Serotonin-dopamine interactions in psychostimulant-induced gene regulation: SSRI antidepressants potentiate gene regulation by methylphenidate (Ritalin) in the striatum and enhance behavioral profile indicative of addiction liability in rodents

Heinz Steiner; Michael Hrabak; Carlos A Bolaños-Guzmán

doi:10.1016/j.neubiorev.2025.106344

. Author manuscript; available in PMC: 2026 Aug 18.

Published in final edited form as: Neurosci Biobehav Rev. 2025 Aug 18;177:106344. doi: 10.1016/j.neubiorev.2025.106344

Serotonin-dopamine interactions in psychostimulant-induced gene regulation: SSRI antidepressants potentiate gene regulation by methylphenidate (Ritalin) in the striatum and enhance behavioral profile indicative of addiction liability in rodents

Heinz Steiner ^1,², Michael Hrabak ¹, Carlos A Bolaños-Guzmán ³

PMCID: PMC12439124 NIHMSID: NIHMS2108086 PMID: 40835201

Abstract

Selective serotonin reuptake inhibitor (SSRI) antidepressants are used in combination with the medical psychostimulant methylphenidate (Ritalin), a dopamine reuptake inhibitor, in a variety of treatments in children and adults. Unintended co-exposure to these medications also occurs in patients on SSRIs who abuse methylphenidate as a “cognitive enhancer” or recreational drug. This review summarizes a series of studies on the neurobehavioral effects of such drug combinations, administered either orally (mimicking clinical doses) or intraperitoneally (abuse doses), in adolescent rats. Prototypical SSRIs such as fluoxetine (Prozac) given together with methylphenidate produce various behavioral changes, including facilitated acquisition of cocaine self-administration and increased reinstatement of cocaine seeking (model for relapse). Consistent with these behavioral effects, prototypical (but not novel atypical) SSRIs potentiate abuse/addiction-associated gene regulation by methylphenidate in dopamine target areas such as the striatum. Studies investigating the mechanisms underlying these effects revealed that 5-HT1A and 5-HT1B serotonin receptors inhibit and facilitate, respectively, such gene regulation. These findings indicate that combining methylphenidate with prototypical SSRIs may increase the abuse/addiction liability for psychostimulants, and that 5-HT1A and 5-HT1B receptors may serve as pharmacological targets to alleviate this risk.

Keywords: gene regulation, immediate–early gene, psychostimulant, antidepressant, methylphenidate, fluoxetine, cocaine, dopamine, serotonin, basal ganglia, striatum, cocaine self–administration

1. Introduction

Treatments with combinations of psychotropic medications are common. These medications include psychostimulants such as methylphenidate (Ritalin), which is useful for managing the symptoms of attention-deficit/hyperactivity disorder (ADHD) (Castle et al., 2007; Kollins, 2008; Swanson et al., 2011), a condition that is found in most cultures in about 5% of children and 2.5% of adults (DSMMD-5, 2013). It was estimated that in 2008, for example, approximately 3 million children between 4 and 17 years of age in the US alone were treated with psychostimulant medications for ADHD (Swanson et al., 2011). This ADHD medication use has increased considerably over the last decades (Raman et al., 2018; Sultan et al., 2018).

Methylphenidate is often also misused as a so-called “cognitive enhancer” or for recreational purposes by students and young adults (Kollins, 2008; Benson et al., 2015; SAMHSA, 2015; Compton et al., 2018; Carlier et al., 2019; Faraone et al., 2020; Hartmayer et al., 2023). According to surveys, up to 20% or more of college students use methylphenidate to improve concentration, stay awake to study, or for getting “high” (White et al., 2006; Kollins, 2008; Wilens et al., 2008; Faraone et al., 2020). The 2011 National Survey on Drug Use and Health reported that approximately 1 million persons age 12 or older in the US admitted to current nonmedical use of prescription psychostimulants (SAMHSA, 2012). The same survey in 2016 found that the number of users had increased to 1.4 million (SAMHSA, 2017). Such misuse may include ingesting more pills (increased oral administration), but can also involve grinding up pills and snorting the powder or dissolving and injecting it intravenously (e.g., Parran and Jasinski, 1991; Barrett et al., 2005; Teter et al., 2006; White et al., 2006; Wilens et al., 2008; Faraone et al., 2020; Butler et al., 2021; Hartmayer et al., 2023). Such parenteral administration will result in exposure to much faster and higher drug peak levels and is thus expected to have a greater potential for inducing maladaptive neuronal plasticity and enhanced addiction liability (Samaha and Robinson, 2005).

Methylphenidate is frequently combined with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) when ADHD is co-morbid with depressive disorders (Rushton and Whitmire, 2001; Safer et al., 2003), which occurs in up to half of pediatric ADHD cases (Waxmonsky, 2003; Spencer, 2006). Moreover, methylphenidate plus SSRI combinations are also used for other purposes, including augmentation of SSRI effects in the treatment of depression (e.g., Lavretsky et al., 2003; Nelson, 2007; Ishii et al., 2008; Ravindran et al., 2008) or other conditions (e.g., Csoka et al., 2008). Besides depressive disorders, SSRIs such as fluoxetine are often prescribed in the treatment of anxiety disorders, post-traumatic stress disorder, obsessive compulsive disorder, and others (Iversen, 2006). Therefore, there are numerous situations in which unintended co-exposure to these drugs can occur when patients on SSRIs also abuse methylphenidate.

What are the behavioral consequences of methylphenidate plus SSRI treatments? Early preclinical studies found that chronic treatment with such combinations in juvenile rats produces a range of long-term behavioral changes (Warren et al., 2011). For one, rats were investigated in the cocaine place preference conditioning (CPP) paradigm, which assesses reinforcing effects of cocaine by first exposing rats to cocaine in a distinctive environment and then testing (without cocaine) whether they seek out/prefer (or avoid) this environment compared with a neutral environment (Tzschentke, 2007). Psychostimulants typically produce conditioned place preference in the CPP paradigm (although high doses can be aversive). For example, conditioning with methylphenidate at doses of 1.25 to 20 mg/kg increased preference for the paired environment (Meririnne et al., 2001). Pretreatment with psychostimulants can further increase or attenuate preference conditioning (Shippenberg and Heidbreder, 1995; Carlezon et al., 2003; Warren et al., 2011), depending on factors such as the age of pretreatment and the conditioning drug/dose. Thus, pretreatment with methylphenidate has been shown to enhance subsequent conditioning by methylphenidate (e.g., Meririnne et al., 2001), but attenuation of conditioning (by cocaine) has also been reported (e.g., Andersen et al., 2002).

In the study by Warren et al. (2011), repeated pretreatment with methylphenidate alone also attenuated subsequent conditioning by cocaine. However, the reverse was found after methylphenidate plus fluoxetine pretreatment, that is, significantly enhanced conditioning by cocaine in the CPP paradigm. This drug combination also increased subsequent sucrose consumption (Warren et al., 2011) and produced several other behavioral changes including altered responsiveness to stress (forced swim test) (Warren et al., 2011) (for review, see Steiner et al., 2014). Overall, these findings suggested a facilitation of reinforcing effects of abused drugs (cocaine), but also natural rewards (sucrose), as well as other behavioral alterations, after repeated pretreatment with methylphenidate plus fluoxetine. Therefore, these methylphenidate plus fluoxetine combinations may increase an abuse or addiction liability for psychostimulants.

A host of preclinical studies demonstrated neuronal changes supportive of a potential increase in an abuse or addiction risk, especially with exposure to such psychotropic medications during brain development (Carlezon and Konradi, 2004; Carrey and Wilkinson, 2011; Marco et al., 2011; Van Waes and Steiner, 2015). Typically, psychostimulant-induced neuronal changes include molecular adaptations resulting in changes in gene regulation, and these are often most pronounced in dopamine target areas, particularly the striatum (for review, see Steiner and Van Waes, 2013). The striatum is a forebrain structure and major component of cortico-basal ganglia-cortical circuits (see Section 2, for a schematic of these circuits), which are critical for motivational, executive, and motor aspects of behavior.

Similar to illicit psychostimulants such as cocaine or amphetamine (e.g., Berke et al., 1998; Yuferov et al., 2005; Heiman et al., 2008), methylphenidate can alter the expression of hundreds of genes in striatal neurons (e.g., Adriani et al., 2006a; Adriani et al., 2006b; for review, see Steiner and Van Waes, 2013). However, at least some of these molecular effects appear to be more moderate than those of cocaine/amphetamine (for reviews, see Yano and Steiner, 2007; Steiner and Van Waes, 2013). For example, while acute and repeated treatment with methylphenidate induce the expression of a number of genes (e.g., immediate-early genes, IEGs) in the striatum in a manner similar to cocaine (Yano and Steiner, 2007; Steiner and Van Waes, 2013), other genes showed modest or no effects (e.g., the opioid peptides dynorphin and enkephalin) (Yano and Steiner, 2005b; Cotterly et al., 2007; Van Waes et al., 2015), in contrast to cocaine/amphetamine (for discussion, see Yano and Steiner, 2007).

These differential molecular changes may be attributable to different neurochemical effects for methylphenidate vs. cocaine/amphetamine. Both cocaine and amphetamine produce increased extracellular levels of dopamine, norepinephrine and serotonin via reuptake blockade and/or reverse transport (see Yano and Steiner, 2007). Methylphenidate also blocks reuptake of dopamine and norepinephrine [as determined in striatum and prefrontal cortex/hippocampus, respectively (Hurd and Ungerstedt, 1989; Kuczenski and Segal, 1997; Gerasimov et al., 2000; Kuczenski and Segal, 2001; Borycz et al., 2008)]. However, in contrast to these other psychostimulants, methylphenidate has low affinity for the serotonin transporter (Schweri et al., 1985; Pan et al., 1994; Gatley et al., 1996) and even in high doses does not produce increased extracellular levels of serotonin [striatum (Kuczenski and Segal, 1997; Segal and Kuczenski, 1999; Kankaanpaa et al., 2002; Borycz et al., 2008); see Yano and Steiner, 2007].

Gene regulation by psychostimulants in the striatum is principally produced by dopamine overflow, and, consequently, overstimulation of striatal dopamine receptors (in interaction with glutamate input) (Steiner and Van Waes, 2013; Steiner, 2017). In agreement with this scheme, methylphenidate-induced gene regulation in striatal neurons is also mediated by striatal dopamine receptors, as these effects are blocked by dopamine receptor antagonists administered systemically or into the striatum (Yano et al., 2006; Alburges et al., 2011). [Given that in the rat the norepinephrine innervation is scarce in the striatum (e.g., Berridge et al., 1997; Baldo et al., 2003) but considerable in the cortex, increased norepinephrine tone produced by psychostimulants may indirectly affect striatal gene regulation by modifying cortical input.]

However, it is well established that, in addition to dopamine, serotonin contributes significantly to striatal gene regulation for drugs such as cocaine; such molecular effects are reduced by serotonin depletion or serotonin receptor antagonism or deletion (e.g., Morris et al., 1988; Bhat and Baraban, 1993; Walker et al., 1996; Lucas et al., 1997; Horner et al., 2005). Therefore, the more moderate molecular effects of methylphenidate (see above) may be a consequence of methylphenidate not increasing serotonin activity. Thus, combinations of methylphenidate with SSRIs (serotonin action) may induce emerging (“cocaine-like”) effects by simultaneously inhibiting the reuptake of both serotonin and dopamine.

Early findings on striatal gene regulation were consistent with this serotonin hypothesis. These findings demonstrated that combining SSRIs (e.g., fluoxetine, citalopram) with methylphenidate indeed potentiated methylphenidate-induced gene regulation in the striatum in adolescent rats (Steiner et al., 2010; Van Waes et al., 2010), For example, fluoxetine potentiated methylphenidate-induced expression of IEGs such as c-fos and zif268 as well as neuropeptides in striatal projection neurons (for reviews, see Steiner and Van Waes, 2013; Van Waes and Steiner, 2015).

