirmed
5-HT6	Mixed	Highest dose of WAY-181187 decreased dopamine in the prefrontal cortex and striatum and was reversed by 5-HT6 antagonist for striatal dopamine [457] ST1936 increased dopamine in the prefrontal cortex and nucleus accumbens shell [458]
5-HT7	Unclear^a

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Impact of engaging various serotonin receptors subtypes on dopamine, which could include changes in dopamine levels, metabolism, impulse- or depolarization-dependent release, and/or electrical activity of dopaminergic neurons. De Deurwaerdère and colleagues’ 2021 review [102] served as the foundation for this table, in addition to a few select references mentioned in the footnotes

^aFor 5-HT7, little to no articles have been published on the effects of selective 5-HT7 agonists on dopamine-related measures. The selective 5-HT7 antagonist SB-269970 has been shown to have no effect on MK-801-induced dopamine levels in rat prefrontal cortex (via microdialysis; [459]) but does inhibit neuronal firing of dopamine neurons following amphetamine treatment in the ventral tegmental area, though not the substantia nigra pars compacta[460]

Serotonergic Mechanisms in Preclinical Studies Relevant to ADHD

The following sections will discuss preclinical evidence of the role of 5-HT in ADHD-relevant behaviors, specifically hyperactivity, impulsivity, emotional dysregulation, inattention, and cognitive inflexibility using healthy rodents, as well as preclinical models of ADHD. Tables 2 and 3 describe these preclinical assays and their corresponding clinical tasks. Tables 4 and 5 summarize the impact of specific 5-HT receptor subtypes on each of these phenotypes, as well as their involvement in stimulant-related effects on these measures.

Table 2.

Preclinical and clinical assays of attention, impulsivity, and cognitive flexibility

Dimension	Preclinical	Clinical	Brief description/behavioral measure
Impulsivity
Impulsive action and sustained attention	five-choice serial reaction time task (5CSRTT)	5CSRTT	Operant task that measures accuracy of identifying signal trials (% hit; % correct) and ability to withhold responding (premature responses)
Impulsive action and sustained attention	five-choice continuous performance task (CPT)	CPT	Operant task that measures accuracy of detecting signal events (% hit; % correct) in contrast to non-signal events and the ability to withhold responding (premature responses)
Impulsive action	Go/no-go	Go/no-go	Operant task including go (action) and no-go (action restraint) trials, measuring impulsive action through withholding of a response on the no-go trials
Stopping	Stop signal reaction time task (SSRTT)	Stop signal	Operant task assessing action cancellation, following signal and stop cues (i.e., time to stop an initiated motor response)
Impulsive choice	Delay discounting task (DDT)	Delay discounting	Measures selection between an immediate, smaller reward (i.e., more impulsive) and a delayed, larger reward (i.e., less impulsive)
Attention/cognitive flexibility
Attention		Test of attentional performance (TAP)	A battery of tests evaluating accuracy of responses (% correct), reaction times, and eye movements when responding selectively to stimuli; it gauges alertness, vigilance, working memory, impulsivity (go/no-go), cognitive flexibility (attentional set-shifting task), and sustained and divided attention
Attentional set shifting	Extradimensional set-shifting; intradimensional set shifting	CANTAB Intra/extradimensional set shift; Wisconsin Card Sorting Task	Task that measures the ability to switch within (intra-dimensional) and between (extra-dimensional) learned attentional sets in a goal-oriented fashion. Cognitive flexibility is assessed as the number of trials required to acquire the new rule and the number of errors made
Reversal learning	Reversal learning	Wisconsin Card Sorting Task; Instrumental reversal learning; Pavlovian reversal; probabilistic reversal learning	Task that measures the ability to reverse the value associated with a pair of stimuli (i.e., previously irrelevant stimulus becomes relevant). Cognitive flexibility is assessed as the number of trials required to acquire the new rule and the number of errors made

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Frequently used preclinical behavioral assessments and their relatively equivalent clinical evaluations for measuring impulsivity, attention, and cognitive flexibility in attention-deficit hyperactivity disorder research

5CSRTT five-choice serial reaction time task, CANTAB Cambridge Neuropsychological Test Automated Battery, CPT continuous performance task, DDT delay discounting task, SSRTT stop signal reaction time task, TAP test of attentional performance

Table 3.

Preclinical and clinical assays of emotional dysregulation

	Reactive aggression model	Brief description
Preclinical^a	Isolation	Rodents have prolonged social isolation prior to exposure to conspecific
	Alcohol	Rodents are given alcohol prior to exposure to conspecific
	Discontinuation of scheduled reward	Rodents are assessed for their interactions with a conspecific following an extinction protocol (i.e., omission of a scheduled reward)
	Social instigation	Intruding conspecifics are placed into the home cage (resident–intruder paradigm)
Clinical	Point subtraction game	Participants compete for points or money against fictitious opponent, often with low or high provocation components (measure “stealing” of points); can also be paired with alcohol
Clinical	Taylor competitive reaction test	Participants exposed to a fictitious interpersonal scenario to compete on a reaction time task; aggression is measured as the number and severity of noxious stimuli (e.g., noise blasts) participant delivers to the opponent

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A variety of preclinical and clinical assessments frequently used to evaluate emotional dysregulation in animal models and individuals with attention-deficit hyperactivity disorder

^aLatency to attack and aggressive behaviors (i.e., frequency and duration of chasing, biting, attacking, dominant postures/sideway threats) are assessed after the initial stimulus/condition

Table 4.

Impact of selective 5-HT receptor ligands on ADHD-relevant behaviors in preclinical species

Target	Activity	Ligand	Administration	Hyperactivity in ADHD models	Impulsive action	Impulsive choice	Aggression	Attention	Cognitive flexibility
TPH	Inhibitor	PCPA		↓ [115]
5-HT1A	Agonist	8-OHDPAT	Systemic^a		↑ [154]	↑ [160, 161]		↓ [153]
			Systemic				↓ [191, 193]
			Intra-OFC			↓ [162]
			Intra-PFC					↑ [153]
			Intra-nucleus accumbens			↑ [160]
	Genetic overexpression on serotonin neurons		^a				↑ [189]
	Lower expression of transcripts and protein						↑ [195]
5-HT1B	Agonist	Anpirtoline	Systemic^a				↓ [55]
		CP-94,253	Intra-DR^a				↓ [195]
		CP-94,253	Intra-PFC^a				↑ [195]
	Antagonist	SB 224289	Systemic	↓ [141]
	5-HT1B KO mice						↑ [205]
5-HT2	Agonist	DOI	Systemic, intra-striatal	↑ [116]		↑ [163]
		Quipazine^b	Systemic	↓ [109]				↓ [210]
		m-Chlorophenylpiperazine	Systemic				↓ [197]
5-HT2A	Antagonist	M100917	Intra-PFC Systemic; intra-nucleus accumbens	↓ [142]	[151] ↓ [158]			↑ [153] ↓ [153]
5-HT2A	Reduced transcripts in the frontal cortex								↓ [227]
5-HT2A/C	Antagonist	Ketanserin	Systemic; intra-PFC	↓ [110]	↓ [152, 164, 325]	↑ [164, 326]	↓ [199]
		Mianserin^b	Systemic	↓ [110]
		Ritanserin^b	Intra-striatal (hyperactivity) Systemic (aggression)	↓ [114, 117]			↓ [199]
5-HT2C	Antagonist	SB 242084	Systemic; intra-nucleus accumbens		↑ [150, 151]
		SB 242084	Intra-PFC		[151]
		SER-082	Systemic			↓ [164]
	Inverse agonist	S32212^b	Systemic				↓ [198]
	Lower expression of transcripts and protein						↑ [195]
	VGV isoform expression						↑ [196]
5-HT3	Antagonist	Granisetron, ondansetron	Systemic			↓ [165]	↓ [201]
		MDL-7222 but not tropisetron	Systemic				↓ [200]
	Higher receptor density						↑ [204]
5-HT6	Antagonist	SB-270146A	Systemic			[164]

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The table illustrates serotonergic receptors and the 5-HT synthesizing enzymes that have been targeted pharmacologically with agonists, antagonists, or inhibitors in preclinical species or were genetically altered (e.g., knockdown) to evaluate their impact on phenotypes observed in ADHD, including hyperactivity, impulsivity (impulsive action and impulsive choice), inattention, cognitive inflexibility, and emotional dysregulation (i.e., aggression). Indicators represent the corresponding changes in behavior after modulation of the receptor/enzyme: ↑ = increased behavior; ↓ = decreased behavior; Inline graphic = no effect on behavior

ADHD attention-deficit hyperactivity disorder, DR dorsal raphe, KO knockout, OFC orbitofrontal cortex, PCPA para-chlorophenylalanine, PFC prefrontal cortex, TPH tryptophan hydroxylase, VGV valine glycine valine

^aPosited to engage the presynaptic receptor

^bA few compounds are nonselective for their designated target. For completeness, these compounds also engage the following targets: S32212 (5-HT2A antagonist, alpha2 adrenergic antagonist); mianserin (histamine 1, α2A, α2C, 5-HT2 antagonist); quipazine (5-HT2, 5-HT3 agonist); ritanserin (5HT2, α1A, α1B, α1D, 5-HT5, 5-HT6, 5-HT7 antagonist)

Table 5.

Selective serotonin receptor modulation of stimulant effects in preclinical species

Target	Activity	Ligand	Administration	Mediation of stimulant effect
5-HT neurons	Lesion	5,7-DHT	Intracerebroventricular	↑ AMPH-induced hyperactivity [260] X AMPH-induced reductions in impulsive choice [159]
TPH	Inhibitor	PCPA		↑ MPH- and AMPH-induced hyperactivity [257–260] ↓ Hyperactivity in 6-OHDA model [115] AMPH-induced decrease in hyperactivity in neonatal 6-OHDA model [115]
TPH knockout mouse				↑ Sensitivity to AMPH-induced hyperactivity [265]
MAO B	Inhibitor	Pargyline	Systemic	↓ AMPH-induced hyperactivity [257, 260]
SERT	Inhibitor	Fluoxetine	Systemic	↑ MPH-induced hyperactivity [140]
5-HT receptors, nonselective	Antagonist	Methysergide	Systemic	X AMPH-induced decrease in hyperactivity in neonatal 6-OHDA model [109]
5-HT1A	Agonist	8-OHDPAT	Intra-accumbal	X AMPH-induced reductions in impulsive choice [160] ↑ Impulsive choice, which was blocked by 6-OHDA lesions [160]
5-HT1A	Antagonist	WAY100635	Systemic	↑ AMPH-induced effects on impulsive choice [160]
5-HT1B	Agonist	CP 94253/ CP 93129	Systemic	↑ MPH-induced hyperactivity [140]
5-HT1B	Antagonist	GR 55562	Systemic	↓ Meth-AMPH- and fluoxetine-potentiated MPH hyperactivity [140]
5-HT2A	Antagonist	MDL 100,907, amperozide	Systemic	X AMPH-induced hyperactivity [278, 461] X AMPH-induced increases in impulsive action [272]
	Antagonist	SR46349B	Systemic, intra VTA (not intra-PFC)	X AMPH-induced hyperactivity [279]
	Antagonist	Ritanserin	Intra-striatal	Fluoxetine-potentiated MPH hyperactivity [140] ↓ D1 hypersensitivity in neonatal 6-OHDA lesioned mice [114, 117]
5-HT2C	Agonist	Ro60-0175	Systemic	X AMPH-induced increases in impulsive action [272]
5HT3	Antagonist	Ondansetron	Systemic, intra-NAc	↓ AMPH-induced hyperactivity [166]

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Involvement of 5-HT receptor subtypes in stimulant-mediated effects for attention-deficit hyperactivity disorder-relevant behaviors, including hyperactivity and impulsivity. See [102] for full review on 5-HT receptor subtype expression and their modulation of dopaminergic signaling in subregions of the brain. Indicators represent the corresponding changes in behavior following modulation of the receptor/transporter/enzyme: ↑ = potentiates the effect; ↓ = attenuates the effect; Inline graphic = no effect; X = blocks or cancels the effect

5,7-DHT 5,7-dihydroxytryptamine, 5-HT serotonin, 6-OHDA 6-hydroxydopamine, AMPH amphetamine, MPH methylphenidate, MAO B monoamine oxidase B, NAc nucleus accumbens, PCPA para-chlorophenylalanine, SERT serotonin transporter, TPH tryptophan hydroxylase, VTA ventral tegmental area

Role of 5-HT in Hyperactivity

Hyperactivity can be easily monitored in the laboratory by assessing locomotor activity in various environments. Locomotor activity is often associated with activation of the dopaminergic system [91, 92]. Serotonin also plays a major role in locomotor activity [93], likely via interactions with several neurotransmitter systems including the mesocorticolimbic dopaminergic pathway [94], and can be impacted by factors such as age and environment. For instance, neonatal 5-HT depletion methods in healthy rodents induce hypolocomotion [95–97]. However, factors such as novelty of the environment or age of the rodent when 5-HT is depleted (i.e., adulthood) can conversely induce hyperactivity or have no effect, respectively [94, 95, 98]. These varied serotonergic effects on locomotion could result from engagement of diverse 5-HT receptor subtypes and their downstream effects on interconnected neurotransmitter systems, including the dopaminergic system. For example, in healthy rodents, activation of 5-HT receptor subtypes that facilitate DA release in the mesocorticolimbic dopaminergic pathway (i.e., 5-HT1B and 5-HT2A receptors) increase locomotor activity, while activation of 5-HT receptors that inhibit this pathway (i.e., 5-HT2C receptors) tend to decrease locomotor activity [87, 99–101]. For a thorough review on 5-HT receptor subtype expression and modulation of dopaminergic signaling in various brain regions, see [102].

Preclinical models of ADHD have been used to assess hyperactivity in rodents, including neonatal 6-hydroxydopamine (6-OHDA) lesions, spontaneously hypertensive rats (SHRs), and DA transporter (DAT) KOs. Each model displays some of the core behavioral features of ADHD, including hyperactivity, impulsivity, inattention (see review by Fan X and colleagues [103]), or reactive aggression [104, 105]; most of these behaviors are attenuated by methylphenidate or amphetamine. Thus, these models demonstrate face and predictive validity. Moreover, these models exhibit significant dopaminergic disruption with corresponding alterations in serotonergic measures, emphasizing the dynamic interaction of these two monoaminergic systems as discussed in [103].

6-OHDA-Lesioned Model

In neonatal rats, a combination of intracranial 6-OHDA and systemic desipramine infusions, to lesion central dopaminergic neurons but preserve noradrenergic neurons, respectively, causes paradoxical motor hyperactivity [106]. Serotonergic agents (citalopram, fluvoxamine, fenfluramine, quipazine, ketanserin, and mianserin) and compounds that primarily target the catecholaminergic system (amphetamine, methylphenidate, nisoxetine, and desipramine) reduced hyperactivity in this rodent model [107–110]. Notably, both d-methylphenidate and selective DAT inhibitors, amfonelic acid, and GBR-12909, induced hyperactivity in controls, whereas methylphenidate but not the selective DAT inhibitors attenuated hyperactivity in rats with neonatal 6-OHDA lesions [108], suggesting that inhibition of the NE transporter (NET) or SERT is critical for these therapeutic effects.

However, this model exhibits compensatory mechanisms after 6-OHDA lesions that may contribute to its manifestation of hyperactivity, such as dopamine D1 receptor hypersensitivity, altered 5-HT2 transcript levels, increased striatal 5-HT and 5-HIAA (5-HT metabolite) levels, and enhanced serotonergic innervation of the striatum, resulting in increased serotonergic tone [111–115]. Hyperactivity in neonatal 6-OHDA-lesioned mice was normalized when striatal 5-HT levels were decreased using para-chlorophenylalanine (PCPA), suggesting that enhanced 5-HT signaling in this region after 6-OHDA lesioning caused an imbalance in motor control [115]. Moreover, functional interactions between striatal D1 and 5-HT2A receptors may mediate hyperactivity in this model; 5-HT2A receptor antagonism (ketanserin and M100907) but not 5-HT2C receptor antagonism attenuated the D1 supersensitivity and corresponding hyperactivity in adult rats [114–117]. These findings demonstrate that 5-HT2A receptor antagonists, via inhibitory effects on the dopaminergic system, are beneficial in mitigating the hyperactive phenotype in this preclinical model of ADHD.

SHR Model

The SHR model is characterized by disruptions in monoaminergic systems, with reports of reduced presynaptic serotonergic function, enhanced dopaminergic presynaptic activity in the accumbens (D2 autoreceptors and DA reuptake via DAT), lower evoked DA release in the striatum and accumbens, and increased D1 and D2 receptor expression in the frontal cortex, dorsal striatum, and nucleus accumbens [118–122]. Discrepant findings of hyper- versus hypo-dopaminergic tone in SHRs are likely brain region dependent or due to comparisons with varying controls (Wistar Kyoto, Wistar, or Sprague Dawley rats). For instance, SHRs and Wistar Kyoto rats showed no difference in 5-HT in the striatum [123, 124], but SHRs had decreased serotonergic activity [125] and 5-HT turnover (5-HIAA/5-HT) in other catecholaminergic brain regions, such as the ventral tegmental area (i.e., dopaminergic neurons) and locus coeruleus (i.e., noradrenergic neurons) [124].

Compounds that enhance 5-HT neurotransmission, including serotonin–norepinephrine reuptake inhibitors (SNRIs; venlafaxine, duloxetine, and milnacipran), attenuate hyperactivity in SHRs but do not impact controls [126]. While these compounds increase prefrontal monoamine concentrations (5-HT, NE, and DA), the improvement in hyperactivity may be due to enhanced noradrenergic and dopaminergic neurotransmission; similar effects were not observed with the SSRI citalopram. Furthermore, methylphenidate and the norepinephrine reuptake inhibitors (NRIs) atomoxetine and reboxetine, which increased prefrontal DA and NE but not 5-HT, decreased hyperactivity in this model. Thus, it appears that compounds that directly target NET or DAT consistently decrease hyperactivity in SHRs. Relative to the catecholaminergic systems, there are far fewer studies that have investigated the role of the serotonergic system on hyperactivity in SHRs. Because of the inconsistent findings with SSRIs (fluvoxamine, citalopram) on hyperactivity [126–128], some question the role of the serotonergic system in the etiology of this phenotype in SHRs, as discussed in [129].

DAT KO Mouse Model

DAT KO mice have increased extracellular DA levels in the striatum [130, 131] and nucleus accumbens [132] but not the frontal cortex, which has low DAT expression under normal physiological conditions [133]. Relative to controls, DAT KO mice have disturbances in their catecholaminergic systems, including reduced D1 and D2 receptor expression in the substantia nigra and ventral tegmental area [134, 135] and increased NET expression in the PFC [136], which is likely because of the capacity of NET to take up both NE and DA from the synapse [137]. However, there are conflicting reports regarding the impact of DAT KO or DAT knockdown on the serotonergic system. One study reported no effect on 5-HT efflux in the PFC, striatum, and nucleus accumbens [133], while Fox and colleagues [138] reported enhanced serotonergic tone and sensitivity in the striatum.

Despite these differing research findings, serotonergic targeting agents attenuate hyperactivity in this model. For example, Gainetdinov et al. [139] showed hyperactivity was reduced by methylphenidate and treatments that increase 5-HT levels, such as l-tryptophan loading and systemic fluoxetine (SSRI). In contrast, infusion of fluoxetine directly into the PFC did not affect hyperactivity [136], suggesting that serotonergic agents are likely active at sites outside of the PFC to induce this normalizing locomotor effect [139]. Increasing prefrontal DA levels is a primary mechanism by which hyperactivity can be normalized in this model; intra-PFC infusions of amphetamine, desipramine (NRI), and nepicastat, which blocks synthesis of NE and thus results in depleted NE and increased DA levels, reversed hyperactivity [136] (though see [139] for conflicting evidence on NRI nisoxetine).

One potential mechanism by which 5-HT may reduce hyperactivity in this model is via 5-HT1B receptors (Table 4; Fig. 3). 5-HT and 5-HT1B receptor agonism can potentiate DA release in the nucleus accumbens [102] and enhance methylphenidate-induced hyperactivity in healthy rodents [140]. In contrast, 5-HT1B receptor antagonism, as well as reduced 5-HT1B receptor expression (i.e., 5-HT1B Het/DAT KOs), normalize locomotor activity levels in DAT KOs [141]. 5-HT2A receptors also are implicated, as 5-HT2A receptor antagonism using M100907 attenuates hyperactivity in DAT KO mice but is ineffective in control mice [142]. Interestingly, the normalizing effects of amphetamine, methylphenidate, fluoxetine, quipazine (5-HT2 receptor agonist), and l-tryptophan were blocked by N-methyl-d-aspartate (NMDA) antagonists in the DAT KO model [143], emphasizing the integrated nature of glutamate, 5-HT, and DA interactions in regulating locomotor activity.

Summary While dysregulation in the dopaminergic system is a primary feature of these preclinical ADHD models, the findings suggest that imbalances in the interplay of serotonergic and dopaminergic neurotransmission can affect hyperactivity in these models. These preclinical findings support a role for monoamine imbalance in the etiology of ADHD rather than deficits within a single neurotransmitter system. The data also suggest that the efficacy of some serotonergic targeting agents may be dependent upon the endogenous tone of the catecholaminergic and serotonergic systems in each model.

Role of 5-HT in Impulsive Action and Impulsive Choice

Impulsivity is a multi-faceted construct that can be measured in a number of ways in experimental animals and humans [144] (Table 2). Basic divisions of impulsivity have been proposed: impulsive action which includes inability to “wait,” impulsive choice (i.e., impulsive decision making), and impulsivity related to the inability to “stop,” which are assessed by different paradigms [145, 146]. Impulsivity can also manifest as emotional impulsivity, though this will be discussed later. In rodents, the five-choice serial reaction time task (5CSRTT) includes a measure of premature, maladaptive responding (e.g., impulsive action). The go/no-go task assesses the capacity to withhold a response during infrequent designated periods (e.g., impulsive action). The temporal discounting of reward paradigm examines impulsive choice of an immediate, but less rewarding outcome. The stop signal reaction time (SSRT) task measures the ability to inhibit a motor response after it has been initiated [145]. Although these test paradigms, which have human equivalents [144] and are relevant to ADHD [147], index some aspects of impulsivity, these impulsivity measures have been shown to be distinct constructs dependent on different neural substrates. Moreover, manipulations of the 5-HT system differentially affect performance in these test settings. It should be noted that, although SHRs have been included in some of these impulsivity assays, most utilized healthy rodents or those behaviorally characterized as more or less impulsive.

Role of 5-HT in Impulsive Action

Regarding impulsive action, profound depletion of central 5-HT using intracerebroventricular (i.c.v.) 5,7-dihydroxytryptamine (5,7-DHT) produced significant increases in the number of premature responses in the 5CSRTT in rats, which depends mainly on dorsal raphe 5-HT projections [148–150]. This impulsivity was exacerbated with a 5-HT2C receptor antagonist but was attenuated by a 5-HT2A receptor antagonist, consistent with apparent opposing actions of these receptors [150]. These opposing effects have also been observed in non-lesioned rats after microinfusions of these receptor antagonists directly into the nucleus accumbens, but not the PFC [151]. By contrast, the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) reduced premature responses when infused into rat mPFC [152, 153]. These effects were likely driven by engagement of the postsynaptic 5-HT1A receptor because activation of presynaptic 5-HT1A receptors, which decreases 5-HT signaling, impaired 5-HT function and enhanced impulsivity [154]. Conversely, general increases in 5-HT at the synapse, via the SSRI citalopram, decreased impulsive action in rats [155].

Role of 5-HT in Impulsive Choice

The effects of similar 5-HT manipulations on impulsive choice, measured through the temporal discounting of the reward paradigm, are less clear. In alignment with the impact of 5-HT on impulsive action, rat studies demonstrated that 5,7-DHT lesions to the serotonergic dorsal and median raphe nuclei, which produced selective and substantial 5-HT depletion in the parietal cortex, hippocampus, amygdala, nucleus accumbens, and hypothalamus, induced a significant bias towards the immediate, smaller reward in the acquisition of a temporal discounting two-choice task [156]. This result suggests increased impulsive choice due to sensitivity of delay. In addition to replicating the effect of 5-HT depletion on selection of the immediate small reward, Bizot and colleagues [157] also observed that the SSRIs fluoxetine and fluvoxamine reduced impulsive choice; though Baarendse and Vanderschuren [155] showed contrasting results for citalopram and paroxetine. Despite an i.c.v. 5,7-DHT treatment that achieved similar levels of 5-HT depletion, Winstanley and colleagues [158–160] found no effect of 5-HT depletion on impulsive choice, either on acquisition or established performance. However, 5-HT depletion significantly blocked the anti-impulsive effects of amphetamine [159], which may indicate that 5-HT modulates how this first-line treatment in ADHD interacts with the circuitry underlying impulsive choice.