The present review summarizes our work investigating the molecular effects and their behavioral correlates of methylphenidate plus SSRI treatments in rats. The first part describes our methodological approaches used to measure changes in gene expression (Section 2). This is followed by a summary of our findings from comparing the gene regulation effects produced by high-dose, intermittent treatments (mimicking drug exposure occurring during intermittent methylphenidate abuse) (Section 3) with the effects of chronic oral treatment (in drinking water; mimicking clinically relevant drug plasma levels) (Section 4); a presentation of behavioral changes produced by these same drug treatments, including changes in subsequent cocaine self-administration (Section 5); a summary of studies investigating the cellular mechanisms underlying the potentiating impact of SSRIs, with a focus on the role of serotonin (5-HT) receptor subtypes (Section 6); a discussion of the potential underlying cellular mechanisms (with a proposed anatomical model), the affected striatal functional domains, as well as the potential functional impact of altered dynorphin signaling, as an example of an affected gene (Section 7); a discussion of the potential clinical consequences of methylphenidate plus SSRI treatments, that is, the potential impact on the abuse/addiction liability of psychostimulants in humans (Section 8) and conclusions (Section 9).

2. Approach to measure gene expression

Our studies focused on drug-induced changes in gene expression in the main dopamine target area, the striatum. One of the main purposes was to determine how these drugs affect the different functional domains of the striatum. We thus assessed changes in gene expression (i.e., mRNA levels) with quantitative in situ hybridization histochemistry combined with autoradiography, based on methods developed by Young and Gerfen and colleagues (Young et al., 1986a; Young et al., 1986b; Gerfen and Young, 1988). Autoradiograms enable high-resolution mapping of such molecular changes throughout brain structures (Yano and Steiner, 2005a, b). In order to measure the drug effects in the different functional domains, we mapped gene expression in 23 striatal sectors, which are largely defined by their predominant cortical inputs (Willuhn et al., 2003; Yano and Steiner, 2005a), on three rostrocaudal levels (rostral, middle, caudal) (Fig. 1, right). Eight of these sectors represent the sensorimotor domain (lateral striatum), 10 the associative domain (medial, central and ventral striatum) and 5 the limbic domain (nucleus accumbens) (Fig. 1, right).

Fig. 1 — Diagram of simplified basal ganglia-thalamo-cortical circuits (sagittal view) and their neurotransmitters in the rat (left) and schematic illustration of the striatal regions in which drug-induced changes in gene expression were measured (right). Striatal output to the basal ganglia output nuclei, substantia nigra pars reticulata (SNr) and internal segment of globus pallidus (GPi), is carried by two pathways, the “direct pathway” (striatonigral neurons) and the “indirect pathway” that begins with the neurons that project to the external segment of the globus pallidus (GPe) (striatopallidal neurons) (Gerfen and Bolam, 2017). Both of these two projection neuron types (medium spiny neurons, MSNs) use GABA as their main neurotransmitter, but they differ in neuropeptides and dopamine receptors they express: substance P (SP), dynorphin (DYN) and mostly D1 receptors in direct pathway neurons (D1-MSNs), and enkephalin (ENK) and mostly D2 receptors in indirect pathway neurons (D2-MSNs) (see text). The effects of dopamine in these neurons are facilitatory (D1-MSNs) or inhibitory (D2-MSNs), based on the G-proteins these receptors are coupled to (Gerfen and Surmeier, 2011). This includes dopamine effects on gene regulation in these neurons.

In order to determine drug effects in the different functional domains of the striatum in our studies, the striatum was subdivided into 23 sectors (18 of the caudate-putamen and 5 of the nucleus accumbens) on rostral, middle and caudal striatal levels. These sectors were largely defined by their predominant cortical inputs (arrows, simplified) and thus reflect different functional domains (see Willuhn et al., 2003; Yano and Steiner, 2005a, for details). The dorsal/lateral sectors on all three levels represent the sensorimotor domain (darkest grey), the medial, central and ventral sectors include the associative domain (intermediate grey), and the sectors of the nucleus accumbens (core and shell) on the rostral level the limbic domain (lightest grey). Abbreviations: Cortical areas: CG, cingulate; M2, secondary motor/medial agranular; M1, primary motor; SS, somatosensory; I, insular; P, piriform; I/LO, insular/lateral orbital; PL, prelimbic; IL, infralimbic. Other: STN, subthalamic nucleus; GLU, glutamate.

We most often investigated drug effects on the expression of IEGs. IEGs are of interest as markers for drug actions because of their considerable dynamic range, which facilitates detection of even minor drug-induced changes. We typically assessed the IEGs zif268 and c-fos, which encode transcription factors that regulate the activity of other genes (e.g., Knapska and Kaczmarek, 2004). Both IEGs are implicated in long-term addiction-related changes induced by psychostimulants. For example, zif268 is critical for reinforcing effects by cocaine (CPP) (Valjent et al., 2006) and for reconsolidation of cocaine memories (Lee et al., 2005; Théberge et al., 2010), among other effects (Valjent et al., 2006). We sometimes also measured the expression of the IEG homer1a, which is a synaptic plasticity regulator (e.g., involved in receptor trafficking) (Xiao et al., 2000; Thomas, 2002) and is also implicated in addiction-related neuronal changes (for review, see Szumlinski et al., 2008). These molecules thus play various roles in addiction-related neuroplasticity.

In addition, we often measured drug effects on the expression of the neuropeptides substance P, dynorphin and enkephalin, which serve as cell-type markers. In the striatum, substance P and dynorphin are both selectively expressed in projection neurons (“medium spiny neurons”, MSNs) that make up the direct striatal output pathway (Gerfen and Young, 1988) and contain predominantly D1 dopamine receptors (D1-MSNs) (Fig. 1, left). In contrast, enkephalin is present in projection neurons that give rise to the indirect pathway and express mostly D2 receptors (D2-MSNs) (Steiner and Gerfen, 1998). These neuropeptide mRNAs thus serve as markers to differentiate drug effects between D1- and D2-MSNs (Steiner and Van Waes, 2013). All the mentioned genes are regulated to various degrees by treatments with psychostimulants/dopamine agonists (Steiner and Van Waes, 2013), including methylphenidate (Yano and Steiner, 2007).

Most of our studies were performed in adolescent male rats. Some were conducted in young adults, or rats were tested as young adults after pretreatment during adolescence, as discussed below. A few studies were repeated in females with principally similar outcomes (not shown). For example, adding fluoxetine to acute methylphenidate treatment produced a potentiation of IEG induction in the striatum in adolescent females that was quantitatively similar to that in males (unpublished results). The behavioral and gene regulation effects of repeated methylphenidate plus SSRI treatments remain to be established in females.

3. High-dose, intermittent (“abuse”) treatment: effects on gene regulation

When methylphenidate pills are misused, they are often taken in higher numbers than prescribed, or even ground up and the powder snorted or dissolved and injected (e.g., Teter et al., 2006; see Steiner and Van Waes, 2013), resulting in high-dose exposure (drug spikes). In our initial studies, we assessed the effects of acute or repeated drug administration by intraperitoneal (i.p.) injections.

3.1. Acute treatment

Our initial results showed that, consistent with earlier findings (Yano and Steiner, 2007), acute i.p. administration of methylphenidate (MP group, Fig. 2) produced dose-dependent induction of IEGs in the striatum in adolescent rats (postnatal day 35, PD35) (Steiner et al., 2010; Van Waes et al., 2010). There were borderline increases in the expression of zif268 and c-fos after 2 mg/kg of methylphenidate, mostly in medial and central striatal areas (associative striatum) (see Van Waes et al., 2010, for regional effects), whereas 5 mg/kg resulted in more robust induction in most striatal regions (Fig. 2; the data presented in Fig. 2 and the following figures are values from all middle sectors pooled) (Van Waes et al., 2010). Fluoxetine (5 mg/kg, i.p.; FLX group, Fig. 2) by itself had no effect on striatal gene regulation. However, when combined with methylphenidate (2 and 5 mg/kg), fluoxetine markedly potentiated IEG induction by methylphenidate (MP+FLX group, Fig. 2) (Van Waes et al., 2010). Potentiation of zif268 and c-fos induction showed an identical regional distribution throughout the striatum. Thus, the potentiation (i.e., the difference between MP and MP+FLX groups, see Fig. 2) was positively correlated across the 23 striatal sectors between zif268 and c-fos, for both 2 mg/kg (not shown) and 5 mg/kg methylphenidate (Fig. 2, right) (Van Waes et al., 2010). This potentiation was most pronounced in (lateral) sectors of the sensorimotor striatum (Fig. 2, right). Another often prescribed SSRI, citalopram (5 mg/kg, i.p.), had principally similar effects as fluoxetine (not shown) (Van Waes et al., 2010).

Fig. 2 — Fluoxetine potentiates acute methylphenidate-induced gene expression in the striatum (Van Waes et al., 2010; Van Waes et al., 2012). Gene expression was measured by *in situ* hybridization histochemistry. Illustrations of film autoradiograms (left) depict expression of the IEGs zif268 (top) and c-fos (middle) (Van Waes et al., 2010), and the neuropeptide substance P (bottom) (Van Waes et al., 2012) in coronal sections from the middle striatum in rats that received a single injection of vehicle (V), fluoxetine (5 mg/kg, i.p.; FLX), methylphenidate (5 mg/kg, i.p.; MP), or methylphenidate+fluoxetine (MP+FLX) and were killed 40 min (zif268, c-fos) or 90 min (substance P) after drug administration. The maximal hybridization signal is black. Also given (center) are mean density values (mean±SEM, expressed in percentage of V controls) for zif268, c-fos and substance P expression measured across the whole striatum on the middle level in these rats. The scatter plot (right) shows the potentiation (i.e., the difference between MP and MP+FLX groups, expressed as percentage of the maximal potentiation for each gene) for zif268 and c-fos induction in the 23 striatal sectors (dots). This potentiation for the two IEGs was significantly correlated (r=0.840) across the striatal sectors (i.e., displayed a similar regional distribution throughout the striatum). Overall, the potentiation was most robust in sectors of the sensorimotor striatum (cyan dots). **P<0.01, ***P<0.001, vs. V controls or as indicated (potentiation).

We also assessed the effects of acute methylphenidate and fluoxetine on striatal neuropeptide expression (Van Waes et al., 2012). Results demonstrated that acute administration of methylphenidate (5 mg/kg, i.p.) alone caused increased expression of substance P (Fig. 2) (Van Waes et al., 2012), consistent with our earlier findings (Yano and Steiner, 2005b), whereas fluoxetine (5 mg/kg, i.p.) alone had no effect. Combining fluoxetine with methylphenidate, however, produced a potentiated increase in substance P expression (Fig. 2) (Van Waes et al., 2012).

Effects on dynorphin expression were more modest (not shown) (Van Waes et al., 2012). While there were tendencies for increased dynorphin expression after methylphenidate alone, these were statistically not significant (Van Waes et al., 2012). Again, fluoxetine alone had no effect. However, the methylphenidate plus fluoxetine combination produced increased (potentiated) dynorphin expression in approximately a third of striatal sectors, again mostly laterally (Van Waes et al., 2012).

In marked contrast to substance P and dynorphin, no significant changes in enkephalin expression were seen after acute methylphenidate, fluoxetine or methylphenidate plus fluoxetine treatment (not shown) (Van Waes et al., 2012). In summary, this acute treatment thus selectively affected the striatal D1-MSNs (substance P, dynorphin).