Serotonin receptor subtypes elicit distinct effects on impulsive choice (Table 4). 5-HT1A receptors are expressed both pre- and post-synaptically, and it is posited that these subpopulations, as well as regional differences in expression, result in divergent effects on impulsive choice. Systemic administration of the 5-HT1A receptor agonist, 8-OHDPAT, presumably acting on presynaptic autoreceptors to reduce 5-HT release, increased impulsive choice [160, 161], and this effect was dependent on DA in the nucleus accumbens [160]. However, when it was infused into the orbitofrontal cortex, 8-OHDPAT decreased impulsive choice, which may be due to postsynaptic receptor engagement or regional, circuit-level differences [162]. Similar to its effects on impulsive action, 5-HT2A receptor agonism with 2,5-dimethoxy-4-iodoamphetamine (DOI) increased impulsive choice upon systemic administration [163], although the 5-HT2A/C receptor antagonist ketanserin had no effect [164]. Conversely, the 5-HT2C receptor antagonist SER-082 reduced impulsive choice while the 5-HT6 receptor antagonist SB-270146-A had no effect [164]. Finally, Mori and colleagues [165] reported that the 5-HT3 receptor antagonists granisetron and ondansetron reduced impulsive choice in mice. These 5-HT3 receptor-mediated effects on impulsive choice may be due to their suppressant effects on the mesolimbic DA system and are consistent with their ability to reduce some DA-dependent behaviors, including hyperactivity and the rewarding properties of drugs of abuse [166, 167]. Hence, the role of 5-HT in impulsive choice depends on the integrated effects of specific 5-HT receptors in different neural locations.

In general, measures of impulsivity in the 5CSRTT and delayed discounting task frequently dissociate in their responses to 5-HT (and catecholamine) manipulations, which may reflect the differential neurobiology underlying these distinct constructs of impulsivity, as well as the diverse functions of 5-HT. Serotonin is often implicated in behavioral inhibition, as originally proposed by Soubrié [168]. Miyazaki et al. [169] showed that infusions of 8-OHDPAT directly into the dorsal raphe reduced “patience” of rats waiting for delayed rewards, with obvious relevance to both the 5CSRTT and the delayed discounting procedures. In addition, 5-HT neurons in the dorsal raphe increased tonic firing during the “waiting” epochs, as rats awaited reinforcing stimuli, showing a direct relationship between the waiting period and 5-HT neuronal firing rate. Serotonin is suggested to enhance the behavioral responses to rewards. For example, similar 5-HT treatments increased the breakpoint in progressive ratios of reinforcement (for either food or cocaine reinforcement), suggestive of a general disinhibitory action on motor function related to reward [170].

Role of 5-HT in Action Cancellation

Another commonly used paradigm for measuring impulsivity is the SSRT procedure, in which a stimulus signals a halt to the completion of an already initiated motor response; impulsivity is exhibited by a prolongation of the SSRT (Table 2). This task has been frequently used in the assessment of individuals with ADHD [147]. Eagle and colleagues [171] showed that 5-HT depletion via i.c.v. 5,7-DHT, at a concentration sufficient to produce high levels of impulsivity on other assays (i.e., premature responding in the 5CSRTT, impaired go/no-go acquisition and performance [172]), had no effect on SSRT performance. Moreover, systemic citalopram had no effects [173]. This relative lack of effect might derive from the consideration that the SSRT task does not involve anticipatory responses to reward, as do the other impulsivity procedures. There has been less systematic analysis of the possible role of 5-HT in stop-signal inhibition in experimental animals. However, there are some indications from human studies that 5-HT agents, such as citalopram and escitalopram, may have significant actions in healthy participants and those with clinical disorders [174, 175]. Thus, it may be premature to conclude at this stage a lack of 5-HT involvement in stop-signal inhibition.

Summary The findings suggest that 5-HT has task-dependent effects on impulsive behaviors. While reduction in 5-HT is generally associated with increased impulsivity, it is more consistently linked with increased impulsive action as measured in the 5CSRTT. Similar to the reported findings with hyperactivity, the overall inhibitory effects of 5-HT on impulsivity may be due to modulatory effects on DA signaling. For example, serotonergic compounds that decrease DA signaling in the mesolimbic pathway (i.e., 5-HT2A and 5-HT3 receptor antagonists) attenuate impulsivity on some tasks (premature responding and impulsive choice), while those that increase DA signaling (i.e., 5-HT2C receptor antagonist) exacerbate impulsivity (premature responding). These findings suggest that 5-HT and DA jointly regulate this form of impulsive behavior, and the nucleus accumbens, mPFC, and orbitofrontal cortex are critical nodes for mediating some of these behavioral effects.

Role of 5-HT in Emotional Dysregulation/Impulsive Aggression

Emotional dysregulation (i.e., emotional impulsivity, reactive aggression) is viewed by many as an inherent feature of ADHD [23]. Here, we describe studies investigating the impact of 5-HT on reactive aggression as one form of emotional dysregulation and exclude studies involving instrumental aggression (i.e., predatory; Table 3). Emotional reactivity can also encompass additional behaviors representative of pathological expression of an emotion (e.g., laughing or crying); however, a larger expanse of studies has assessed impulsive aggression and thus permit evaluation of the underlying role of 5-HT. It is also worth noting that even though many view emotional dysregulation as an inherent feature of ADHD [22, 23], increased cognitive, behavioral, and emotional impulsivity are not directly linked, as discussed in [22]. These findings suggest distinct neurocircuitry and/or neurochemical substrates may regulate these types of impulsivities.

Serotonin deficiency, whether induced by genetic variation, diet (i.e., tryptophan depletion), or pharmacologically, induces aggression in rodents [176–182]. Consistent with these findings, TPH2 KO rodents and TPH knock-in mice expressing a mutation in the TPH2 gene had lower levels of 5-HT and displayed increased impulsivity, compulsivity, and aggression than healthy controls [183–188]. Conditional overexpression of 5-HT1A receptors located on serotonergic neurons to reduce serotonergic firing increased aggression, strengthening the argument for a role of 5-HT in impulsivity and aggression [189]. Corroborating these findings, increased serotonergic tone observed in SERT KO rats resulted in reduced aggression and improved impulsivity [190]. Similarly, acute treatment with the 5-HT precursor, 5-hydroxytryptophan (5-HTP), some SSRIs (i.e., sertraline, fluoxetine, and fluvoxamine; but not citalopram or paroxetine), and the 5-HT releasing agent fenfluramine attenuated aggression in the isolation-induced aggressive rat model [191]. However, the effects of chronic SSRI treatment on aggression in rats are complex; Peeters and colleagues [192] found that chronic citalopram reduced aggression in some Long Evans rats but increased it in others. Baseline aggression, 5-HT1A receptor density, anxiety measures, and cue responsivity did not predict the interindividual differences in response to citalopram on aggression; thus, the precise role of the 5-HT system in these chronic effects of citalopram is unclear.

Role of 5-HT Receptors in Impulsive Aggression

In terms of specific receptor subtypes, 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, and 5-HT3 receptors are implicated in aggression (Table 4). The 5-HT1A receptor agonist 8-OHDPAT consistently reduced aggression in rodents [191, 193], with its effect potentiated by 5-HT depletion (via PCPA), which suggests that it elicited these effects primarily through postsynaptic 5-HT1A receptors. Emphasizing the integrated nature of 5-HT receptors on behaviors, blockade of other 5-HT receptors modulated this 5-HT1A receptor agonist effect. The 5-HT2A/5-HT2C receptor antagonist ketanserin potentiated the anti-aggressive effects of 8-OHDPAT, while (-)-penbutolol (a 5-HT1A/5-HT1B receptor antagonist) weakened its effects [191]. Transcript and protein expression of the 5-HT1A and 5-HT2C receptors vary according to trait aggression in rats, with a lower level of 5-HT1A and 5-HT2C mRNA and functional state receptors observed in the cortico-limbic circuitry of aggressive rats compared with tame counterparts [194, 195]. Moreover, variations in 5-HT2C receptor expression and activity via alternative RNA splicing/editing (VGV isoform) increased aggression in mice [196]. 5-HT2C receptor agonism is purportedly linked with anti-aggressive behaviors in Syrian hamsters (although the authors reached this conclusion with the nonselective 5-HT receptor agonist m-chlorophenylpiperazine (mCPP) [197]). S32212, a compound with 5-HT2C receptor inverse agonism (i.e., blocking constitutive activity of the 5-HT2C receptor), 5-HT2A receptor antagonism, and alpha2 adrenoreceptor antagonism, reduced aggressive behavior in mice [198]. The anti-aggressive effects of S32212 may be due to its 5-HT2A or 5-HT2C receptor properties because the 5-HT2A/5-HT2C receptor antagonist ritanserin also decreased aggression in isolation-reared mice [199]. 5-HT3 receptor antagonists (MDL-7222, odansetron) also reduced aggression in rats and mice [200, 201], which is consistent with their capacity to attenuate dopamine-mediated behaviors including amphetamine-induced hyperactivity [166] and impulsive choice [165]. While compounds that target 5-HT3 receptors modulate aggressive behavior, their ability may depend on the methods used to induce aggression (isolation versus apomorphine versus alcohol) [200–203]. In addition, its expression varied by baseline levels of aggression; highly aggressive hamsters displayed increased 5-HT3 receptor density relative to those with low levels of aggression [204].

In alignment with the view that 5-HT reduces aggression, 5-HT1B KO mice displayed increased aggression [205]. Some of these receptors reportedly act as presynaptic terminal receptors, where they regulate not only the release of 5-HT but also other neurotransmitters including GABA, glutamate, and DA [206]. Through these means, 5-HT1B receptors likely influence both inhibitory and excitatory signaling in the brain. Consistent with the data from KO mice, pharmacological evidence demonstrated that systemic administration of the 5-HT1B receptor agonist anpirtoline reduced “frustration” after omission of a scheduled reward in mice [55]. Selective infusions of the 5-HT1B receptor agonist CP-94,253 into the dorsal raphe versus PFC produced contrasting effects on aggression in the alcohol drinking-induced aggression model (reviewed in [195]), demonstrating regional differences in how the 5-HT1B receptor affects aggressive behavior. These divergent effects may arise from serotonergic modulation of other neurotransmitter systems in these brain regions.

Agonists of 5-HT1B and 5-HT1A receptors reduce aggression in rodents, but it is a challenge to identify their exact mechanism given that these targets include autoreceptors and postsynaptic receptors. De Boer and Koolhaas [207] proposed that 5-HT1A and 5-HT1B receptor agonists reduced social aggression (comparatively to pathological aggression) via presynaptic action at inhibitory somatodendritic receptors (5-HT1A) or inhibitory terminal receptors (5-HT1B), suggesting that a decrease in serotonergic tone reduced this type of aggression. These findings challenge the viewpoint that 5-HT deficiency is solely linked to aggression, as discussed in [207], and suggest that, consistent with its modulatory role, aberrant serotonergic signaling (too low or too high) may induce certain types of aggressive behavior.

Serotonin and Dopamine Interactions in Impulsive Aggression

Several findings suggest that the serotonergic and dopaminergic systems interact and jointly regulate hyperactivity-impulsivity [208] and impulsive aggression [209]. Whereas serotonergic deficiency is associated with increased aggression, dopaminergic hyperactivity is associated with increased aggression, suggesting opposing roles for these systems in mediating aggressive phenotypes. Seo and colleagues [209] proposed that dysfunction in 5-HT-DA signaling at the level of the ventral PFC may be important in understanding how these two systems interact to influence impulsive aggression and other comorbid disorders. Loss of inhibitory control of the PFC over subcortical regions such as the nucleus accumbens and amygdala is linked to increased impulsivity, as well as depression and anxiety, which are common comorbid conditions in ADHD. In this vein, deficits in serotonergic neurotransmission in the PFC may increase risk for cognitive and aggressive impulsivity, likely owing to altered interactions with the mesocorticolimbic dopaminergic system and the ensuing impact on downstream targets that regulate motor inhibition, reward, and emotional processing (nucleus accumbens, amygdala).

Summary While the data overwhelmingly indicate that deficits in 5-HT neurotransmission, such as lower 5-HT1A and 5-HT2C receptor expression levels, increase impulsive aggression, while 5-HT1A, 5-HT1B, and 5-HT2A receptor agonism decrease impulsive aggression, there is some pharmacological evidence that challenges this viewpoint, potentially owing to utilization of different models of aggression and the diverse impact of specific brain regions (PFC versus dorsal raphe nucleus) and serotonergic receptors on aggressive behavior. Overall, these findings suggest that aberrant serotonergic signaling contributes to emotional dysregulation. These data also highlight functional interactions between the serotonergic and dopaminergic systems, as well as glutamatergic and GABAergic neurons, and support hypotheses of how these two neurotransmitter systems interact to mediate certain indices of emotional dysregulation.