3.2. Repeated treatment

In clinical treatments and with abuse, psychotropic medications are typically administered chronically. The molecular consequences of repeated treatment with methylphenidate and fluoxetine are thus most relevant for long-term neurobehavioral changes. Repeated psychostimulant treatments cause a variety of molecular changes (neuroadaptations), including upregulation of expression for some genes and repression for others (McClung and Nestler, 2003; Yuferov et al., 2005; Heiman et al., 2008). Often the exact consequences for cellular function (dysfunction) of such alterations in gene expression remain unknown. However, the long-term functional integrity of neurons depends on balanced regulation of gene expression, as most or all cellular components have limited half-lives and must be replaced, typically by gene expression (e.g., neuropeptides are released and metabolized, and replenished by increasing gene expression). Disruption of such homeostatic gene regulation by psychostimulants will thus likely result in deficient neuronal function contributing to behavioral manifestations of psychostimulant addiction (e.g., Hyman and Nestler, 1996; Nestler, 2001).

In our early repeated treatment studies, we administered these drugs i.p. once daily for 5-6 days in adolescents (starting on PD35). Some mRNA levels were measured within a few hours after the last drug injection. In other studies, gene responses to a cocaine challenge injection were determined 24 h or 14 days after the repeated pretreatment to assess the longevity of these molecular changes.

Figure 3A (top) shows that a 5-day repeated treatment with combined methylphenidate plus fluoxetine (5 mg/kg each), but not with individual drugs, resulted in a robust increase in dynorphin mRNA levels (Van Waes et al., 2015). This increase was present on all 3 rostrocaudal levels, mostly in dorsal and lateral (sensorimotor) sectors (see Van Waes et al., 2015, for regional effects). There was also a modest increase in enkephalin expression after this repeated methylphenidate plus fluoxetine treatment (Fig. 3A, bottom). However, in contrast to dynorphin, the effect on enkephalin was limited to the medial/central (associative) sectors on the middle level (not shown) (Van Waes et al., 2015). These findings thus confirm a preferential effect of methylphenidate plus fluoxetine treatment on D1-MSNs of the sensorimotor striatum, but they indicate that D2-MSNs in (parts of) the associative striatum are also altered by this repeated treatment.

Fig. 3 — Fluoxetine potentiates gene regulation induced by repeated i.p. treatment with methylphenidate in the striatum. (A) Neuropeptide expression after repeated methylphenidate plus fluoxetine treatment (Van Waes et al., 2015). Mean density values (mean±SEM, expressed in percentage of V controls) for dynorphin (top) and enkephalin expression (bottom) measured in the whole middle striatum are given for rats that received 5 daily injections of vehicle (V), fluoxetine (5 mg/kg, i.p.; FLX), methylphenidate (5 mg/kg, i.p.; MP), or methylphenidate+fluoxetine (MP+FLX) and were killed 2 h after the last drug administration. (B) Induction of IEGs by cocaine after repeated methylphenidate plus fluoxetine pretreatment (Van Waes et al., 2014). Illustrations of film autoradiograms depict expression of zif268 (top) and homer1a (bottom) in the middle striatum in rats that received 5 daily injections of vehicle (V), fluoxetine (5 mg/kg, i.p.; FLX), methylphenidate (5 mg/kg, i.p.; MP), or methylphenidate+fluoxetine (MP+FLX), followed one day later by a cocaine challenge injection (25 mg/kg, i.p.; /C) or vehicle (/V). *P<0.05, **P<0.01, vs. V controls or as indicated (potentiation).

In further studies, we investigated how striatal gene regulation (and behavior, see Section 5) would respond to cocaine after repeated methylphenidate, fluoxetine and methylphenidate plus fluoxetine pretreatment, in order to gauge a possible impact on the effects of illicit psychostimulants (addiction risk) by repeated pretreatment with these psychotropic medications.

One of the best-established molecular adaptations produced by repeated cocaine/amphetamine treatment is repression (“blunting”) of IEG inducibility in the striatum. That is, with repeated treatment, a given dose will elicit a progressively reduced (blunted) IEG (or other gene) response (e.g., Steiner and Gerfen, 1993; for review, see Steiner and Van Waes, 2013). This effect is the result of epigenetic modifications (Renthal et al., 2008) and other neuronal alterations produced by the repeated drug treatment (for review, see Steiner and Van Waes, 2013). Several labs showed that repeated methylphenidate treatment likewise produces blunting of IEG induction (by a methylphenidate challenge) in the striatum (e.g., Brandon and Steiner, 2003; Chase et al., 2003; Chase et al., 2005; Cotterly et al., 2007). It was thus of interest to investigate whether the IEG response to cocaine was also modified by pretreatment with methylphenidate and/or fluoxetine.

Previous findings had shown that repeated daily cocaine treatment (25 mg/kg, i.p.) for 5 days was sufficient to produce marked blunting of the induction (by a subsequent 25 mg/kg cocaine challenge) of IEGs such as zif268 and homer1a in the striatum and that this blunting lasted for at least 3 weeks after the pretreatment (Unal et al., 2009). Our results with methylphenidate (5 mg/kg, i.p.) and fluoxetine (5 mg/kg, i.p.) once daily for 5 days demonstrated that methylphenidate alone produced minor blunting of subsequent zif268 and homer1a induction by cocaine (25 mg/kg; C) one day later (MP/C vs. V/C groups, Fig. 3B), while fluoxetine alone had no effect (FLX/C vs. V/C, Fig. 3B) (Van Waes et al., 2014). In contrast, adding fluoxetine to methylphenidate during the pretreatment strongly potentiated blunting of both zif268 and homer1a induction by the subsequent cocaine challenge (MP+FLX/C vs. MP/C, Fig. 3B) (Van Waes et al., 2014). Our regional analysis showed that this potentiation of blunting (i.e., the difference between MP+FLX/C and MP/C effects, Fig. 3B) occurred in most striatal sectors on all 3 rostrocaudal levels (not shown) and was again maximal in the sensorimotor sectors for both zif268 and homer1a (Fig. 3B) (Van Waes et al., 2014).

Overall, there was a positive correlation between the potentiation of acute zif268 induction (by MP+FLX; Van Waes et al., 2010) and the potentiation of blunting of zif268 induction (by the cocaine challenge) after the repeated methylphenidate plus fluoxetine treatment (not shown) (Van Waes et al., 2014). This correlation demonstrates that occurrence and magnitude of such neuroadaptations after repeated methylphenidate plus fluoxetine treatment are predicted by the acute gene response, which thus serves as an acute marker for the risk for such neuroadaptations (see Steiner and Van Waes, 2013).

In a further study, we showed that this potentiated gene blunting after repeated methylphenidate plus fluoxetine treatment lasted for at least 14 days after the repeated pretreatment, into the young adulthood of the animals (not shown) (Beverley et al., 2014). These neuronal changes are thus quite enduring. The behavioral correlates of such neuronal changes are addressed in Section 5 below.

In summary, these findings demonstrate that SSRIs given chronically in conjunction with methylphenidate produce more robust and enduring neuroadaptations in striatal gene regulation than chronic methylphenidate alone.

4. Chronic oral (“clinical”) treatment: effects on gene regulation

In clinical use methylphenidate is almost always administered orally, which entails slower bioavailability and lower blood plasma levels than with i.p. injections. In order to investigate neuronal and behavioral effects of clinically relevant blood plasma levels in animal models, Thanos and colleagues recently developed an oral administration procedure for methylphenidate, which provides drugs via drinking water (Thanos et al., 2015). This procedure has several advantages over other oral administration methods (e.g., gavage), as it allows voluntary drug intake in a relatively stress-free manner (Thanos et al., 2015). In a series of studies, this procedure was employed to assess gene regulation and behavioral effects of chronic oral administration of methylphenidate and fluoxetine.

In these studies, drugs were given daily for 4 weeks, starting during adolescence (PD35) (Moon et al., 2021). The doses used were methylphenidate 30/60 mg/kg/day (see Moon et al., 2021, for details), fluoxetine 20 mg/kg/day, or methylphenidate plus fluoxetine. Rats had access to these drugs in their drinking water for 8 h per day. Controls received regular drinking water. Gene expression in the striatum was assessed 24 h after the last drug treatment day. We measured the expression of dynorphin, substance P and enkephalin. In addition, potential changes in the expression of the 5-HT1B serotonin receptor were analyzed.

Figure 4 presents our findings for dynorphin expression (Moon et al., 2021); results for substance P, enkephalin and 5-HT1B expression (Moon et al., 2021) are not shown here. Chronic oral methylphenidate alone produced a tendency for increased dynorphin expression in several striatal sectors (Fig. 4), but had no effect on substance P or enkephalin expression (Moon et al., 2021). Oral fluoxetine alone also did not increase gene expression [and actually produced a decrease in substance P expression in the rostral ventral striatum/nucleus accumbens (Moon et al., 2021)].

In contrast, when given together, fluoxetine greatly potentiated methylphenidate-induced expression of dynorphin (Fig. 4) and to a lesser degree substance P (Moon et al., 2021). Not only was the magnitude of the potentiation of dynorphin expression substantially greater (Fig. 4) than that produced by the 5-day repeated i.p. treatment (Fig. 3A) (Van Waes et al., 2015), but the rostrocaudal spread was also magnified. Thus, after the 4-week oral treatment, significant potentiation of dynorphin expression was found in 20 of the 23 sectors on all 3 rostrocaudal levels (POT; Fig. 4) (substance P, 14/23 sectors; Moon et al., 2021), whereas the 5-day i.p. treatment resulted in potentiated dynorphin expression only in 10 of the 23 sectors (substance P was not assessed; Van Waes et al., 2015). Enkephalin expression was again less affected than dynorphin and substance P also by oral treatment (significant potentiation in 5/23 sectors; Moon et al., 2021).

Matching the regional pattern produced by the shorter i.p. treatment (Van Waes et al., 2015), the three functional domains of the striatum were again differentially affected, as the longer oral treatment also impacted dynorphin and substance P expression (D1-MSNs) most robustly in the sensorimotor sectors (Fig. 4), with relatively lesser effects in associative and limbic sectors (Moon et al., 2021). Enkephalin expression (D2-MSNs) was again altered only in some associative sectors (Moon et al., 2021).

Interestingly, the expression of the 5-HT1B receptor in the striatum was hardly affected by chronic oral methylphenidate or methylphenidate plus fluoxetine treatment (Moon et al., 2021). This was in notable contrast to the effects of the repeated i.p. treatment (Van Waes et al., 2015). The 5-day repeated i.p. methylphenidate treatment also produced upregulated striatal 5-HT1B expression, and this effect was also potentiated by adding fluoxetine (potentiated in 7/23 sectors; Van Waes et al., 2015). However, perhaps surprisingly, the 4-week oral methylphenidate plus fluoxetine treatment had minimal or no effects on striatal 5-HT1B expression (potentiated in 1/23 sectors; Moon et al., 2021).

The reasons for these differential effects on striatal gene expression for long-term oral (Moon et al., 2021) vs. short-term i.p. (Van Waes et al., 2015) treatments remain unclear, given that drug doses, treatment durations and the survival times varied between our two studies. For example, gene induction dynamics and half-lives for the assessed mRNAs likely played a role. For one, it has been shown that fast drug administration that results in drug spikes produces much more robust gene regulation (and behavioral) changes than slow administration of the same dose (Samaha et al., 2004; Samaha and Robinson, 2005). High-dose i.p. treatment could thus be expected to result in greater changes (as seen for 5-HT1B expression; Van Waes et al., 2015), despite the shorter treatment duration. On the other hand, dynorphin mRNA has a long half-life, as mRNA levels were found to be increased for at least 18-30 h after a single drug administration (Smith and McGinty, 1994; Wang and McGinty, 1995) and remained elevated for several weeks past cessation of a repeated dopamine agonist treatment (Andersson et al., 2003). The more pronounced effects on dynorphin expression after the longer daily treatment (Moon et al., 2021) may thus reflect more accumulated mRNA, despite the lower drug plasma levels.