Role of 5-HT in Executive Function

Role of 5-HT in Attention

There have been surprisingly few studies on the role of 5-HT in attentional processes. Profound 5-HT depletion by i.c.v. 5,7-DHT had no major effect on the ability of rats to detect brief visual signals of reward, despite producing excessive impulsive responding in the 5CSRTT [148]. Selective 5-HT depletion of the median raphe had no effect on detection accuracy; however, 5-HT depletion of structures innervated by the dorsal raphe (primarily neocortex and striatum) generated a transient improvement in accuracy [149], supporting the concept that serotonergic inputs to corticostriatal circuits may impact attention. Microinfusion of the 5-HT1A receptor agonist 8-OHDPAT or the selective 5-HT2A receptor antagonist M100917 into rat mPFC also enhanced attentional accuracy [153]. In contrast to the selective 5-HT2A receptor antagonist M100917, the 5-HT2/5-HT3 receptor agonist quipazine selectively impaired attentional accuracy [210]. Neither acute treatment with the SSRI citalopram nor the 5-HT releasing agent fenfluramine had major effects on attentional accuracy in rats in the 5CSRTT [155], demonstrating that general increases in serotonergic tone do not alter sustained attention. These data suggest that increased 5-HT does not enhance attention per se, but circuit- and receptor-specific alterations of the 5-HT system can impact attentional capacities.

Some of these brain region-specific effects of 5-HT modulation on attention may be due to interactions between 5-HT and distinct neuronal subtypes. For example, the impairments on attentional accuracy, as well as impulsive responding, produced by the NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) could be reversed by treatment with either 8-OHDPAT or the 5-HT2A receptor antagonist M-100907 when infused into rat mPFC [211, 212]. Thus, it appears that 5-HT can modulate some of the “top-down” PFC mechanisms influencing attention. In addition to circuit-specific effects, 5-HT may impact attention in a performance-dependent manner. A recent study in rhesus monkeys showed that the 5-HT precursor 5-HTP modulated attention directed towards social images in a baseline-dependent manner. 5-HTP supplementation improved attention in those with low baseline attention levels, with cerebrospinal fluid concentrations of 5-HTP across all rhesus monkeys positively correlating with looking duration and thus attention [213]. This baseline-dependency might conceivably be relevant to the ADHD phenotype.

Role of 5-HT in Cognitive Flexibility

Several studies in rats and monkeys have demonstrated the importance of 5-HT to various capacities categorized under executive function, including cognitive flexibility (Table 2). Global 5-HT depletion [214] and local depletion in the mPFC or orbitofrontal cortex [215–218] impaired reversal learning, a measure of cognitive flexibility. Notably, vortioxetine, a serotonergic targeting compound that enhances 5-HT neurotransmission in the mPFC, prevented these deficits in reversal learning [219–221]. Importantly, vortioxetine not only enhanced 5-HT neurotransmission but also indirectly increased DA, NE, and acetylcholine, which could contribute to its improved effects on reversal learning [220–222]. Serotonergic contributions to cognitive flexibility are specific to reversal learning; serotonergic lesions do not induce deficits in another measure of cognitive flexibility, attentional set-shifting [216], or a spatial self-ordered sequencing task [223]. Utilizing more translational means for evaluating the effect of lower 5-HT levels on ADHD-related behaviors, diet-induced tryptophan depletion has been applied in rodents and nonhuman primates. In contrast to 5-HT depletion studies, Van der Plasse and Feenstra [224] did not observe a significant impact of tryptophan depletion on spatial reversal learning, which the authors suggested may be indicative of a differential role of 5-HT on visual versus spatial reversal learning. However, they did not verify the degree of 5-HT reduction in their rats. Based on Merchán and colleagues’ findings [225], a more sustained protocol of tryptophan depletion may be necessary to induce sufficient reductions in 5-HT, and thus, an observable effect on spatial reversal learning.

Initial findings demonstrated that rats with inferior performance on spatial reversal learning due to perseveration had lower orbitofrontal levels of 5-HT and its metabolite 5-HIAA, as well as decreased expression of 5-HT2A receptors [226]. Their behavior was remediated by acute citalopram treatment. In addition, rats characterized as more compulsive exhibited reversal learning deficits, as well as reduced expression of 5-HT2A mRNA transcripts in the frontal cortex [227], suggesting that dysfunction in cortical 5-HT2A receptors may underlie these deficits in reversal learning. Moreover, individual variability in basal impulsive or compulsive behaviors, as well as species differences, may mediate sensitivity to serotonergic effects. For instance, reduced 5-HT levels via chronic tryptophan depletion increased cognitive inflexibility (compulsive behaviors) in Wistar rats that exhibited higher basal compulsivity but not those with low basal compulsivity [225]. Lister hooded rats, however, displayed normal levels of compulsivity, despite hyperactivity, with tryptophan depletion. The 5-HT-mediated effects on cognitive flexibility are receptor subtype- (e.g., 5-HT2A, 5-HT2C receptors) and brain-region specific (e.g., lateral versus medial orbitofrontal cortex, mPFC, striatum). Refer to the following review for the contribution of specific 5-HT receptors on behavioral flexibility [228].

Summary Overall, there is some evidence that 5-HT plays a role in the prominent cognitive symptoms of ADHD, including inattention, but these findings are more consistent in measures of impulsivity and cognitive inflexibility. Moreover, the data underscore a critical role for balanced 5-HT neurotransmission and serotonergic interactions with other neurotransmitter systems in cortico-striatal-limbic regions, including the mPFC and orbitofrontal cortex, in attenuating these ADHD behavioral phenotypes. Lastly, inter-individual variability in basal levels of specific phenotypes (i.e., cognitive inflexibility) can mediate the effect of 5-HT manipulation on these behaviors.

Stimulant-Mediated Effects on the Serotonergic System in Preclinical Models

Stimulant Effects on DA and NE

For decades, stimulants (amphetamine and methylphenidate) have been the first-line treatment for ADHD. The main mechanism of action of stimulants is attributed to their ability to enhance catecholaminergic neurotransmission in ADHD-relevant brain networks, which improves inattention, hyperactivity–impulsivity, and other indices of executive function in individuals with ADHD. This stimulant-mediated effect occurs in several ways, with a primary mechanism including binding to catecholaminergic transporters, DAT and NET, and ultimately increasing synaptic catecholamine concentrations; see review by Faraone [45].

Compounds that target monoamine transporters are typically categorized as reuptake inhibitors or neurotransmitter releasers (Fig. 4). Methylphenidate acts as a reuptake inhibitor by preventing NE and DA from cycling back into the presynaptic terminal via NET and DAT, as reviewed in [45]. Stimulants that act as releasers, such as amphetamine, increase extracellular concentrations of monoamines by stimulating their efflux through reverse transport of the transporter, inducing channel-like activity at the transporter, or disrupting monoamine storage in presynaptic vesicles via interactions with the vesicular membrane associated transporter 2 (VMAT2) [229–231]. To this end, amphetamine enhances DA release by causing reversed efflux of the DAT, leading to transport of DA into the synapse [232]. Amphetamine is also a potent releaser of NE in vitro [233, 234] and in vivo [235]. A more novel mechanism of action of amphetamine is attributed to its interaction with trace amine associated receptor 1 (TAAR1) [236], which plays a critical role in regulating the monoamine balance in the brain, particularly DA and 5-HT. In addition, amphetamine inhibits monoamine oxidase [237, 238]. Although both methylphenidate and amphetamine ultimately enhance DA and NE activity, they do so via distinct mechanisms (for further reviews, see [45, 239]).

Stimulant Effects on 5-HT

While the primary mechanism of action of stimulants is attributed to effects on dopaminergic and noradrenergic neurotransmission, amphetamine may also have relevant serotonergic effects. Amphetamine stimulates the release of [³H]-5-HT from rat synaptosomes [234, 240] and rat cortical [241] and hippocampal slices [242]. Notably, a therapeutically relevant dose of amphetamine also increases 5-HT in the basal ganglia (caudate-putamen, accumbens) in rodents [243, 244] and in the frontal cortex, hippocampus, caudate-putamen, and thalamus in nonhuman primates [245]. In healthy human volunteers, an acute oral amphetamine challenge increased extracellular 5-HT release throughout the cortex (frontal, parietal, temporal) but not in the cerebellum [246], suggesting brain-region specific effects. Because it is only a weak inhibitor of the human and murine SERT [247], amphetamine is presumed to enhance serotonergic neurotransmission via interaction with VMAT2, TAAR1, and/or the MAO enzyme. Overall, these findings support that clinically relevant doses of amphetamine serve to stimulate 5-HT release in ADHD-relevant brain regions across species and experimental modalities.

In contrast to amphetamine, methylphenidate exhibits selective inhibition of NET and DAT but not SERT. In a microdialysis study, methylphenidate did not increase extracellular levels of 5-HT in rat striatum or hippocampus even at high systemic doses [248], consistent with earlier data on the drug showing low affinity for SERT and minimal effects on 5-HT reuptake in vitro [249–251]. However, a recent study in rats demonstrated that therapeutically relevant doses of methylphenidate increased 5-HT levels in the mPFC (using high-performance liquid chromatography) and was associated with improved memory [252]. These limited findings suggest that the impact of methylphenidate on serotonergic neurotransmission may be brain region-specific and/or sensitive to different experimental methodologies.

Summary Undoubtedly, catecholamines are the primary target for stimulants, but the aforementioned studies also indicate a stimulatory role of amphetamine and methylphenidate on serotonergic neurotransmission in ADHD-relevant brain networks. However, relative to methylphenidate, the impact of amphetamine on serotonergic neurotransmission appeared more robust. It is worth noting that on average the effect size for amphetamine in ADHD clinical trials is reportedly greater than for methylphenidate [253–256], but whether serotonergic effects are a contributing factor remains to be determined.

Does Serotonergic Manipulation Affect Stimulant Efficacy in ADHD-Relevant Preclinical Models?

In this section we set out to answer: Does 5-HT have a modulatory effect on ADHD treatment? We discuss evidence of stimulant-mediated effects that are altered in the presence of serotonergic drugs (Table 5), as well as under conditions associated with serotonergic dysfunction (i.e., dietary, genetic, or molecular).

Serotonin Modulation of Stimulant Effects on Hyperactivity

Overall, there has been little evidence that amphetamine and methylphenidate elicit behavioral effects through direct 5-HT actions. However, 5-HT does modulate behavioral responses to stimulants. Depletion of 5-HT, following treatment with PCPA or the neurotoxin 5,7-DHT, potentiates methylphenidate- or amphetamine-induced hyperactivity [257–259]. Conversely, enhanced 5-HT neurotransmission with pargyline (monoamine oxidase B inhibitor) blocks amphetamine-mediated hyperactivity [260]. These behavioral patterns are consistent with the concept of DA-5-HT opponency observed in some brain regions [259, 261–264]. Although not viewed as a model of hyperactivity given its normal basal activity levels, the TPH2 knockout mouse displayed enhanced sensitivity to amphetamine-induced hyperactivity [265]. Interestingly, this serotonergic effect on amphetamine-induced locomotion was mediated by a noradrenergic mechanism, as evidenced by normalization of motor activity and striatal NE release separately by the 5-HT precursor, 5-HTP, and the NE precursor, DOPS [265]. Thus, the integral signaling across monoaminergic systems is critical to efficacious responsivity to ADHD treatments in reducing hyperactivity.

The neonatal 6-OHDA lesioned rodent, a model of ADHD, has provided evidence that 5-HT mechanisms modulate stimulant-mediated effects on hyperactivity (with the caveat that this model exhibits altered serotonergic innervation and content). Heffner and Seiden [109] observed that methysergide (a nonselective 5-HT receptor antagonist and 5-HT2B receptor partial agonist) was able to block the hyperactivity-reducing effects of amphetamine, whereas drugs that antagonized DA, NE, muscarinic, or opiate receptors could not. In contrast, Avale and colleagues [115] showed that 5-HT depletion (via PCPA) reduced 6-OHDA-induced hyperactivity but did not impact the effects of amphetamine. However, these results could be due to floor effects. Overall, these findings (1) confirm the oppositional relationship between DA and 5-HT and (2) suggest that selective 5-HT receptor engagement may mediate the therapeutic effects of stimulants in an ADHD model.