However, other factors likely also contributed to these differential effects. In a more recent study (Hrabak et al., 2025), we compared the effects of fluoxetine on methylphenidate-induced dynorphin expression with those of a novel SSRI, vilazodone (see Section 6.2.1, below). In that study, fluoxetine, for comparison with vilazodone, had to be injected (5 mg/kg, i.p., twice daily, 4 weeks; plus methylphenidate, in drinking water) because vilazodone cannot be dissolved in drinking water. Our results demonstrate that overall oral methylphenidate plus i.p. fluoxetine produced very similar potentiation of dynorphin expression (Hrabak et al., 2025) as described above for oral methylphenidate plus oral fluoxetine (Fig. 4) (Moon et al., 2021). There was, however, one notable difference. Oral methylphenidate plus oral fluoxetine had major potentiating effects on dynorphin expression also in the rostral dorsolateral striatum, but only minor effects in the nucleus accumbens (Fig. 4) (Moon et al., 2021). In contrast, oral methylphenidate plus i.p. fluoxetine produced inverse effects, modest or no changes in the rostral dorsal striatum, but a robust potentiation of dynorphin expression throughout the nucleus accumbens (Hrabak et al., 2025).

These findings are difficult to explain considering differential drug plasma levels or gene dynamics alone. However, drug-induced striatal gene regulation is principally driven by glutamate inputs from the cortex and thalamus (which are then modulated by striatal dopamine, serotonin and other receptors) (for reviews, see Steiner and Van Waes, 2013; Steiner, 2017). Differential excitatory inputs, due to differential network engagements (Manza et al., 2024), during drug treatments are thus likely major determinants of drug-induced gene regulation and behavioral consequences (Steiner and Van Waes, 2013; Steiner, 2017). Future work will have to ascertain whether this was indeed also the case with these methylphenidate plus fluoxetine treatments.

In summary, our findings show that chronic oral methylphenidate plus fluoxetine treatment causes in many ways similar, or even greater, changes in striatal gene regulation compared with repeated i.p. treatments. With both treatment versions these changes preferentially occur in direct pathway neurons (D1-MSNs) arising in the sensorimotor striatum, mimicking cocaine effects (Steiner and Van Waes, 2013). Minor changes in indirect pathway neurons (D2-MSNs) are predominantly seen in associative striatal sectors. Future studies will have to determine the exact functional consequences of these differential changes. The following section presents behavioral alterations produced by these chronic i.p. and oral methylphenidate plus fluoxetine treatments, including their impact on cocaine-induced behavior.

5. Behavioral changes after methylphenidate plus fluoxetine treatment

5.1. Methylphenidate plus fluoxetine-induced behavior

As far as we are aware, Borycz et al. (2008) were the first to demonstrate an interaction between the SSRI fluoxetine and methylphenidate in behavior. Fluoxetine (10 mg/kg, i.p.) potentiated acute methylphenidate (10 mg/kg, i.p.)-induced locomotor activity in adult male rats (Borycz et al., 2008). Another study in juvenile male rats assessed the effects of chronic pretreatment (PD20-34) with methylphenidate plus fluoxetine (2.0 and 2.5 mg/kg, respectively; i.p., twice daily) on the subsequent reactivity to reward- and mood-related stimuli 24 h or 2 months after drug exposure (Warren et al., 2011). As mentioned earlier, the results demonstrated that methylphenidate plus fluoxetine pretreatment induced a variety of behavioral changes, including increased sucrose consumption and enhanced place preference conditioning by cocaine (CPP), as well as increased sensitivity to stress-inducing circumstances (forced swim test). Notably, many of these effects were long-lasting (endured for 2 months) or even increased over time (Warren et al., 2011).

In some of our molecular studies described above, we assessed behavioral effects (open-field behavior) in parallel to striatal gene regulation. Thus, an early study in adolescent male rats demonstrated that acute administration of fluoxetine (5 mg/kg, i.p.) given together with methylphenidate (2 or 5 mg/kg, i.p.) did not alter locomotor activation (ambulation) by methylphenidate (Van Waes et al., 2010). However, fluoxetine potentiated the increase in rates of behavioral “stereotypies” (focal repetitive movements, mostly repetitive sniffing/whisking and head bobbing with these drugs) induced by methylphenidate (5 mg/kg, but not 2 mg/kg) (Van Waes et al., 2010). Fluoxetine (5 mg/kg) alone had no effects on behavior (Van Waes et al., 2010). The behavioral changes induced by methylphenidate plus fluoxetine treatment are thus dose-dependent (and perhaps age-dependent).

In a recent study (Thanos et al., 2023), we also investigated the impact of chronic oral co-administration of methylphenidate and fluoxetine on behavior, using the treatment regimen that produced altered striatal gene regulation (Moon et al., 2021). In this study, adolescent male rats received methylphenidate (30/60 mg/kg/day), fluoxetine (20 mg/kg/day) or methylphenidate plus fluoxetine (in drinking water, 8 h access per day) for 4 weeks (Thanos et al., 2023). This chronic oral treatment caused various and complex behavioral changes. For example, rats treated with methylphenidate plus fluoxetine displayed a considerable increase in locomotor activity in the open-field test, while methylphenidate or fluoxetine alone had no significant effect (stereotypies were not assessed) (Thanos et al., 2023). Moreover, the groups treated with methylphenidate plus fluoxetine or fluoxetine alone both showed a reduction in food intake and attenuated weight gain (Thanos et al., 2023), consistent with earlier findings for fluoxetine (see Thanos et al., 2023). However, chronic oral methylphenidate plus fluoxetine (and to some lesser degree fluoxetine alone) significantly increased sucrose consumption compared with water controls or methylphenidate alone (Thanos et al., 2023), thus confirming the earlier effects of chronic i.p. methylphenidate plus fluoxetine treatment (Warren et al., 2011).

There were also significant changes in depression- and anxiety-related behaviors, although the increased locomotor activity in methylphenidate plus fluoxetine-treated rats may complicate interpretation of these findings. Thus, in the forced-swim test, the methylphenidate plus fluoxetine group displayed a significantly longer latency to immobility than the other three groups, with no differences noted for methylphenidate or fluoxetine alone (Thanos et al., 2023). In the elevated plus-maze, the methylphenidate plus fluoxetine group spent significantly more time in the open arms than the control and fluoxetine groups, with a similar tendency for the methylphenidate group (Thanos et al., 2023). Future studies will have to clarify how these changes relate to possible antidepressive and anxiolytic actions, respectively, of methylphenidate plus fluoxetine exposure.

In summary, these findings demonstrate that acute and chronic treatments with high (i.p.) and low (oral) doses of methylphenidate plus fluoxetine can produce complex behavioral changes in a variety of behavioral tasks. The mechanisms underlying this complexity are not understood. It is likely that variables such as drug dose, route of drug administration, treatment duration, and developmental stages during treatment play a role.

5.2. Cocaine-induced behavior after methylphenidate plus fluoxetine pretreatment

Our above molecular studies demonstrate that exposure to methylphenidate plus fluoxetine, with both high-dose and oral treatment regimens, can produce changes in gene regulation similar to changes induced by illicit psychostimulants such as cocaine, which are considered part of the cellular basis of addiction (see Steiner and Van Waes, 2013). Therefore, we determined whether and how these treatments would impact subsequent behavioral responses to cocaine, that is, locomotion/stereotypies in the open field and especially the acquisition of cocaine self-administration.

5.2.1. Locomotion and stereotypies

In an early study (Beverley et al., 2014), adolescent rats were treated daily with methylphenidate, fluoxetine or methylphenidate plus fluoxetine (5 mg/kg each, i.p.) for 6 days. Fourteen days after this pretreatment, they received a cocaine challenge injection (25 mg/kg) and were tested for 40 min in an open-field test (Beverley et al., 2014). Our results showed that the rats pretreated with methylphenidate plus fluoxetine, but not with either drug alone, displayed increased levels of cocaine-induced stereotypies (MP+FLX/C group, Fig. 5A) (Beverley et al., 2014). This effect was maximal in the first part of the test session; that is, these rats showed an accelerated increase in stereotypy levels at the beginning of the testing period (Beverley et al., 2014).

However, we also noted considerable interindividual differences in the stereotypy counts in the MP+FLX/C group (Fig. 5A). In a subsequent study (Lamoureux et al., 2023), we therefore investigated the development of stereotypies, assessing individual differences during a 6-day repeated treatment with methylphenidate or methylphenidate plus fluoxetine (5 mg/kg each, i.p.) and compared these changes with cocaine-induced open-field behavior (ambulation, stereotypies) 14 days later (Lamoureux et al., 2023).

Our results demonstrate that the group that received methylphenidate plus fluoxetine during the pretreatment, but not the other groups, could be subdivided into two subgroups based on their development of stereotypies (results not shown) (Lamoureux et al., 2023). One subgroup, approximately half of the methylphenidate plus fluoxetine-treated rats (termed “MP+FLX/high reactivity” group), displayed maximally elevated ambulation counts on treatment days 1-2 and then increasingly high levels of focal stereotypies from day 3 onwards. These stereotypies were so intense that during the period of peak stereotypies, ambulation was suppressed (Lamoureux et al., 2023). The other subgroup (“MP+FLX/low reactivity” group) expressed high levels of ambulatory activity from day 2 onwards and some stereotypies only towards the end of the 6-day treatment (Lamoureux et al., 2023). During the cocaine challenge test 14 days later, the cocaine-induced stereotypy counts were positively correlated with the counts during the repeated methylphenidate plus fluoxetine pretreatment (Lamoureux et al., 2023). That is, the “MP+FLX/high reactivity” group, but not the “MP+FLX/low reactivity” group, displayed high levels of cocaine-induced stereotypies.

These findings indicate that there may be subgroups responding differently to repeated methylphenidate plus fluoxetine treatment (and subsequent cocaine exposure), one that preferentially develops high levels of stereotypies and one that predominantly expresses increased ambulation (Lamoureux et al., 2023).

In a follow-up study, we investigated whether pretreatment with these doses of methylphenidate and/or fluoxetine would affect the subsequent acquisition of cocaine self-administration, and whether there was a relationship between cocaine intake and the observed differential development of stereotypies during the pretreatment.

5.2.2. Cocaine self-administration

Most drugs abused by humans, including cocaine and methylphenidate (Kollins et al., 2001), are also self-administered by animals. The drug self-administration paradigm is an animal model used to assess the abuse/addiction liability of drugs such as cocaine (O’Connor et al., 2011). In this paradigm, animals learn to perform an operant (e.g., press a lever or poke their nose into a hole) in order to obtain an intravenous infusion of cocaine. Pretreatment with cocaine or amphetamine typically facilitates subsequent psychostimulant seeking and self-administration (Vezina, 2004). This is also the case for repeated pretreatment with methylphenidate (Brandon et al., 2001; Schenk and Izenwasser, 2002; Crawford et al., 2011). These findings suggest an enhanced risk for psychostimulant abuse in humans after methylphenidate pretreatment (O’Connor et al., 2011).

In our follow-up study to determine a potential impact of pretreatment with methylphenidate plus fluoxetine on subsequent cocaine self-administration, rats received daily methylphenidate, fluoxetine or methylphenidate plus fluoxetine (5 mg/kg each, i.p.) for 8 days (Lamoureux et al., 2023). Again, the methylphenidate plus fluoxetine-treated animals, but not the other groups, could be subdivided into two subgroups (“MP+FLX/high reactivity/C” and “MP+FLX/low reactivity/C”, Fig. 5B) based on their development of ambulation/stereotypies during the pretreatment, using the previously established criteria (Lamoureux et al., 2023). Fourteen days later, the rats began their cocaine self-administration training (nose poking, 2-h cocaine access per day), which commenced for 10 days.