Serotonin Modulation of Stimulant Effects on Impulsivity

Amphetamine effectively reduces impulsivity in the temporal discounting of reward paradigm [159], a well-validated, highly translational assay assessing impulsive choice [147], though its effects have been found to vary based on experimental parameters (e.g., delay length, schedule of reinforcement, visual cue signaling the reward), baseline impulsivity, and treatment duration [159, 266–269]. 5-HT depletion via i.c.v. 5,7-DHT did not impact performance in the assay, but it did block amphetamine-induced effects, mainly at the highest dose of amphetamine and in rats with high basal levels of impulsivity [159]. Cis-flupenthixol, a mixed DA receptor antagonist, blocked the behavioral effects of lower doses of amphetamine but only in the presence of 5-HT depletion. This experiment suggests a contributory role for 5-HT and DA in mediating amphetamine effects on impulsivity. Similarly, a series of pharmacological manipulations further demonstrated an essential role for 5-HT in mediating amphetamine effects [160]. At a dose that did not affect temporal discounting of reward on its own, intra-accumbal 8-OHDPAT (5-HT1A receptor agonist) blocked the ability of amphetamine to reduce impulsive choice in intact rats, and this inhibitory effect of 8-OHDPAT was attenuated in rats with a 6-OHDA lesion. Administration of the 5-HT1A receptor antagonist WAY100635 potentiated the effect of a large dose of amphetamine to reduce impulsive choice. In contrast, high doses of the 5-HT1A receptor agonist 8-OHDPAT increased impulsive choice, but this was blocked by a 6-OHDA lesion of the nucleus accumbens but not an i.c.v. 5,7-DHT lesion. Moreover, 6-OHDA infusion into the nucleus accumbens, which lesioned DA and NE neurons, had no impact on amphetamine-mediated reductions in impulsivity [160]. These results suggest that the ability of amphetamine to decrease impulsive choice is not solely dependent on catecholaminergic function in the accumbens but also involves engagement of accumbal 5-HT1A receptors and potentially other neurotransmitters in other brain regions. This interpretation is consistent with observations that systemic administration of 8-OHDPAT inhibited the increase in DA in the nucleus accumbens, dorsal striatum, and frontal cortex produced by amphetamine [270, 271]. These findings imply that the effects of amphetamine on this form of impulsive responding depend on both DA and 5-HT, but the precise neural mechanisms underlying these interactions are unclear.

5-HT2A and 5-HT2C receptors may also modulate impulsivity induced by stimulant drugs in rodents. Amphetamine increased impulsivity (i.e., premature responding) in the 5CSRTT [272]. Stimulant-mediated impulsive responses were blocked by both a 5-HT2C receptor agonist and a 5-HT2A receptor antagonist. 5-HT2C receptors may mediate these effects through modulation of dopaminergic pathways (mesolimbic, mesocortical, and nigrostriatal), where they colocalize with dopaminergic and GABAergic neurons [273]. For instance, activation of 5-HT2C receptors localized on GABAergic interneurons in the ventral tegmental area (VTA) may inhibit DA neurotransmission in afferent regions (e.g., mPFC, nucleus accumbens, VTA) [273, 274]. The 5-HT2 receptor agonist DOI potentiated amphetamine-induced DA increases in the striatum [275]. Conversely, systemic 5-HT2A receptor antagonists attenuated amphetamine-induced DA increases in the mPFC, striatum, and nucleus accumbens [271, 275–279]. Interestingly, only when the 5-HT2A receptor antagonist SR46349B was infused systemically or into the VTA (but not the PFC) did it reduce these amphetamine-mediated effects on DA release [279]. These findings demonstrate that 5-HT receptors moderate dopaminergic signaling and behaviors (e.g., impulsivity, locomotion, compulsivity); however, there is no evidence that amphetamine is able to directly or indirectly (through its release of 5-HT) engage these 5-HT receptors.

Summary Based on these preclinical studies, 5-HT can modify some ADHD-relevant actions of stimulants. In general, activation of 5-HT receptors that increase DA neurotransmission (e.g., 5-HT2A receptors) potentiate stimulant-mediated effects, while activation of those that decrease DA neurotransmission (e.g., 5-HT2C receptors) attenuate stimulant-mediated effects. Collectively, the experiments show that 5-HT and DA (and likely NE) interact to influence behavioral responses of stimulants, most notably hyperactivity and impulsivity.

Clinical Studies

The initial link between 5-HT and behavioral manifestations of ADHD was proposed by Coleman [280]. Coleman reported that lower 5-HT platelet levels were associated with hyperactivity, while increased levels were associated with improved attention span. Although limited by small sample size, correlative analyses, and uncertain diagnostic criteria, the findings fostered the hypothesis that serotonergic dysfunction is linked to core ADHD behavioral features. Following this seminal study, several candidate gene studies have reported associations between ADHD presentation and single-nucleotide polymorphisms (SNPs) in genes related to 5-HT synthesis (TPH2), reuptake (5-HTT), degradation (MAOA, MAOB), and receptor subtypes (5-HT1B, 5-HT2A, 5-HT2C) [281–290], which may be indicative of serotonergic dysfunction in some populations with ADHD. Owing to small sample sizes and a lack of replicability of these findings across studies, as well as a failure to identify SNPs in serotonin-related genes significantly associated with ADHD in recent large scale genome-wide association studies [291–294], these findings from candidate gene studies should be interpreted with caution. However, these results also do not preclude the possibility that dysfunction in serotonergic genes increase the risk for ADHD in subsets of the population.

Whereas the technical bandwidth for manipulating the serotonergic system is broader in preclinical experiments, clinical and neuroimaging studies are primarily limited to the use of acute diet-induced tryptophan depletion or acute or chronic treatment with serotonergic targeting compounds. These studies have evaluated the role of 5-HT in ADHD-relevant behaviors in healthy controls, ADHD populations, and individuals presenting with ADHD-associated symptoms (e.g., impulsive aggression) or comorbidities (e.g., depression). Because of the limited number of published studies investigating the role of serotonergic neurotransmission in ADHD, when relevant, we extrapolate from findings where serotonergic function was evaluated in conditions with closely related behavioral and neuroanatomical phenotypes (e.g., conduct disorder, depression) (Table 6).

Table 6.

Clinical studies evaluating the effects of 5-HT-targeting agents on behavioral outcomes relevant to ADHD phenotypes

Target/activity	Ligand	Population	Hyperactivity	Impulsive action	Impulsive choice	Aggression	Attention
5-HT1A agonist (presynaptic) /partial agonist (postsynaptic)	Buspirone	ADHD	↓ [321]	↓ [321]			↑ [321]
5-HT2A antagonist	Pipamperone	Intellectual disabilities				↓ [350]
5-HT2A antagonist	Quetiapine^a	Borderline personality		↓ [322]	↓ [322]
5-HT2C agonist	Lorcaserin	Intermittent explosive disorder				↓ [351]
5-HT2A/5-HT2C antagonist	Ketanserin	Healthy			↓ [324]
SERT inhibitor	Paroxetine	Healthy					↓ [357]
		Conduct disorder			↓ [341]	↓ [341]
		Depression					[341]
		ADHD	[53]	[53]			[53]
	Fluoxetine	Healthy					↓ [357]
		Personality disorder				↓ [342]
		Depression					[363]
		ADHD + depression	[54]	[54]			[54]
	Escitalopram Citalopram	Healthy					↓ [357, 358]
	Escitalopram Citalopram	Depression					[364, 365]
	Sertraline	Depression					[363–365]
	Venlafaxine ER	Depression					[363–365]
	Venlafaxine ER	ADHD	↓ [51]	↓ [51]			↑ [51]
SERT inhibitor; 5-HT2 agonist	Fenfluramine	Healthy			[315]
SERT inhibitor; 5-HT2 agonist	Fenfluramine	Conduct disorder			↓ [314, 315]	↓ [314]
SERT inhibitor; 5-HT receptor modulator	Vortioxetine	Depression					↑ [367, 368]
SERT inhibitor; 5-HT receptor modulator	Vortioxetine	ADHD	[418]	[418]			[418]
NET/DAT/SERT inhibitor	Desipramine Imipramine	ADHD	↓ [406]	↓ [406]			↑ [406]
NET inhibitor; 5-HT receptor modulator	Viloxazine ER	ADHD	↓ [417]	↓ [417]			↑ [417]

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The table displays clinical studies evaluating ADHD-relevant phenotypes, such as hyperactivity, impulsivity (impulsive action and impulsive choice), attention, cognitive inflexibility, and emotional dysregulation (i.e., aggression), after administration of compounds that pharmacologically engage serotonergic targets. These studies were conducted in different populations, including individuals denoted as healthy and those diagnosed with ADHD, conduct disorder, depression, intellectual disabilities, intermittent explosive disorder, or personality disorder. Indicators represent the corresponding changes in behavior following modulation of the receptor/transporter: ↑= increased behavior; ↓ = decreased behavior; Inline graphic = no effect on behavior

5-HT serotonin, ADHD attention-deficit hyperactivity disorder, DAT dopamine transporter, ER extended release, NET norepinephrine transporter, SERT serotonin transporter

^aQuetiapine has a complex pharmacological profile, but one of its primary actions is antagonistic effects at 5-HT2A receptors [323]

Role of 5-HT in Impulsivity in ADHD and Non-ADHD Populations

Many of the behavioral tasks designed to gauge impulsivity in preclinical studies have human-equivalent versions (Table 2). For example, behavioral tests that assess impulsive action and impulsive choice in humans include go/no-go, four-choice serial reaction time task (4CSRTT), continuous performance test, the SSRT task [145], and delayed discounting of reward [295]. There is some genetic evidence suggesting that serotonergic deficiency is linked with impulsive behaviors. The functional TPH2 gene polymorphism (G-703T; rs4570625) and DNA methylation in the 5′ untranslated region of TPH2 (TPH2-5′UTR) are associated with altered neural processing in the 4CSRTT [296]. Some groups hypothesized that this SNP may be associated with lower enzyme activity, and thus, decreased serotonergic neurotransmission, as briefly discussed in [282, 297]. A previous study reported that DNA methylation in the TPH2-5′UTR and the SNP G-703T (rs4570625) led to decreased TPH2 mRNA expression and even decreased DNA-protein interactions for the SNP [298], which would theoretically disrupt serotonergic neurotransmission; though see [299]. Notably, on the 4CSRTT, higher levels of DNA methylation correlated with more premature responses (i.e., impulsive action) in participants with ADHD, but not in healthy controls, suggesting that individuals with ADHD may be particularly more sensitive to lower levels of 5-HT in the manifestation of impulsivity. However, for a more thorough evaluation of a putative role of 5-HT in impulsive phenotypes, several studies have experimentally altered serotonergic neurotransmission via tryptophan modulation in diverse clinical populations and healthy participants; these are reviewed below.

Tryptophan Studies

Two studies have investigated the impact of acute tryptophan depletion on impulsivity in an ADHD population [300, 301]. In a randomized controlled trial of adults with ADHD and healthy controls, neither tryptophan loading nor tryptophan depletion impacted performance on a version of a go/no-go task, delay discounting task, or Iowa gambling task [300]. In another study, adolescent males with high trait aggression and ADHD committed more inhibition errors on a go/no-go task following acute tryptophan depletion relative to those given placebo. In contrast, adolescent males with low trait aggression and ADHD had fewer inhibition errors following acute tryptophan depletion relative to those given placebo. These findings imply that the impact of 5-HT neurotransmission on impulsivity in ADHD is dependent upon trait aggression. If intact serotonergic neurotransmission is critical for impulse control, then its disruption could induce this phenotype in otherwise “healthy” subjects. Several studies indicate that disruption in serotonergic signaling via acute tryptophan depletion increases impulsivity in neurotypical participants [302–308]; however, see [309, 310] for null effects of tryptophan depletion. Similar to preclinical studies, 5-HT is more closely linked with impulsive action than impulsive choice, with the majority of studies reporting no effect of tryptophan depletion on impulsive choice [303, 307, 310] and one study reporting that low 5-HT increased delayed discounting of reward [311].

Enhancing serotonergic neurotransmission via l-tryptophan loading or pharmacological manipulations has yielded mixed results on impulsivity. These differences may be due to the nature of the assessments (e.g., questionnaire versus laboratory-based tests), differences in the mechanism of action of the serotonergic compounds, or duration of treatment with serotonergic compounds (acute versus chronic). Dougherty and colleagues [304] found that acute tryptophan depletion increased impulsivity from baseline performance while l-tryptophan loading had no significant effects on impulsivity in the immediate memory task (a modified version of the continuous performance test). The lack of an effect with tryptophan loading could be because of the fact that these were otherwise healthy individuals; these effects might have been more pronounced in vulnerable populations, perhaps with lower baseline levels of 5-HT, as suggested by [312, 313]. Consistent with this, fenfluramine reduced impulsive choice (delay discounting) in men with a history of conduct disorder [314] but not in those without the disorder [315]. Conversely, in healthy individuals, acute treatment with the SSRI escitalopram improved impulsivity on a SSRT task [316].

Serotonin Receptor Subtypes

A handful of clinical studies have evaluated the contribution of 5-HT receptor subtypes on impulsive behaviors in humans, but few have included participants with ADHD. Studies have utilized compounds targeting specific 5-HT receptor subtypes in individuals with borderline personality (a condition characterized by impulsivity and high-risk taking behaviors) or people with a history of cocaine use, which may be of relevance to the defining characteristic of impulsivity. ADHD is often comorbid with substance abuse disorder [28, 29] and risk-taking behaviors [317, 318], and decreased 5-HT signaling is associated with these comorbidities [319, 320].

Most clinical studies have primarily focused on the role of 5-HT1A and 5-HT2A receptors in impulsive behaviors; however, the overall evidence is preliminary. For example, research on the 5HT1A receptor is limited to a small double-blind study of buspirone in individuals with ADHD, suggesting 5-HT1A receptor agonism may improve symptoms including impulsivity [321]; buspirone is characterized as a full agonist at 5-HT1A presynaptic receptors and partial agonist on 5-HT1A postsynaptic receptors (Table 6). With regard to 5-HT2A receptors, Van den Eynde and colleagues [322] reported that quetiapine, a 5-HT2A and D2 receptor antagonist, decreased impulsivity (Stroop Color Word Task) and risky decision making (Iowa Gambling Task) in individuals with borderline personality disorder. It is important to note that quetiapine has a complex pharmacological profile, but one of its primary actions is its 5-HT2A receptor antagonism [323]. Consistent with the decrease in impulsive and risk-taking behaviors with quetiapine administration, blockade of 5-HT2A/2C receptors with ketanserin increased risk aversion in a gambling task in healthy volunteers [324]. These clinical findings are consistent with preclinical studies reporting that systemic blockade of 5-HT2A/2C receptors with ketanserin decreased premature responding (impulsivity) in the 5CSRTT [325] and risky decision making in rats [326]. Moreover, these data underscore the potential utility of compounds targeting the 5-HT2A receptor for conditions that are associated with increased impulsivity and risk-taking behaviors.

Role of 5-HT in Emotional Dysregulation in ADHD and Non-ADHD Populations

Emotional dysregulation (e.g., frustration, reactive aggression, emotional impulsivity) occurs in approximately 25–50% of children and 30–70% of adults with ADHD [22, 327–329] and significantly contributes to poorer clinical outcomes across the lifespan [330]. Aggression is classified into premeditated (predatory) or impulsive (affective) aggression; here we focus on the latter (Table 3).

Tryptophan Studies

Given the association between serotonergic dysfunction and emotional dysregulation, several studies have evaluated the impact of acute tryptophan depletion on reactive aggression in ADHD populations [301, 331–335]. These studies consistently demonstrated an inverse relationship between 5-HT and reactive aggression in adolescents and adults with ADHD, which was dependent upon baseline levels of impulsivity or trait aggression. Similar to clinical populations, acute tryptophan depletion increased aggressive responding in healthy males [336] and in men with high levels of baseline aggression [337–339]. However, the study by Cleare and Bond [339] did not find marked differences in impulsive aggression in response to acute tryptophan depletion in people with low trait impulsivity, suggesting that individuals with a predisposition for high aggression may be more sensitive to alterations in serotonergic neurotransmission. Women have exhibited enhanced sensitivity to serotonergic modulation as well, though it was dependent upon basal plasma tryptophan levels [340]. For example, behavioral responses to tryptophan depletion or tryptophan loading, including increased and decreased aggression, respectively, were more evident in women with higher baseline levels of plasma tryptophan.

Serotonin Receptor Subtypes

In alignment with the theory that deficits in serotonergic neurotransmission increase aggression in some individuals, fenfluramine and the SSRIs paroxetine and fluoxetine reportedly decreased aggression in individuals with conditions characterized by emotional dysregulation, including conduct and personality disorders [314, 315, 341, 342]. Although larger, more robust studies are needed, genetic and pharmacological studies have implicated 5-HT1B, 5-HT2A, and 5-HT2C receptors in emotional dysregulation (reactive aggression). Based on a meta-analysis evaluating associations between 5-HT1B, 5-HT2A, and 5-HT2C genetic variants and ADHD, the SNP rs6296 in the 5-HT1B gene may increase risk for ADHD [52] and in a candidate gene study (N = 967) was significantly associated with childhood aggression and hostility [343]. Preclinical studies also report enhanced aggression in 5-HT1B receptor knockout mice [205]. These genetic findings align with pharmacological evidence demonstrating that the 5-HT1B/1D receptor agonist zolmitriptan and the 5-HT1B receptor agonist CP-94,253 decreased alcohol-induced aggression in individuals reporting modest alcohol consumption [344]. These anti-aggressive effects with 5-HT1B receptor agonism may be due to enhanced serotonergic signaling in the orbitofrontal cortex [345], a critical brain region for the inhibitory control of emotion. Moreover, the orbitofrontal cortex appears to play an important modulatory role in reactive, but not instrumental, aggression [346].

Polymorphisms in the 5-HT2A gene (rs7322347, A-1438G) may predispose individuals to aggressive [347] and impulsive behaviors [348]. Likewise, in two candidate gene studies focused on serotonin-related genes, SNPs in the 5-HT2C gene (rs6318, rs518147) may increase susceptibility to violent behavior/criminal impulsivity [349] and ADHD [289]. 5-HT2A receptor antagonism with pipamperone [350] and 5-HT2C receptor agonism with lorcaserin [351] decreased aggressive responding in individuals with intellectual disabilities and intermittent explosive disorder, respectively, indicating that these compounds can decrease aggressive responding in diverse populations (Table 6). These effects on aggressive behavior are consistent with preclinical findings demonstrating opposing roles of these receptor subtypes in motor, cognitive, and emotional impulsivities [197, 199].

Role of 5-HT in Attention in ADHD and Non-ADHD Populations

Tryptophan Studies

Two published studies have evaluated the impact of acute tryptophan depletion on attention in ADHD populations [352, 353], and these showed contrasting effects. Zepf and colleagues conducted an intra-subject cross-over study of male children and adolescents with ADHD. Tryptophan depletion improved lapses of attention relative to sham treatment but had no effect on phasic alertness on a test battery of attentional performance [352]. Conversely, Mette and colleagues conducted an intra-subject crossover study of adult males with and without ADHD, showing that tryptophan depletion worsened attention on the continuous performance test in adults with ADHD but not in controls [353]. These findings suggest that effects of acute tryptophan depletion may be age- or task-dependent; however, additional studies are needed, involving broader populations (e.g. including females and pediatric controls) and comparable measures of attention.

Unlike the consistent findings with impulsivity and emotional dysregulation, acute tryptophan depletion did not induce prominent effects on different aspects of attention, including sustained attention or attentional set-shifting, in healthy subjects (see [354] for a systematic review). Tryptophan depletion impaired Pavlovian and instrumental reversal learning, which is consistent with preclinical studies [355], but it did not impact probabilistic reversal learning [356], indicating task-specific effects. While acute tryptophan depletion did not strongly impact attentional processes in healthy individuals, there is evidence to suggest that vulnerable populations (e.g., depressed) may be more sensitive to its impact on sustained attention and executive function, as discussed in [354].

Serotonin Receptor Subtypes

Few clinical studies have evaluated the role of specific 5-HT receptor subtypes in attention-related processes. SSRIs are known to impair divided attention and sustained attention in healthy individuals [357]. In a four-arm study, Wingen and colleagues [358] evaluated the effects of placebo, escitalopram alone, or escitalopram co-administered with either the 5-HT2A receptor antagonist ketanserin or the 5-HT1A receptor antagonist pindolol on divided and sustained attention in healthy participants. When given alone or in combination with ketanserin or pindolol, escitalopram impaired divided and sustained attention relative to placebo treatment [358]. Neither ketanserin nor pindolol potentiated or attenuated the effect of escitalopram on divided attention but the combination of escitalopram and ketanserin induced greater deficits on sustained attention. The authors attributed this potentiating effect of 5-HT2A receptor antagonism to increased inhibitory effects on the mesocorticolimbic dopaminergic pathway [359–361], which is consistent with the notion that diminished dopaminergic neurotransmission is linked with attention deficits [362].

SSRIs and Vortioxetine

SSRIs, including escitalopram, sertraline, fluoxetine, and paroxetine, have been shown to worsen or have no effect on various attentional processes in healthy individuals [357] or individuals with depression (comorbid with ADHD) [363–365]. Treatment duration may impact these effects. For instance, acute treatment of escitalopram in a healthy population impaired learning on a probabilistic reversal learning task, as well as extradimensional set shifting and reversal performance [316]; however, chronic administration of escitalopram had no impact on these measures, though a reduction in reinforcement sensitivity was observed [366]. While SSRIs induce little, or impairing, effects on attention, there is some evidence that newer serotonergic targeting agents may be beneficial (Table 6). For example, vortioxetine, a SSRI with 5-HT1A receptor agonism, 5-HT1B receptor partial agonism, and 5-HT3, 5-HT7, and 5-HT1D receptor antagonism, improved selective and sustained attention and other indices of executive dysfunction in individuals with depression [367, 368]. The contrasting effectiveness of vortioxetine versus other SSRIs on cognitive impairment may reflect differences in their engagement of distinct 5-HT receptors (Fig. 5), indirect effects on other neurotransmitter systems, or differences in disorder-specific effects (depression versus ADHD) [220, 221, 369]. Taken together, the findings suggest that therapeutic effects on attention may depend on engagement of specific 5-HT receptors rather than a general increase in 5-HT. The data also highlight some divergent effects of these compounds on attention based on the disease status of the individual (healthy versus depressed), which may be due to altered brain neurochemistry mediating treatment response and treatment duration.

Fig. 5 — Binding affinity of select FDA-approved drugs at serotonergic receptors. Heatmap represents data as a ratio of binding affinity for the specific target in relation to its primary target [norepinephrine transporter or serotonin transporter; i.e., pK_i (negative log of the inhibition constant) of 5-HT2A/pK_i of serotonin transporter for vortioxetine]. These data were acquired using human receptor isoforms, except for fluoxetine, which utilized rat receptors. The ratio of binding affinity is ranked by color, with greater activity shown in dark-red and less activity shown with white. Data were acquired from the International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS) Guide to Pharmacology, except for viloxazine [413]

Summary Although several candidate gene studies identified associations between polymorphisms within the serotonergic system and manifestations of distinct ADHD behavioral phenotypes, including impulsivity and emotional dysregulation, limitations within these studies, such as small sample sizes, inability to control for covariates, and a general lack of replication, lend to cautious interpretation of the results. Moreover, the associations with serotonergic genes identified in candidate gene studies have not been observed in larger genome-wide association study reports. Though limited, available studies using tryptophan depletion show differential (e.g., task-dependent) effects on attention and increased impulsivity in individuals with ADHD. In healthy individuals, acute tryptophan depletion is more frequently linked to impulsivity, with little impact on attention; however, various compounds that facilitate serotonergic neurotransmission (SSRIs) appear to impair attention in healthy individuals. A newer serotonergic targeting agent (vortioxetine) appears to improve attention and executive deficits in individuals with depression. The differences in efficacy of serotonergic targeting compounds on behavioral features core to ADHD versus those expressed in psychiatric conditions comorbid with ADHD may depend upon heterogeneity of brain function across individuals. In both neurotypical and ADHD populations, 5-HT deficiency via acute tryptophan depletion is consistently linked with increased reactive aggression, underscoring the importance of intact serotonergic neurotransmission to emotion regulation. Taken together, these data suggest a role for 5-HT in the pathogenesis of some core ADHD behavioral features and may implicate the utilization of compounds with specific effects on the serotonergic system (e.g., 5-HT1B, 5-HT2A, and 5-HT2C receptors) for ADHD treatment on the basis of presentation subtype (hyperactivity–impulsivity versus inattention) or co-expression of emotional dysregulation.

Role of 5-HT on Brain Networks in ADHD and Non-ADHD Populations

Much of the knowledge regarding the neural circuitry regulating attention, behavioral inhibition, and emotional dysregulation is driven by preclinical studies, yet there is cross-species convergence in implicated brain regions. One of the most consistently studied networks in ADHD is the default mode network (DMN), including the mPFC, anterior and posterior cingulate gyri, ventral precuneus, parietal cortex, and hippocampus [370, 371]. While there are no universally accepted biomarkers for ADHD, altered function of the DMN has been advanced as a putative neuroanatomical biomarker for this disorder [372, 373]. Theoretically, ADHD is characterized by hyperactivity of the DMN and visual attention network, which may manifest as “daydreaming” or hypersensitivity to visual stimuli leading to disruption of goal-oriented activities [374]. Thus, in a neurotypical brain the DMN is upregulated when the mind is wandering but downregulated during attention-demanding tasks, and conversely the task positive network (TPN), which includes the dorsolateral PFC and anterior cingulate, increases in activity. This divergent synchronization between the TPN and DMN during attention-demanding tasks is believed to be disrupted in ADHD. For example, increased connectivity between the DMN and TPN while performing a go/no-go task was linked with impaired impulse control [375]. Notably, stimulants increased task-related suppression of DMN brain regions, potentially restoring the TPN/DMN balance in ADHD [376–378]. Given the impact of stimulants on monoaminergic neurotransmission, these findings implicate the potential for monoaminergic modulation of the DMN to improve its functionality in ADHD. Interestingly, a recent study using a machine-based ADHD classification model combining PET imaging and genetic screening suggested that altered SERT binding in DMN nodes, including the precuneus and posterior cingulate gyrus, and SNPs in the 5-HT1B (rs130058) and 5-HT2A (rs1328684) genes confer risk for ADHD [379]. There are some limitations to this study, including lack of external validation, but it implies that serotonergic dysfunction in ADHD-relevant brain networks may also be an underlying factor in the etiology of the condition.