Results showed that all groups progressively increased their cocaine intake over the 10 days (Fig. 5B) (Lamoureux et al., 2023). When both methylphenidate plus fluoxetine-treated groups were pooled, they displayed a tendency for faster acquisition of cocaine self-administration. However, when the “MP+FLX/high reactivity/C” and “MP+FLX/low reactivity/C” groups were considered separately (Fig. 5B), it became clear that this effect was driven by the “MP+FLX/high reactivity/C” group; the “MP+FLX/low reactivity/C” group did not differ from controls (Fig. 5B) (Lamoureux et al., 2023). By the end of the 10-day training, the “MP+FLX/high reactivity/C” group self-administered a number of daily cocaine infusions approximately twice as high as the other groups. However, this intake was already maximal by training days 4-6 and then leveled off (Fig. 5B). Temporal analysis showed that this differential cocaine intake was seen when the total number of cocaine infusions over the entire 2-h sessions was considered, but this effect was most robust during the first 10 min of the daily sessions (Fig. 5B) (Lamoureux et al., 2023). In summary, pretreatment with methylphenidate plus fluoxetine produced, in a subpopulation, facilitated acquisition and higher levels of cocaine self-administration.

In the above two studies (Lamoureux et al., 2023), the behavioral effects of methylphenidate and fluoxetine were examined using intermittent high (i.p.) doses in young adults (Lamoureux et al., 2023). Would methylphenidate plus fluoxetine pretreatment with clinically relevant doses in adolescents, which are considered more susceptible to drug-induced neuronal changes, similarly facilitate subsequent cocaine self-administration? We thus next assessed whether the previous (Moon et al., 2021) oral drug treatment regimen of methylphenidate (30/60 mg/kg/day), fluoxetine (20 mg/kg/day) or methylphenidate plus fluoxetine (in drinking water, 8 h access per day) for 4 weeks, starting at PD28, would impact subsequent cocaine consumption (Senior et al., 2023). Cocaine self-administration training (lever pressing) began 1 week after the pretreatment and lasted for 2 weeks (Senior et al., 2023). In this study, potential subgroups regarding a differential development of stereotypies during the chronic oral treatment could not be investigated. The results are thus reported for all methylphenidate plus fluoxetine-treated rats pooled.

Our findings (not shown) demonstrate differential outcomes for the first and second week of cocaine self-administration (Senior et al., 2023). Thus, during the first week, rats pretreated with oral methylphenidate alone showed significantly greater numbers of active lever presses and cocaine infusions than the controls (Senior et al., 2023), consistent with earlier findings after i.p. pretreatment with methylphenidate (Brandon et al., 2001; Crawford et al., 2011). In contrast, during week two of cocaine self-administration, the rats pretreated with methylphenidate plus fluoxetine displayed significantly more active lever presses and cocaine consumption compared with controls (Senior et al., 2023).

These results thus show that methylphenidate plus fluoxetine pretreatment can also facilitate subsequent cocaine self-administration when the pretreatment uses clinically relevant (oral) drug doses and occurs during adolescence. Moreover, given that this facilitation was seen irrespective of potential differential development of stereotypies, these findings suggest that in younger animals and/or with longer pretreatment, even at lower doses, eventually most or all rats may show such facilitation of cocaine seeking and taking.

Further findings demonstrate that, in addition to such detrimental effects of chronic methylphenidate plus fluoxetine pretreatment, these drugs can also have acute effects on cocaine seeking (Lamoureux et al., 2024). Thus, results in a rat model for relapse show that an acute injection of methylphenidate in combination with fluoxetine (5 mg/kg each, i.p.), or alone, triggered reinstatement of cocaine seeking after extinction from cocaine self-administration, similar to a cocaine (15 mg/kg, i.p.) injection (Lamoureux et al., 2024). These findings suggest that acute exposure to a relatively high dose of methylphenidate, with or without fluoxetine, may increase the risk for relapse in former cocaine users.

In summary, our studies demonstrate that methylphenidate plus fluoxetine treatment produces a variety of behavioral alterations, including facilitation of subsequent cocaine self-administration and triggering of reinstatement of cocaine seeking in a relapse model in rats. These findings thus suggest that methylphenidate plus fluoxetine exposure may confer an enhanced risk for cocaine consumption or addiction and other behavioral changes.

6. Mechanisms for serotonin-dopamine interactions in striatal gene regulation

In order to mitigate the detrimental impact of fluoxetine on methylphenidate effects, it is important to understand the underlying mechanisms, that is, the serotonin receptor subtypes that mediate the fluoxetine-induced potentiation of gene regulation by methylphenidate and behavior. The mechanisms for such serotonin-dopamine interactions are likely complex (Muller and Huston, 2006; Cunningham and Anastasio, 2014; De Deurwaerdère and Di Giovanni, 2017), as there are at least 14 different serotonin receptor subtypes in various parts of the brain, including several with relatively high level of expression in the striatum [e.g., 5-HT1B, 5-HT2C and others (Barnes and Sharp, 1999; De Deurwaerdère and Di Giovanni, 2017)]. Indeed, early work determined that the 5-HT1B receptor mediates serotonin effects of cocaine on striatal gene regulation and behavior (Lucas et al., 1997; Castanon et al., 2000). Similarly, the 5-HT1B receptor was found to contribute to the potentiating effects of SSRIs on methylphenidate-induced behavior. A 5-HT1B receptor antagonist attenuated and a 5-HT1B receptor agonist mimicked the effects of fluoxetine on methylphenidate-induced locomotion (Borycz et al., 2008). We thus first assessed a potential role for 5-HT1B in the above described potentiation of methylphenidate-induced gene regulation by fluoxetine.

6.1. Role of 5-HT1B receptor

The 5-HT1B receptor is one of the most highly expressed serotonin receptor subtypes in striatal projection neurons (Barnes and Sharp, 1999; De Deurwaerdère and Di Giovanni, 2017). In contrast to other serotonin receptor subtypes, the 5-HT1B receptor in the striatum is dynamically regulated by various drugs, suggesting that this receptor may participate in adaptive responses induced by repeated drug treatments. For example, 5-HT1B expression is dramatically upregulated by repeated dopamine agonist (L-DOPA) treatment after dopamine depletion in an animal model of Parkinson’s disease (Zhang et al., 2008; Altwal et al., 2020; Padovan-Neto et al., 2020), which is likely produced by supersensitive D1 dopamine receptor signaling in the dopamine-depleted striatum (see Padovan-Neto et al., 2020). However, in the normal striatum, psychostimulants such as cocaine can also modify 5-HT1B expression (e.g., Hoplight et al., 2007; Neumaier et al., 2009). Moreover, as mentioned above, we previously found that repeated i.p. treatment with methylphenidate produced increased 5-HT1B (but not 5-HT2C) expression (Van Waes et al., 2015), and that this effect was considerably potentiated by co-administration of fluoxetine with methylphenidate (Fig. 6A). These findings show an association between the 5-HT1B receptor and methylphenidate plus fluoxetine-induced neuronal effects.

Fig. 6 — Role of 5-HT1B serotonin receptor in regulation of methylphenidate-induced gene expression in the striatum. (A) Upregulation of 5-HT1B receptor expression in the striatum by repeated methylphenidate plus fluoxetine treatment (Van Waes et al., 2015). Mean density values (mean±SEM, expressed in percentage of MP group) (left) for 5-HT1B receptor expression in the middle striatum are given for rats that received 5 daily injections of vehicle (V), fluoxetine (5 mg/kg, i.p.; FLX), methylphenidate (5 mg/kg, i.p.; MP), or methylphenidate+fluoxetine (MP+FLX). Also shown (right) are maps depicting the regional distribution of the increases in 5-HT1B expression (i.e., differences vs. V group) in the 23 striatal sectors for the FLX, MP and MP+FLX groups. Potentiation (POT) denotes the difference between MP and MP+FLX groups. The data are expressed relative to the maximal increase observed (% of max.). Sectors with a significant difference (P<0.05) are coded as indicated. Sectors without a significant difference are in white. (B) Differential effects of acute 5-HT1B receptor stimulation on methylphenidate-induced IEG expression in the striatum (Alter et al., 2017). Illustrations of film autoradiograms (left) depict zif268 (top), c-fos (middle) and homer1a expression (bottom) in coronal sections from the middle striatum in rats that received an injection of vehicle (V) or the 5-HT1B receptor agonist CP94253 (3 or 10 mg/kg, i.p.; CP3 or CP10), followed 15 min later by an injection of vehicle (V), methylphenidate (5 mg/kg, i.p.; MP), or methylphenidate+fluoxetine (5 mg/kg each, i.p.; MP+FLX) (groups V, CP10, MP, MP+CP3, MP+CP10 or MP+FLX). Mean density values (mean±SEM, expressed in percentage of MP group) (right) for zif268, c-fos and homer1a expression in the middle striatum are also presented for these groups. The 5-HT1B receptor agonist CP94253 potentiated methylphenidate-induced expression of zif268 and c-fos in a dose-dependent manner (MP+CP10 vs. MP groups). However, this 5-HT1B receptor stimulation did not alter homer1a expression induced by methylphenidate. This is in marked contrast to fluoxetine, which potentiates methylphenidate-induced expression of homer1a as well (MP+FLX vs. MP groups). *P<0.05, **P<0.01, ***P<0.001, vs. MP or as indicated.

We thus assessed whether acute stimulation of the 5-HT1B receptor by the selective 5-HT1B receptor agonist CP94253 modified IEG induction by methylphenidate (Alter et al., 2017). Our results demonstrate that CP94253 (3, 10 mg/kg, i.p.) produced dose-dependent potentiation of acute methylphenidate (5 mg/kg)-induced expression of zif268 and c-fos (Fig. 6B) (Alter et al., 2017). This potentiation was widespread in the striatum and was maximal in lateral (sensorimotor) sectors [which show the highest levels of 5-HT1B mRNA (Van Waes et al., 2015)], thus mimicking the effects of fluoxetine (Alter et al., 2017). However, surprisingly, in marked contrast to fluoxetine, this 5-HT1B agonist did not influence methylphenidate-induced expression of homer1a (Fig. 6B, bottom) (Alter et al., 2017).

These findings highlight the complexities of (systemic) serotonin agonist-induced gene regulation in the striatum. For example, CP94253 given alone also produced some induction of IEGs (including homer1a) in the rostral dorsal striatum (not shown) (Alter et al., 2017), which likely reflected increased cortical (or other) inputs as a consequence of 5-HT1B receptor stimulation outside of the striatum (see Alter et al., 2017, for discussion). However, in the middle and caudal striatum, the CP94253-induced potentiation of zif268 and c-fos induction by methylphenidate was positively correlated with the local levels of 5-HT1B mRNA (Alter et al., 2017), suggesting that 5-HT1B receptors expressed by striatal neurons were involved (see Section 7, for potential cellular mechanisms).

Most importantly, the lack of an effect of the 5-HT1B receptor agonist (in contrast to fluoxetine) on homer1a expression induced by methylphenidate indicates that 5-HT1B receptor stimulation alone was insufficient to mimic all fluoxetine effects. Therefore, additional serotonin receptor subtypes must participate in the full impact of fluoxetine on methylphenidate-induced gene regulation in the striatum (see Alter et al., 2017, for discussion). In studies reviewed in the following section, we assessed a potential role for another serotonin receptor subtype, the 5-HT1A receptor.

6.2. Role of 5-HT1A receptor

The 5-HT1A receptor is the main serotonin autoreceptor located in the somatodendritic region of serotonin neurons in the raphe nuclei (Barnes and Sharp, 1999; De Deurwaerdère and Di Giovanni, 2017). Stimulation of this inhibitory receptor attenuates activity in serotonin neurons and reduces serotonin release (De Deurwaerdère and Di Giovanni, 2017). 5-HT1A heteroreceptors are expressed, for example, in the cortex (De Deurwaerdère and Di Giovanni, 2017).