Tryptophan Studies and SSRIs

Relative to healthy individuals, there are limited studies investigating serotonergic neurotransmission on DMN activity in ADHD populations. Collectively, these studies indicate that the DMN is sensitive to serotonergic manipulation (i.e., acute tryptophan depletion and SSRIs); however, the functional consequences of these brain changes are not consistently explored across studies. In adolescent boys with ADHD, acute tryptophan depletion decreased functional connectivity of the right superior premotor cortex with the DMN during resting state, which may be of relevance to motor planning [380]. In neurotypical individuals, acute tryptophan depletion consistently reduced functional connectivity of the precuneus nucleus (self-referential processing) with the DMN during resting state [381, 382]. It also modulated the functional activity of the orbitofrontal cortex, which was associated with more depressive mood, and the superior parietal lobe, which correlated with increased anger–hostility [381, 382]. Acute tryptophan depletion in healthy individuals reduced sensorimotor network activity and increased DMN activity [78]. In contrast, either single or short-term administration of the SSRIs escitalopram or sertraline, or the SNRI duloxetine, decreased intra-DMN functional connectivity with the precuneus or anterior and posterior cingulate gyri [383–386] and connectivity within the TPN [384] during resting state. Moreover, based on modeling of resting-state networks, the primary nuclei of the serotonergic and dopaminergic systems have opposing effects on the sensorimotor network and DMN, which could have implications not only for ADHD but also other psychiatric conditions [78].

It is important to note that the referenced studies investigating the impact of 5-HT on DMN activity in neurotypical individuals utilized acute tryptophan depletion or short-term drug administration, so these changes in brain activity may not be evident with long-term use, which is more relevant to clinical populations. Therefore, neuroimaging studies that employ clinically relevant drug regimens combined with various behavioral assays (e.g., impulsivity) would provide greater insight regarding the contributions of 5-HT to the functional coherence of the DMN and its putative role in the etiology of ADHD.

Role of 5-HT on ADHD-Related Brain Networks Relevant to Impulsivity

Only one neuroimaging study evaluated the impact of a serotonergic targeting agent on impulsive behaviors in individuals with ADHD. This functional magnetic resonance imaging (fMRI) study revealed that an acute dose of fluoxetine normalized hypoactivity of the orbitofrontal cortex and dorsal striatum (caudate) in boys with ADHD in response to a task designed to gauge motor inhibition. Interestingly in this study, boys with autism spectrum disorder exhibited hyperactivation in the right frontal cortex, and fluoxetine normalized these functional measures as well. Although there were no effects of fluoxetine on overall performance in the task, these changes in brain activation correlated with inhibitory responses [387], suggesting that targeting the 5-HT system may modulate ADHD-relevant functions. The authors proposed that the differential effects of fluoxetine in these disorders might be due to baseline differences in 5-HT levels, with autism spectrum disorder associated with elevated 5-HT and ADHD associated with lower levels of 5-HT [388–390]. While they did not assess 5-HT levels in this study, there are reports that baseline levels of 5-HT impact the sensitivity to sertraline (SSRI) treatment [391]. There are several limitations to this study, including acute administration of fluoxetine and a small sample size; however, it may provide a conceptual framework to better understand how 5-HT signaling in cortico-striatal-limbic regions modulates some impulsive behaviors in diverse populations.

Role of 5-HT on ADHD-Related Brain Networks Relevant to Emotional Dysregulation

No neuroimaging studies investigating the impact of serotonergic targeting agents on emotion dysregulation in individuals with ADHD were identified. However, the few neuroimaging studies of relevance supported the involvement of dysfunctional 5-HT signaling in various cortical regions to impulsive aggression. For example, relative to healthy controls, adults with impulsive aggression displayed decreased metabolic responses in the left medial orbitofrontal cortex and the ventral medial and anterior cingulate in response to mCPP, a non-selective 5-HT agonist [392], and in response to fenfluramine [393]. In addition, individuals with impulsive aggression have reduced SERT availability in the anterior cingulate [394]. Collectively, these findings suggest that altered serotonergic activity in brain regions implicated in behavioral inhibition and emotional regulation may contribute to increased impulsive aggression in some individuals. It is important to note that individuals can display impulsivity and emotional dysregulation independent of having ADHD. Nonetheless, these findings provide some neural underpinnings for serotonergic influence on impulsive aggression, which may be of relevance for individuals with ADHD presenting with symptoms of emotional dysregulation.

Role of 5-HT on ADHD-Related Brain Networks Relevant to Attention

At this time, no neuroimaging studies were identified examining the effects of serotonergic targeting agents on various cognitive processes (e.g., sustained, selective, divided attention) or executive function in relation to attention networks in individuals with ADHD. Therefore, studies are needed to explore the putative involvement of 5-HT on these endpoints via modulation of distinct ADHD-relevant brain networks (e.g., frontoparietal). Broadly, 5-HT is hypothesized to modulate the excitation/inhibition balance of neural circuitry to serve as a “thresholding” mechanism, which impacts executive function [78, 395]. The impact of 5-HT on attentional processes appears to exhibit an inverted “U” shape and is likely influenced by the interaction of 5-HT and catecholamines in these brain regions.

Summary Overall, the findings demonstrate that 5-HT modulates ADHD-relevant brain networks and suggest that some of these neural adaptations may drive changes in distinct ADHD behaviors (e.g., impulsivity and emotional regulation). More clinical studies are needed to evaluate the functional consequences of these brain changes in ADHD populations. The highlighted studies indicate that the impact of serotonergic neurotransmission on core behavioral features of ADHD and associated brain networks is nuanced and likely dependent upon several factors (not discussed in detail above), including age [396, 397], basal 5-HT levels [387], symptom constellation (predominant inattentive versus hyperactivity–impulsivity) [398], presentation of other comorbidities [302], gene–environment interaction [399], treatment duration, and sex [400, 401].

Does 5-HT Play a Role in ADHD Treatment?

Despite significant preclinical and clinical evidence linking the serotonergic system to core behavioral features of ADHD and emotional dysregulation, the potential role of 5-HT in ADHD treatment has been largely discounted for two main reasons: (1) SSRIs as monotherapy are regarded as ineffective [53, 54] and, as discussed in [402], (2) the primary mechanism of action of standard ADHD treatments is attributed to their potent ability to enhance DA and NE neurotransmission in critical cortico-striatal-limbic circuits. However, we have provided evidence that stimulants also increase 5-HT neurotransmission in similar brain regions across species [234, 240–246, 252]. Thus, the serotonergic system could also contribute to stimulant-mediated effects. Preclinical data support this postulate; various methods that manipulate the serotonergic system (i.e., pharmacological agents, lesions, TPH2 KO) modulate behavioral responses to stimulants in healthy rodents and in some preclinical models of ADHD [109, 159, 257–260, 265, 270–272, 275]. Although there are limited studies, clinical evidence further supports these preclinical data. For example, polymorphisms in the genes for TPH2 [403] and SERT [404] not only increase risk for ADHD but may also mediate the behavioral responses to methylphenidate in individuals with ADHD. Furthermore, in children and adolescents with ADHD and comorbidities (dysthymic symptoms, oppositional defiant disorder, conduct disorder, anxiety) who initially experienced inadequate treatment responses to methylphenidate alone displayed improvements in inattention, hyperactivity, impulsivity, depression, and anxiety scores when fluoxetine (8-week treatment) was combined with methylphenidate [405]. Together, these data implicate dysfunction in the serotonergic system as a risk factor for ADHD and support a facilitatory role for 5-HT in ADHD treatment. Moreover, these findings highlight the utility of treatment regimens that target both the catecholaminergic and serotonergic systems in ADHD comorbid with depression and anxiety [405].

Role of 5-HT in Nonstimulant-Mediated Effects

We can further speculate on a putative role for 5-HT in ADHD treatment by evaluating the efficacy of treatment options on the basis of their pharmacological activity on serotonergic and catecholaminergic systems (Figs. 4, 5). Tricyclic antidepressants with known inhibitory effects on SERT, NET, and DAT, such as imipramine and desipramine, and newer monoamine transporter inhibitors, including dasotraline and centanafadine, demonstrated efficacy in ADHD treatment [406–408]. However, it is difficult to determine if their serotonergic properties contributed to their mechanism of action, because imipramine, desipramine, dasotraline, and centanafadine have strong binding affinity to NET or DAT (Fig. 4; [407, 409, 410]), which may drive these changes in ADHD treatment efficacy independent of their effects on SERT. Venlafaxine, an SNRI with predominant inhibition of SERT and modest NET inhibition, has demonstrated efficacy in a few small studies (Fig. 4; Table 6). It is suggested that at lower therapeutic doses venlafaxine primarily engages SERT [411], suggesting that the serotonergic properties could contribute to its mechanism of action. Completion of preclinical studies that manipulate SERT activity via pharmacological/genetic techniques would allow a more thorough evaluation of the contribution of 5-HT to venlafaxine’s efficacy. One caveat with the venlafaxine findings is that there are limited controlled clinical trials (N = 2), as several of the reported findings were in open-label studies with small sample sizes; reviewed in [51]. Nonetheless, these findings suggest that 5-HT may play a role in ADHD treatment.

Other nonstimulant options with demonstrated efficacy in ADHD and pharmacological activity on catecholaminergic and serotonergic systems include viloxazine and atomoxetine. Even though both drugs are classified as NRIs, there are differences in their pharmacological profiles towards serotonergic targets, which could result in differences in treatment efficacy (Figs. 4, 5). Atomoxetine has moderate binding at SERT [412], while viloxazine has negligible binding affinity for SERT [413] but unique effects at 5-HT receptors that are not observed with atomoxetine and may theoretically contribute to its mechanism of action. For instance, based on preclinical in vitro and in vivo studies, viloxazine exhibited antagonistic effects on 5-HT2B receptors and agonistic effects at 5-HT2C receptors [413]. Moreover, in microdialysis studies, viloxazine increased 5-HT in addition to DA and NE in rat mPFC at therapeutically relevant concentrations [413, 414]; this enhanced prefrontal 5-HT release has not been reported with atomoxetine treatment [369]. It is tempting to speculate that these unique serotonergic receptor modulating properties could potentially contribute to the mechanism of action of viloxazine, especially given the role of 5-HT2C receptors in hyperactivity–impulsivity and emotional dysregulation in both rodents and humans. However, as yet, there are no mechanistic studies to specifically support or refute this contention. Far less has been reported on 5-HT2B receptors with regard to the etiology of and treatment for ADHD. However, there are some reports that 5-HT2B receptors are linked with distinct behavioral phenotypes (i.e., impulsive aggression) and comorbidities (depression) in mice and humans [195, 415] and are required for the antidepressant effects of SSRIs [416].

A recent nonrandomized study by Price and Price [417], conducted as a step-down treatment from atomoxetine to viloxazine (extended-release formulation) in a small sample of patients with ADHD, suggested greater improvement from baseline ADHD-RS-5 and Adult ADHD Investigator Symptom Rating Scale (AISRS) mean scores in inattention and hyperactivity–impulsivity and faster speed of onset in adolescents and adults with extended-release viloxazine treatment compared with the initial atomoxetine treatment. One potential implication of these findings is that the unique 5-HT receptor modulating properties of viloxazine may theoretically contribute to these differences in treatment efficacy, though well-controlled studies are necessary to evaluate this assertion. Given the unique 5-HT receptor modulating properties of viloxazine (i.e., 5-HT2C receptors), this compound could be advantageous for individuals with ADHD and other behavioral features sensitive to 5-HT modulation (i.e., emotional dysregulation and depression); however, there are no clinical studies that have directly tested this hypothesis.