6.2.1. Effects of 5-HT1A receptor agonist vilazodone on methylphenidate-induced gene regulation

The 5-HT1A receptor has emerged as a potential target for alleviating excessive dopamine input to the striatum and resulting motor complications in Parkinson’s disease (Eskow et al., 2007; Eskow et al., 2009; Lindgren et al., 2010; Iderberg et al., 2015). In late-stage Parkinson’s disease, when most dopamine terminals have degenerated, dopamine replacement therapy with the dopamine precursor L-DOPA works, at least in part, via uptake of L-DOPA into serotonin terminals, followed by conversion to dopamine and release from these terminals (Carta et al., 2007; Carta and Tronci, 2014). As this release is unregulated by dopamine autoreceptors (Sellnow et al., 2019), extracellular dopamine levels typically fluctuate and can be massive and consequently drive various neuronal changes, including enhanced gene regulation (Cenci and Konradi, 2010; Cenci, 2017), in striatal output pathways, resulting in L-DOPA-induced dyskinesia (Cenci and Konradi, 2010; Carta and Tronci, 2014; Cenci, 2017; Carta and Björklund, 2018; Lanza and Bishop, 2018). A wealth of studies have attempted to attenuate this aberrant dopamine outflow from serotonin terminals by modifying activity in serotonin neurons using SSRIs and serotonin receptor agonists, with variable success because these drugs often also attenuated the anti-Parkinsonian (pro-motor) effects of L-DOPA (see Lanza and Bishop, 2018; Cenci et al., 2022; Alsalmi et al., 2024; Zimmer and Newman-Tancredi, 2025, for reviews).

This work recently revealed the usefulness of a novel, atypical SSRI, vilazodone, which, in addition to blocking serotonin reuptake, also acts as a 5-HT1A partial agonist (Hughes et al., 2005; Owen, 2011; Cruz, 2012). Vilazodone was FDA-approved as an SSRI in 2011 (Sahli et al., 2016). In animal models of Parkinson’s disease, vilazodone was found to inhibit L-DOPA-induced dyskinesia, while maintaining the anti-Parkinsonian effects of L-DOPA (Meadows et al., 2018; Altwal et al., 2020; Altwal et al., 2021; Smith et al., 2022). It is thought that this partial agonist, in contrast to full agonists, only dampens activity in serotonin neurons, thus allowing some L-DOPA-derived dopamine to be released. In the striatum, vilazodone suppressed L-DOPA-induced aberrant neuronal activity (Altwal et al., 2021) and attenuated L-DOPA-induced gene regulation (Meadows et al., 2018; Altwal et al., 2020), consistent with such a dampening effect on serotonin neuron activity (Meadows et al., 2018). These vilazodone effects were reversed by co-administration of a 5-HT1A receptor antagonist, WAY-100635, thus demonstrating an inhibitory role for 5-HT1A receptors (Meadows et al., 2018; Altwal et al., 2021).

We tested the notion that 5-HT1A receptor stimulation by vilazodone could also be useful to temper SSRI effects on methylphenidate-induced gene regulation, and that vilazodone thus may be a better adjunct SSRI for combination treatment with methylphenidate than fluoxetine. In a first study (Hrabak et al., 2024), we compared the effects of acute treatment with vilazodone (10-20 mg/kg, i.p.) with those of fluoxetine (5 mg/kg, i.p.) on striatal gene regulation (zif268, substance P, enkephalin) induced by methylphenidate (5 mg/kg, i.p.). We further assessed the impact of blocking 5-HT1A receptors by the selective 5-HT1A receptor antagonist WAY-100635 (0.5 mg/kg, i.p.) on this gene regulation.

Our results show that, in contrast to fluoxetine, vilazodone had minimal or no potentiating effects on methylphenidate-induced zif268 expression (MP+VIL vs. MP+FLX groups, Fig. 7A, top) or substance P and enkephalin expression (not shown) in the striatum (Hrabak et al., 2024), in agreement with a dampening effect of vilazodone on serotonin neuron activity. However, when 5-HT1A receptors were blocked by concurrent administration of the 5-HT1A antagonist WAY-100635 together with vilazodone and methylphenidate, a potentiating effect of vilazodone on methylphenidate-induced striatal gene regulation was unmasked (MP+VIL+WAY vs. MP+VIL groups, Fig. 7A, bottom) (Hrabak et al., 2024). That is, with 5-HT1A receptors blocked, vilazodone acted like the prototypical SSRI fluoxetine and potentiated methylphenidate-induced gene regulation. These results thus demonstrate an inhibitory effect of 5-HT1A receptor activation on such gene regulation. These findings are the first to indicate a more benign molecular profile for vilazodone, compared with fluoxetine, regarding such abuse/addiction-associated gene regulation.

Fig. 7 — Role of 5-HT1A receptor in regulation of methylphenidate-induced gene expression in the striatum. (A) Effects of acute administration of the SSRI/5-HT1A receptor partial agonist vilazodone, without or with concurrent blockade of 5-HT1A receptors by the selective 5-HT1A antagonist WAY-100635, on methylphenidate-induced IEG expression in the striatum (Hrabak et al., 2024). Illustrations of film autoradiograms (left) depict zif268 expression in the mid-level striatum in rats that received (from upper left) vehicle (V), methylphenidate (5 mg/kg, i.p.; MP), methylphenidate+fluoxetine (5 mg/kg, i.p.; MP+FLX), vilazodone (10 mg/kg, i.p.; VIL), methylphenidate+vilazodone (MP+VIL), WAY-100635 (0.5 mg/kg, i.p.; WAY), methylphenidate+WAY-100635 (MP+WAY), or methylphenidate+vilazodone+WAY-100635 (MP+VIL+WAY). Mean density values (mean±SEM, expressed in percentage of MP group) (right) for zif268 expression in the middle striatum are also presented for these groups. The 5-HT1A receptor antagonist WAY-100635 unmasked a potentiating effect for vilazodone on methylphenidate-induced zif268 expression (MP+VIL+WAY vs. MP+VIL groups), similar to the potentiating effect of fluoxetine (MP+FLX vs. MP groups). (B) Effects of chronic treatment with the SSRI/5-HT1A receptor partial agonist vilazodone vs. fluoxetine on methylphenidate-induced dynorphin expression in the striatum (Hrabak et al., 2025). Illustrations of film autoradiograms (left) depict dynorphin expression in the mid-level striatum in rats that had access to regular drinking water (8 h/day; water) or water+vilazodone (10 mg/kg, i.p., twice daily; VIL), methylphenidate (30/60 mg/kg/day, oral; MP) in drinking water, methylphenidate+fluoxetine (5 mg/kg, i.p., twice daily; MP+FLX) or methylphenidate+vilazodone (MP+VIL) for 4 weeks. Mean density values (mean±SEM, expressed in percentage of MP group) (right) for dynorphin expression in the middle striatum are also shown for these groups. In contrast to fluoxetine, vilazodone had diminished or no potentiating effects on methylphenidate-induced dynorphin expression in the striatum. *P<0.05, **P<0.01, ***P<0.001, vs. MP or as indicated.

The next study investigated how chronic vilazodone treatment in adolescents affected gene regulation in the striatum (Hrabak et al., 2025). We compared the effects of chronic treatment (4 weeks) with vilazodone (10 mg/kg, i.p.; twice daily) with those of fluoxetine (5 mg/kg, i.p.; twice daily) on striatal dynorphin expression induced by oral methylphenidate treatment (30/60 mg/kg/day in drinking water, 8 h access daily). Our results demonstrate that, in contrast to fluoxetine, vilazodone had reduced or no potentiating effects on methylphenidate-induced dynorphin expression (MP+VIL vs. MP+FLX groups, Fig. 7B) (Hrabak et al., 2025). This diminished impact on gene regulation was seen throughout the striatum, including the nucleus accumbens (Hrabak et al., 2025), where increased dynorphin expression has previously been associated with various aspects of addiction (see Section 7, below). Importantly, these findings thus confirm reduced gene regulation effects for vilazodone also for a chronic treatment.

In conclusion, in as far as such striatal gene regulation is associated with a risk for psychostimulant addiction, our findings thus indicate that vilazodone may serve as a better adjunct SSRI for methylphenidate treatment, with a lower risk for such gene regulation compared with fluoxetine. Moreover, our results identify the 5-HT1A receptor as a potential pharmaceutical target to mitigate such an abuse/addiction liability risk.

6.2.2. Effects of repeated vilazodone treatment on subsequent abuse/addiction-related behavior

In a further study, we assessed vilazodone effects on abuse/addiction-related behavior, that is, cocaine-induced place preference conditioning in the CPP paradigm after vilazodone pretreatment. As discussed in the Introduction, the CPP paradigm is used to determine the influence of drug (or other) treatments on reinforcing effects of cocaine. Adolescent mice were pretreated with methylphenidate (5 mg/kg, i.p.), fluoxetine (5 mg/kg, i.p.), vilazodone (1 mg/kg, i.p.) or a combination, daily for 12 days (Bolaños-Guzmán et al., in preparation). The vilazodone dose of 1 mg/kg was chosen because this dose produced maximal antidepressant-like effects in the forced-swim test in adolescent mice (Bolaños-Guzmán et al., in preparation). Starting 24 h after the pretreatment, animals were conditioned with cocaine (5 mg/kg, i.p.) or saline on 4 consecutive days in the CPP paradigm (Cardona-Acosta et al., 2023).

As can be seen in Figure 8, animals pretreated with vehicle (V group) did not develop place preference conditioning with this low dose of cocaine (5 mg/kg). However, groups pretreated with methylphenidate alone (MP), fluoxetine alone (FLX) or methylphenidate plus fluoxetine (MP+FLX) displayed significant place preference conditioning, consistent with earlier findings in rats (Warren et al., 2011). [As seen before (Warren et al., 2011), chronic pretreatment with fluoxetine alone also facilitated cocaine place preference conditioning (Fig. 8). In our previous gene regulation studies, the chronic (oral) fluoxetine pretreatment produced a decrease in substance P expression (D1-MSNs) in several striatal sectors. This effect was most robust in the nucleus accumbens (Moon et al., 2021) (see Section 4, above), which is thought to mediate reinforcing effects in the CPP paradigm. Future studies will have to determine whether there is a relationship between changes in substance P signaling in the nucleus accumbens (or other neuronal changes) and altered place preference conditioning after repeated fluoxetine treatment.]

In marked contrast to the effects of fluoxetine, groups pretreated with vilazodone alone (VIL) or methylphenidate plus vilazodone (MP+VIL) (Fig. 8) did not develop cocaine place preference conditioning (Bolaños-Guzmán et al., in preparation). In fact, vilazodone seemed to protect from the facilitating methylphenidate effects on cocaine conditioning (MP+VIL vs. MP). Thus, in contrast to fluoxetine, vilazodone pretreatment did not facilitate reinforcing effects of cocaine in this test. Future studies will have to determine the impact of vilazodone on subsequent cocaine self-administration or relapse to cocaine seeking.

In conclusion, these findings support a more benign neurobehavioral profile regarding abuse/addiction-associated processes for vilazodone compared with fluoxetine.

7. Functional considerations

The following sections address potential anatomical mechanisms by which serotonin receptors may modify methylphenidate-induced gene regulation in the striatum and behavior. Moreover, the affected striatal functional domains and their role in addiction are discussed, as well as the potential impact of altered dynorphin signaling, as an example for how altered gene regulation after these treatments could affect behavior.

7.1. Potentially involved anatomical circuits

The wide distribution of the many serotonin receptors in the brain (Barnes and Sharp, 1999), together with the fact that our drugs were administered systemically, precludes conclusions regarding the exact anatomical mechanisms that mediate the SSRI potentiation of psychostimulant effects discussed in this review. However, several studies using local neuronal manipulations, summarized below, point to potential contributing mechanisms within the basal ganglia. Nevertheless, it is likely that indirect effects, such as altered striatal inputs (Steiner, 2017) modified by serotonin receptors expressed outside of the basal ganglia (e.g., in the cortex), interact with intrinsic mechanisms/local serotonin receptors to determine the impact of serotonin on striatal gene regulation induced by dopamine/psychostimulants. Figure 9 presents a schematic representation of relevant basal ganglia circuits and focuses on serotonin receptors within these circuits that have been proposed as potentially underlying the discussed gene regulation effects.

Fig. 9 — Proposed mechanisms by which serotonin (5-HT) receptors may mediate SSRI potentiation of methylphenidate-induced gene regulation in striatal projection neurons (D1-MSNs). Methylphenidate (MP) is a dopamine (DA) reuptake blocker and thus indirectly increases stimulation of dopamine receptors, which is facilitatory or inhibitory on gene expression in D1-MSNs or D2-MSNs, respectively, based on the G-proteins these receptors are coupled to (see text). There are several mechanisms by which serotonin [i.e., SSRIs such as fluoxetine (FLX) or vilazodone (VIL)] may modify dopamine input (i.e., MP)-induced gene regulation in MSNs. Three mechanisms are discussed here (see text, for details and references): (1) Inhibition of GABA release from D1-MSNs by inhibitory 5-HT1B receptors (stimulated by increased local serotonin tone due to SSRI-induced serotonin reuptake inhibition) located on terminals of D1-MSNs in the substantia nigra. This mechanism would disinhibit dopamine input to the striatum and presumably potentiate methylphenidate (i.e., dopamine)-induced gene regulation in D1-MSNs. (2) Inhibition of GABA release from striatal axon collaterals of MSNs by inhibitory 5-HT1B receptors located on terminals of collaterals from D2-MSNs (or D1-MSNs). This mechanism would disinhibit MSNs directly and presumably potentiate gene regulation induced by other inputs in these neurons (e.g., dopamine). (3) Inhibition of serotonin release from serotonin neurons by inhibitory 5-HT1A autoreceptors presumably located in the somatodendritic region in the raphe nuclei. This mechanism would reduce serotonin tone at other serotonin receptors (e.g., 5-HT1B) and thereby disinhibit GABA release (among other effects), thus reducing dopamine input to the striatum (via mechanism 1) and/or activity in MSNs (via mechanism 2). Either would be expected to result in attenuated SSRI-induced potentiation of gene regulation in D1-MSNs. These 5-HT receptors may thus serve as pharmaceutical targets to mitigate a potentially increased abuse/addiction liability for methylphenidate in combination treatments with SSRIs. Abbreviations: SNc, substantia nigra pars compacta; GLU, glutamate.

Changes in gene regulation in the striatum determined by in situ hybridization area measures on film autoradiograms, as presented here, reflect changes in projection neurons (Fig. 9). Striatal projection neurons, the so-called “medium spiny neurons” (MSNs) [i.e., medium-sized (~15 μm) neurons whose dendrites are densely laden with spines that receive the bulk of striatal inputs], make up approximately 95% of striatal neurons (Kemp and Powell, 1971; Gerfen and Bolam, 2017). The remaining 5% consist of a variety of interneuron types (Gerfen and Bolam, 2017). Because of their low numbers, these interneurons do not provide enough of a mRNA signal to affect our area measures, and single cell analysis would have to be performed to determine potential changes in gene regulation in these neurons. Relatively little is known on drug-induced changes in gene expression in interneurons (Steiner, 2017).

As mentioned earlier, the striatal projection neurons can be subdivided into two types, which are intermingled and approximately equal in number and give rise to the two canonical striatal output pathways (Fig. 9) (Gerfen and Bolam, 2017). One type, the direct pathway neurons, also called striatonigral neurons, projects directly to the basal ganglia output nuclei (internal pallidum, substantia nigra pars reticulata). The other type, striatopallidal neurons, forms the initial segment of the indirect pathway, which projects to the output nuclei via external pallidum and subthalamic nucleus. Both types of projection neurons use GABA as their main neurotransmitter (and are thus inhibitory), but importantly, they differ in a number of receptors and neuropeptides they express (Gerfen and Bolam, 2017): as mentioned above, simplified, direct pathway neurons predominantly express D1 receptors (and are thus often called D1-MSNs) and the neuropeptides substance P and dynorphin, whereas indirect pathway neurons contain mostly D2 receptors (D2-MSNs) and enkephalin (Steiner and Gerfen, 1998) (Fig. 9). [Note, the organization of the output pathways from ventral striatal regions is more complex, with in part different receptor distributions and projection targets (Steiner, 2017).]

The differential dopamine receptor distribution between D1-MSNs and D2-MSNs (Fig. 9) is responsible for the differential impact of dopamine on these neurons: stimulation of the Gα_s- and Gα_olf-coupled D1 receptors facilitates activity in D1-MSNs, whereas stimulation of the Gα_i/o-coupled D2 receptors inhibits activity in D2-MSNs (Gerfen and Surmeier, 2011). Overall, these pathways have opposite effects on behavior: according to the canonical basal ganglia model, activity in D1-MSNs facilitates motor output, while activity in D2-MSNs inhibits motor output (Gerfen and Surmeier, 2011), including psychostimulant-induced behavior (see Lobo and Nestler, 2011). [Note, recent studies show that the MSNs that reside in the striatal patch/striosome compartment and target dopamine neurons have reversed effects on behavior (Cai et al., 2024; Lazaridis et al., 2024; Okunomiya et al., 2025)].

Moreover, this differential dopamine receptor distribution is also responsible for differential gene regulation by psychostimulants/dopamine agonists in these neurons (Gerfen et al., 1991; see Steiner, 2017, for review). Consistent with their associated G-proteins and second messenger cascades (Warren et al., 2017), stimulation of D1 receptors increases gene expression in D1-MSNs, while stimulation of D2 receptors inhibits gene expression in D2-MSNs (that is, it is blockade of inhibitory D2 receptors or loss of dopamine input that produce pronounced increases in gene expression in D2-MSNs, presumably due to disinhibition of glutamate inputs) (see Steiner, 2017, for discussion). Therefore, psychostimulants, including methylphenidate, produce increased gene expression (e.g., substance P, dynorphin, IEGs) via stimulation of striatal D1 receptors (Yano et al., 2006) predominantly in D1-MSNs (Steiner, 2017). [It should be noted that there are also long-loop mechanisms involving increased glutamate input from the cortex (and thalamus) by which psychostimulants and dopamine agonists (Steiner and Kitai, 2000) can indirectly affect striatal gene regulation (Steiner, 2017). These probably underlie the “paradoxical” increases in enkephalin expression in D2-MSNs, as seen in our present and other studies (see Steiner, 2017, for discussion). These indirect mechanisms are likely complex and are not further discussed here.]

The most parsimonious mechanisms by which serotonin activity (SSRIs) can potentiate dopamine (methylphenidate)-induced gene regulation in the striatum involve serotonin receptors expressed by striatal neurons (or their afferents). Among the several serotonin receptor subtypes expressed by striatal projection neurons (Barnes and Sharp, 1999; De Deurwaerdère and Di Giovanni, 2017), the 5-HT1B receptor is relatively highly expressed in both D1-MSNs and D2-MSNs (Sari, 2004; Heiman et al., 2014). This receptor is predominantly located presynaptically on neuronal terminals and acts to inhibit neurotransmitter release (Boschert et al., 1994; Sari, 2004; De Deurwaerdère and Di Giovanni, 2017), that is, inhibition of GABA release in the case of striatal projection neurons (Sari, 2004).

As discussed above, work by Hen and colleagues (Lucas et al., 1997; Castanon et al., 2000) first identified the involvement of the 5-HT1B receptor in cocaine-induced striatal gene regulation. In those studies, antagonism or genetic deletion of 5-HT1B receptors reduced IEG induction by cocaine in the striatum (Lucas et al., 1997; Castanon et al., 2000). Consistent with these findings, our results and those of others, summarized above (Section 6.1), show that the 5-HT1B receptor also contributes to the potentiating effects of serotonin (fluoxetine) on methylphenidate-induced behavior (Borycz et al., 2008) and gene expression in the striatum (Van Waes et al., 2015; Alter et al., 2017). Given that the regional distribution of this potentiation of striatal gene regulation roughly matches the distribution of 5-HT1B mRNA in the striatum (highest levels laterally; Van Waes et al., 2015), 5-HT1B receptors expressed by striatal projection neurons are likely involved.

There are several potential mechanisms for such local serotonin receptor actions. (1) One potential mechanism involving 5-HT1B receptors, as previously proposed by Hen and colleagues (Castanon et al., 2000), is thought to be disinhibition of dopamine input to the striatum, as a consequence of serotonin action at 5-HT1B receptors in the substantia nigra (Fig. 9, mechanism 1). In this scenario, the relevant 5-HT1B receptors are expressed by D1-MSNs that target dopamine neurons (Gerfen, 1985; Fujiyama et al., 2011; Crittenden et al., 2016) and are situated on their terminals in the substantia nigra to inhibit GABA release from these terminals (Johnson et al., 1992; Sari, 2004; Ding et al., 2015; see Castanon et al., 2000, for discussion). Reduced GABA release onto dopamine neurons would be expected to increase (disinhibit) dopamine input to striatal neurons (Cai et al., 2024; Lazaridis et al., 2024; Okunomiya et al., 2025). Such enhanced dopamine input would be consistent with the increased dopamine-mediated gene regulation after methylphenidate plus SSRI co-treatment found in our studies.

However, there are additional potential mechanisms involving 5-HT1B receptors. (2) For example, striatal projection neurons also feature extensive local axon collaterals in the striatum (Wilson and Groves, 1980) with 5-HT1B receptors on their terminals. These axon collaterals provide a mechanism for lateral inhibition between striatal projection neurons (Czubayko and Plenz, 2002; Tunstall et al., 2002; Plenz and Wickens, 2017). Indeed, recent studies demonstrated that GABA release from these collaterals, especially those of D2-MSNs synapsing onto D1-MSNs (Burke and Alvarez, 2022), is under inhibitory control of 5-HT1B receptors (Pommer et al., 2021; Burke and Alvarez, 2022) (Fig. 9, mechanism 2). Stimulation of these striatal 5-HT1B receptors would thus disinhibit D1-MSNs directly and presumably potentiate gene induction by other inputs in these neurons. Future studies will have to ascertain a potential contribution of either of these two 5-HT1B-mediated mechanisms to SSRI-induced potentiation of striatal gene regulation.

Furthermore, our findings show that other serotonin receptor subtypes can also modify this SSRI-induced potentiation of striatal gene regulation. (3) The 5-HT1A receptor has inhibitory effects on dopamine agonist-induced striatal gene regulation, especially on gene regulation in D1-MSNs (Altwal et al., 2020). As discussed in Section 6.2, this effect is likely mediated by the 5-HT1A autoreceptor located in the somatodendritic region of serotonin neurons (Eskow et al., 2009) (Fig. 9, mechanism 3), although a contribution of other 5-HT1A receptors can not be ruled out (e.g., Dupre et al., 2011; see Altwal et al., 2021, for discussion). Our findings (Altwal et al., 2020; Hrabak et al., 2024) and those of others (Meadows et al., 2018) demonstrate that vilazodone, an SSRI/5-HT1A partial agonist, reduced striatal gene regulation, presumably by lowering the activity of serotonin neurons (Sellnow et al., 2019) and thus reducing the serotonin tone on striatal (Iderberg et al., 2015) and nigral 5-HT receptors (see Section 6.2). Consistent with this notion, our results show that blocking 5-HT1A receptors disinhibited vilazodone-mediated potentiation of methylphenidate-induced striatal IEG expression (Hrabak et al., 2024). These findings thus identify 5-HT1A as an inhibitory serotonin receptor to limit SSRI effects on striatal gene expression.

However, given that this and other serotonin receptor subtypes are also expressed in other brain areas (De Deurwaerdère and Di Giovanni, 2017) [and thus may regulate striatal input (Dupre et al., 2011)] and other serotonin receptors are abundant in the striatum (De Deurwaerdère and Di Giovanni, 2017), there may well be additional mechanisms by which serotonin can modulate methylphenidate-induced gene regulation in the striatum.