As previously mentioned, a prevailing viewpoint in the field is that the efficacy of ADHD treatments, including stimulants and nonstimulants, is because of their potent ability to enhance DA and NE neurotransmission in cortico-striatal and limbic circuits, notably in the mPFC. However, vortioxetine, a multi-targeting serotonergic compound, also increased DA and NE in the mPFC [220, 221] but was ineffective in ADHD [418]. It is likely that vortioxetine (with negligible binding to DAT or NET) indirectly enhanced DA and NE neurotransmission via interactions with specific 5-HT receptors (e.g., 5-HT1A, 5-HT1B heteroreceptors) that modulate catecholaminergic neurotransmission [419]. Similarly, fluoxetine increased prefrontal DA and NE neurotransmission [420], likely via 5-HT2C receptors, yet was also ineffective in ADHD as monotherapy. The lack of effect with vortioxetine and fluoxetine in ADHD may be because these compounds do not enhance prefrontal catecholamine levels to the same degree as stimulant and nonstimulant ADHD treatments (i.e., viloxazine extended-release, atomoxetine). Conversely, approved stimulants and nonstimulants may alter catecholamine levels in brain areas beyond the PFC that are important for treatment efficacy. These findings suggest that indirectly enhancing DA and NE neurotransmission in the mPFC may not be sufficient for optimal ADHD treatment efficacy. The data suggest that successful treatment of core ADHD behavioral features requires direct engagement of at least one of the catecholaminergic systems.

Role of 5-HT in ADHD Comorbidities

Approximately 50–80% of people with ADHD are diagnosed with another psychiatric condition [2, 421–423], most commonly mood and anxiety disorders [424]. In fact, relative to the general population, mood and anxiety disorders are disproportionately more common in people with ADHD [2, 425]. High genetic correlation between ADHD symptoms and other constructs (e.g., autism spectrum disorder traits, cognitive phenotypes, and externalizing symptoms), as well as common genetic variants shared between ADHD and depression, lend support to the high prevalence of comorbidities in ADHD [426]. It is unclear if untreated ADHD increases risk for depression and anxiety or vice versa, but ADHD, comorbid with anxiety or depression, significantly impairs daily functioning and is associated with poorer long-term outcomes [330, 427]. Thus, effective treatment for these comorbidities is essential for long-term success in individuals with this disorder; however, most ADHD clinical trials exclude patients with symptomatic comorbidities.

While SSRIs as monotherapy appear to be relatively ineffective in treating the core behavioral features of ADHD (inattention, hyperactivity, impulsivity), they are mainstay treatments for anxiety and depression across age groups [428–430]. Although limited in number, available studies support their utility in combination with ADHD treatments [53, 54, 405] and suggest that compounds targeting both the catecholaminergic and serotonergic systems are necessary for treating both core ADHD symptoms and its psychiatric comorbidities. In some instances, ADHD treatments that primarily target the catecholaminergic system (methylphenidate, amphetamine, and atomoxetine) successfully treated emotional dysregulation and the core behavioral features of inattention and hyperactivity–impulsivity [431]. However, these treatments were more effective at attenuating core ADHD symptoms compared with emotional lability, suggesting the need for adjunctive treatments to mitigate this behavioral feature in some individuals with ADHD. In this vein, citalopram adjunctive to psychostimulant treatment mitigated emotional dysregulation in children and adolescents with severe mood dysregulation who had been unresponsive to stimulant treatment alone [432], demonstrating beneficial effects of serotonergic targeting agents.

In double-blind trials, atomoxetine showed positive effects in treating comorbid anxiety with ADHD (generalized anxiety disorder in children and social anxiety disorder in adults) but has not shown a clear signal in treating depression [433, 434]. The only well-controlled study of atomoxetine for depression in ADHD showed improvement in ADHD but not depression. A second double-blind pediatric trial showed significant improvement from baseline in ADHD, anxiety, and depression when atomoxetine was combined with fluoxetine [435]. The fluoxetine group showed greater responsivity of depressive symptoms; however, owing to the study design (no placebo only control group), it is unclear whether improvements in depression were due to the addition of atomoxetine or other factors. To fully evaluate the utility of serotonergic targeting compounds in treating psychiatric comorbidities, studies that include individuals with ADHD comorbid with psychiatric disorders are needed.

Prior to showing efficacy as a treatment for ADHD, viloxazine had been approved as a treatment for depression in Europe. The unique serotonergic targeting properties of viloxazine may be connected to its reported antidepressant efficacy [436], which could provide an avenue to treat both conditions with a single medication. A decentralized clinical trial enrolling adults with a primary diagnosis of ADHD as well as anxiety and/or depression symptoms (NCT06185985) showed that participants treated with viloxazine extended-release experienced improvement in ADHD, anxiety, and depression symptoms [437].

Despite overlapping features, ADHD, depression, and anxiety are distinct conditions with different brain neurochemistry that likely impacts treatment response. Nonetheless, based on the presented preclinical and clinical data, treatment strategies that target select 5-HT receptor subtypes may be particularly advantageous for individuals with distinct comorbidities. For example, compounds targeting 5-HT1B, 5-HT2C, and 5-HT3 receptors may be useful for individuals with impulsive aggression [55, 197, 200, 201, 205, 343, 351, 415], whereas those targeting 5-HT2B and 5-HT7 receptors may be useful for ADHD with comorbid depression or anxiety [416, 438, 439]. Given the abundance of preclinical data showing serotonergic contributions to ADHD behaviors, additional well-controlled clinical studies are warranted to further understand the role of serotonergic medications adjunctive with ADHD-approved treatments or as monotherapies in treating ADHD comorbid with certain psychiatric conditions.

Conclusions

Both preclinical and clinical studies support the notion that disruption in 5-HT neurotransmission can induce behaviors consistent with ADHD phenotypes, most notably impulsive action and emotional dysregulation. We presented findings demonstrating that ADHD treatments, including stimulants and nonstimulants, impact serotonergic neurotransmission in brain regions implicated in behavioral inhibition and emotional regulation, which could contribute to their efficacy. We also presented compelling preclinical data demonstrating that various 5-HT receptor subtypes modulate behavioral responses to stimulants, likely through interactions with catecholamine systems but also by affecting other neurotransmitters (e.g., glutamate, GABA). In totality, the data suggest that monoamine imbalance, rather than deficiencies in any one neurotransmitter system, contributes to the behavioral manifestations of ADHD. Moreover, based on preclinical data and current therapeutic treatments, direct engagement of at least one of the catecholaminergic appears to be important for medication efficacy in treating the suite of core ADHD symptoms; however, this may be expanded as new therapeutic targets are identified. Meanwhile, compounds that predominately target the serotonergic systems are effective in treating mood and anxiety disorders, which is particularly notable given that most individuals with ADHD have at least one psychiatric comorbidity, with depression and anxiety having the highest frequency. Thus, compounds that target both serotonergic and catecholaminergic systems may be necessary for comprehensive treatment of individuals with complex ADHD. Indeed, more studies are warranted to test these suppositions more thoroughly.

Future Directions

Throughout this review, we emphasize the critical questions that remain unanswered and provide some potential future directions for preclinical and, more substantially, clinical studies. Additional clinical studies are required to determine the extent to which stimulant-mediated effects are dependent upon serotonergic activity. Clinical studies evaluating preferential treatment response show that ADHD medications are not therapeutically interchangeable and suggest that mechanistic differences are important to individual responses. Additional studies may help to isolate the degree to which serotonergic effects contribute to differences in efficacy. Given that the serotonergic system is tightly linked with emotion regulation, more studies should also investigate the potential benefit of serotonergic targeting agents to mitigate this behavioral feature in ADHD. In addition, consideration of how real-world factors (e.g., stress, normal or pathological brain aging, comorbidities, and sex) impact 5-HT signaling in ADHD-relevant brain networks is important. Of note, given the reported sex differences in monoaminergic functioning, it is likely that sex is an important factor with regard to the manifestation of core behavioral features and treatment efficacy (see [440] for a review). Lastly, gaining greater insight into the dynamic interactions between the catecholaminergic and serotonergic systems may be critical to further advance our understanding of the etiology of ADHD. This knowledge may assist in the development of novel treatment strategies or repurposing of existing compounds that target multiple monoaminergic systems to more effectively treat ADHD based on ADHD subtype (hyperactivity–impulsivity versus inattention) and comorbid symptom constellations.

Funding

This work was funded by Supernus Pharmaceuticals Inc. Authors employed by Supernus were involved in the design and writing of this manuscript. Editorial support, funded by Supernus, was provided by Lisa M. Pitchford, PhD, ISMPP CMPP™ of JB Ashtin. Supernus funded open access for this publication.

Declarations

Conflict of interest

M.B.S. was formerly employed by Supernus Pharmaceuticals Inc. B.Y. and J.R. are currently employed by Supernus Pharmaceuticals Inc. T.R., J.N., and V.M. are consultants and/or advisory board members for Supernus Pharmaceuticals Inc. J.N. is also a consultant for Hippo T&C, Lumos, MindTension, NFL, and OnDosis; an advisory board member for Medice, Mind Tension, OnDosis, Otsuka; and receives research support from Otsuka. V.M. is also a consultant for AbbVie/Allergan, Acadia Pharmaceuticals, Inc. Alfasigma, USA, Inc., AlkernesInc., Axsome, Eisai, Ironshore, Intra-Cellular Therapies, Janssen, H. Lundbeck A/S, Jazz Pharmaceuticals, NovenPharmaceuticals Inc., Otsuka America Pharmaceutical, Inc., Sage Pharmaceuticals, Sunovion Pharmaceuticals, and Takeda Pharmaceutical Company Limited. T.R. is also a consultant with Cambridge Cognition, has a research grant with Shionogi, and receives editorial honoraria from Springer-Nature and Elsevier.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

Not applicable.

Code availability

Not applicable.

Author contributions

J.R., M.B.S., and B.Y. conceptualized and designed the review. M.B.S., B.Y., and T.W.R. conducted the literature search. M.B.S., B.Y., T.W.R., and V.M. drafted the initial manuscript. V.M. was not able to review or approve the final version of the manuscript, as he sadly passed away prior to the revision stage. His inclusion as a co-author was approved by his family in recognition of his contributions to the original submission. All remaining authors critically reviewed the manuscript, read and approved the final submitted manuscript, and agree to be accountable for the work.

Footnotes

Matia B. Solomon and Brittney Yegla: Denotes co-first authors.

With great sadness, the authors wish to acknowledge the passing of Dr. Vladimir Maletic, and recognize his substantial contributions and counsel in drafting the initial manuscript.

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PERMALINK

Revisiting the Role of Serotonin in Attention-Deficit Hyperactivity Disorder: New Insights from Preclinical and Clinical Studies

Matia B Solomon

Brittney Yegla

Jeffrey H Newcorn

Vladimir Maletic

Jonathan Rubin

Trevor W Robbins

Abstract

Key Points

Introduction

Fig. 1.

Serotonin (5-HT)

Fig. 2.

Table 1.

Serotonergic Mechanisms in Preclinical Studies Relevant to ADHD

Table 2.

Table 3.

Table 4.

Table 5.

Role of 5-HT in Hyperactivity

6-OHDA-Lesioned Model

SHR Model

DAT KO Mouse Model

Fig. 3.

Role of 5-HT in Impulsive Action and Impulsive Choice

Role of 5-HT in Impulsive Action

Role of 5-HT in Impulsive Choice

Role of 5-HT in Action Cancellation

Role of 5-HT in Emotional Dysregulation/Impulsive Aggression

Role of 5-HT Receptors in Impulsive Aggression

Serotonin and Dopamine Interactions in Impulsive Aggression

Role of 5-HT in Executive Function

Role of 5-HT in Attention

Role of 5-HT in Cognitive Flexibility

Stimulant-Mediated Effects on the Serotonergic System in Preclinical Models

Stimulant Effects on DA and NE

Fig. 4.

Stimulant Effects on 5-HT

Does Serotonergic Manipulation Affect Stimulant Efficacy in ADHD-Relevant Preclinical Models?

Serotonin Modulation of Stimulant Effects on Hyperactivity

Serotonin Modulation of Stimulant Effects on Impulsivity

Clinical Studies

Table 6.

Role of 5-HT in Impulsivity in ADHD and Non-ADHD Populations

Tryptophan Studies

Serotonin Receptor Subtypes

Role of 5-HT in Emotional Dysregulation in ADHD and Non-ADHD Populations

Tryptophan Studies

Serotonin Receptor Subtypes

Role of 5-HT in Attention in ADHD and Non-ADHD Populations

Tryptophan Studies

Serotonin Receptor Subtypes

SSRIs and Vortioxetine

Fig. 5.

Role of 5-HT on Brain Networks in ADHD and Non-ADHD Populations

Tryptophan Studies and SSRIs

Role of 5-HT on ADHD-Related Brain Networks Relevant to Impulsivity

Role of 5-HT on ADHD-Related Brain Networks Relevant to Emotional Dysregulation

Role of 5-HT on ADHD-Related Brain Networks Relevant to Attention

Does 5-HT Play a Role in ADHD Treatment?

Role of 5-HT in Nonstimulant-Mediated Effects

Role of 5-HT in ADHD Comorbidities

Conclusions

Future Directions

Funding

Declarations

Conflict of interest

Ethics approval

Consent to participate

Consent for publication

Availability of data and material

Code availability

Author contributions

Footnotes

References

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