Irrespective of the exact underlying anatomical mechanisms, our findings of a role for 5-HT1B (facilitatory) and 5-HT1A (inhibitory) in modifying methylphenidate-induced striatal gene regulation suggest that co-formulating a 5-HT1B receptor antagonist or a 5-HT1A receptor (partial) agonist together with methylphenidate may help lower methylphenidate’s potential for gene regulation and abuse/addiction liability.

7.2. Psychostimulant-induced gene regulation in the different functional domains of the striatum: Effects in limbic vs. associative vs. sensorimotor domains

We mapped gene regulation effects induced by methylphenidate plus SSRI treatments throughout the striatum in order to determine which functional domains are impacted. These domains range from the limbic domain (nucleus accumbens) that mediates motivational aspects of behavior (reward processes), to the associative domain (medial/central striatum) that mediates goal-directed behavior, to the sensorimotor domain (lateral striatum) that mediates habit formation and automatic responses (Graybiel, 1995; Packard and Knowlton, 2002; Yin and Knowlton, 2006). In our studies, overall, altered gene regulation after methylphenidate plus SSRI treatment was found in all functional domains, although the magnitude of these changes typically varied between domains. Importantly, the most pronounced gene regulation effects were almost always identified in the sensorimotor domain. Our further studies showed that these gene regulation effects were associated with facilitated cocaine self-administration (and other behavioral changes) after these methylphenidate plus SSRI treatments, suggesting an increased abuse/addiction risk.

This is supported by a host of previous findings that revealed an abnormal engagement of sensorimotor striatal circuits in processes of addiction in animal models. For example, findings in rodents showed that cocaine seeking is initially a goal-directed behavior that is dependent on the medial striatum and the nucleus accumbens, whereas with extended cocaine self-administration, cocaine seeking/taking becomes habitual, under the control of the lateral striatum (Olmstead et al., 2001; Vanderschuren and Everitt, 2005; Belin and Everitt, 2008; Zapata et al., 2010; Murray et al., 2012). The lateral striatum is also important for compulsive cocaine use (Jonkman et al., 2012) and for relapse to cocaine seeking following abstinence from chronic cocaine self-administration (Vanderschuren et al., 2005; Fuchs et al., 2006; See et al., 2007). Similarly, metabolic imaging studies in non-human primates revealed a progressive shift from limbic and associative to abnormal sensorimotor striatal activities during prolonged psychostimulant self-administration (Porrino et al., 2004; Porrino et al., 2007). The same shift from goal-directed to habitual drug-seeking modes, and their respective medial versus lateral striatal control, was also demonstrated for alcohol drinking in rats (Corbit et al., 2012).

These findings led to the proposal that the progression from casual drug-taking behavior to addiction is mediated by a shift in the neuronal systems that control drug taking, that is, a shift from limbic and associative systems to sensorimotor systems that underlie habitual and automatic/compulsive behavior (e.g., Everitt and Robbins, 2005; Belin et al., 2013; Everitt, 2014). These findings thus support our conclusion that altered gene regulation preferentially in the sensorimotor domain after chronic methylphenidate plus SSRI treatments may produce an increased addiction liability for methylphenidate, cocaine and other psychostimulants.

7.3. Psychostimulant-induced gene regulation in striatal neurons: Potential impact of altered dynorphin signaling

As mentioned earlier, psychostimulants, including methylphenidate (Adriani et al., 2006b), alter the expression of hundreds or more of genes in these striatal regions. We have focused on a few genes for their utility as markers, IEGs for ease of mapping of drug effects and neuropeptides as cell-type markers. However, it has been shown that the genes affected by psychostimulants range from those encoding transcription factors, to various signaling molecules, to structural proteins needed for drug-induced morphological remodeling of neurons (Robinson and Kolb, 1997; Jedynak et al., 2007). It is thus difficult to determine the exact behavioral consequences of such altered gene regulation for individual genes and more so for gene combinations. However, a few genes have been investigated intensively over the last three decades, and knowledge gained from these studies can offer some insights into possible behavioral consequences for such neuronal changes.

A good example is dynorphin, which was considerably affected in our studies. Indeed, increased expression of dynorphin (mRNA and peptide levels) in the striatum is one of the best-established molecular changes found after a variety of psychostimulant (and other) treatments (for reviews, see Steiner and Van Waes, 2013; Steiner, 2017), including cocaine self-administration in non-human primates (Fagergren et al., 2003). Notably, increased dynorphin expression has also been described in human cocaine addicts (Hurd and Herkenham, 1993; Frankel et al., 2008).

What are the functional consequences of increased dynorphin signaling in the striatum? As mentioned, dynorphin is released by D1-MSNs, both in the striatum from local axon collaterals and in the target areas from projection terminals of these neurons (Steiner and Gerfen, 1998). In both locales dynorphin seems to act, at least in part, as a negative feedback mechanism (Steiner and Gerfen, 1998) to inhibit dopamine (and glutamate) input (Steiner, 2017). Upregulated dynorphin expression after repeated pharmacological treatments is thus considered a compensatory mechanism by which dynorphin, via binding to inhibitory kappa opioid receptors, acts as a “brake” to moderate inputs and maintain systems homeostasis (Hyman and Nestler, 1996; Steiner, 2017).

It remains unclear how altered dynorphin levels after psychostimulant treatments impact function in the various regions of the striatum. Perhaps the best-established effects of altered dynorphin signaling are related to the nucleus accumbens (limbic domain). For example, increased dynorphin signaling in the nucleus accumbens after repeated psychostimulant exposure has been associated with somatic signs of withdrawal, such as anhedonia, dysphoria, anxiety and depression (Nestler and Carlezon, 2006; Shippenberg et al., 2007; Butelman et al., 2012). These effects are thought to promote maintenance of psychostimulant use or relapse during abstinence. Our findings that increased dynorphin expression in the nucleus accumbens (Moon et al., 2021; Hrabak et al., 2025) was associated with facilitated cocaine self-administration (Lamoureux et al., 2023; Senior et al., 2023) after chronic methylphenidate plus fluoxetine treatment support these earlier conclusions.

However, dynorphin in striatal projection neurons has likely other functions as well. For example, there is good evidence that the dynorphin/kappa receptor system also controls inputs to midbrain dopamine neurons that play a role in stress effects (resilience) and interactions between stress and drug addiction (e.g., Land et al., 2008; for reviews, see Bruchas et al., 2010; Van’t Veer and Carlezon, 2013).

Moreover, dynorphin also modulates activity in GABA neurons of basal ganglia output nuclei (substantia nigra pars reticulata; e.g., Thompson and Walker, 1990), which implies a broader impact on motor function. For example, in models of advanced Parkinson’s disease, L-DOPA treatment produces massive upregulation of dynorphin signaling in D1-MSNs of the sensorimotor striatum (e.g., Cenci et al., 1998; Andersson et al., 1999; Altwal et al., 2020; Padovan-Neto et al., 2020). This effect is thought to contribute to circuit dysfunction responsible for L-DOPA-induced dyskinesia (see Cenci, 2017, for discussion).

On the other hand, repeated psychostimulant treatments that produce increased dynorphin expression in the sensorimotor striatum typically also cause behavioral stereotypies (Steiner, 2017). The term behavioral or motor “stereotypies” refers to rhythmic repetition of certain behavioral elements over and over without apparent purpose, to the exclusion of other behaviors (DSMMD-5, 2013; McBride and Parker, 2015). Behavioral stereotypies are present in a range of neuropsychiatric disorders, including tic disorders, obsessive-compulsive disorder and others (DSMMD-5, 2013; McBride and Parker, 2015). Stereotypies may reflect deficient switching between motor programs (Redgrave and Gurney, 2006; McBride and Parker, 2015) and have long been associated with dysfunctional sensorimotor striatal circuits (Canales and Graybiel, 2000; Graybiel et al., 2000; see McBride and Parker, 2015; Steiner, 2017, for reviews). It is unclear whether psychostimulant-induced stereotypies are related to addiction processes (or reflect other behavioral dysfunction), or whether/how enhanced dynorphin signaling contributes to this abnormal behavior. However, it is noteworthy that a number of studies showed that stimulation of 5-HT1A receptors attenuates both stereotypic behavior (see Alvarez et al., 2022, for review), as well as methylphenidate plus SSRI-induced upregulation of striatal dynorphin expression (Hrabak et al., 2025), consistent with an attenuation of serotonin input to the striatum as proposed by our model (Figure 9) and possibly a reduced abuse/addiction risk.

Overall, these results show that, depending on which functional domains are affected, altered dynorphin signaling can have a wide range of behavioral consequences.

8. Enhanced Abuse/Addiction Liability?

As discussed, the observed gene regulation effects in the striatum induced by methylphenidate plus fluoxetine treatment mimic molecular effects of psychostimulants such as cocaine, which are considered part of the molecular basis of psychostimulant addiction (e.g., Berke and Hyman, 2000; Nestler, 2001, 2012). Methylphenidate alone can induce some of these molecular changes (Yano and Steiner, 2007; Steiner and Van Waes, 2013), but as reviewed here, the addition of SSRIs such as fluoxetine to methylphenidate typically potentiates such gene regulation and enhances behavioral changes (e.g., acquisition and reinstatement of cocaine self-administration) indicative of an abuse/addiction liability in animal models. Our findings thus suggest a potential for an enhanced psychostimulant abuse/addiction liability (O’Connor et al., 2011) for this combination treatment. If there is such a risk, it may be greater for methylphenidate misuse as a cognitive enhancer or recreational drug, which often involves higher doses and routes of administration (e.g., Kollins, 2008; Wilens et al., 2008; Hartmayer et al., 2023) that result in faster uptake and higher drug serum levels. Both of these are risk factors for addiction-related gene regulation and behavior (Samaha et al., 2004).

While it is established that methylphenidate alone is abused in humans (see Introduction), it is less clear whether/to what degree this psychostimulant is addictive. And although other substances are often used to enhance its effects, it is not known whether combining methylphenidate with an SSRI would reveal or increase an abuse/addiction liability for methylphenidate (or other psychostimulants such as cocaine).

Current clinical studies do not support an increased risk for addiction/substance use disorder after medical use of methylphenidate in ADHD treatment (oral administration). Thus, early studies in ADHD patients indicated that, with a possible exception of an increased risk for smoking (Lambert and Hartsough, 1998), the risk for substance use disorder was unchanged or even decreased short-term after treatment with psychostimulant medications (e.g., Barkley et al., 2003; Wilens et al., 2003; Chang et al., 2014). More recent long-term follow-up studies indicated that ADHD medications neither protect from nor increase the risk for substance use disorder (e.g., Biederman et al., 2008; Molina et al., 2013; Chang et al., 2019; Molina et al., 2023) (see also Volkow and Insel, 2003; Kollins, 2008; Berman et al., 2009; Shellenberg et al., 2020, for discussions). Assessing long-term effects is important, as preclinical studies demonstrated that behavioral (e.g., Warren et al., 2011) and molecular (e.g., Bolanos et al., 2003; Tropea et al., 2008) effects of psychotropic treatments are frequently more pronounced (or may only appear) at later stages of life.

To our knowledge, there are no clinical studies to date that assessed the risk for substance use disorder in healthy human subjects who were exposed to psychostimulants, either due to ADHD misdiagnosis or because of cognitive enhancer use (higher doses). We are also not aware of studies that evaluated a potential risk of methylphenidate plus SSRI co-exposure. However, notably, a recent study reported an increased risk for substance use associated with SSRI treatments in patients (Quinn et al., 2017). Thus, such a risk may be enhanced by combinations of methylphenidate with SSRIs.

As discussed above, preclinical research has addressed the question of a potentially altered abuse/addiction liability in animal models of addiction, with fairly unequivocal outcomes. For example, repeated methylphenidate pretreatment in juvenile rats was shown to have a facilitatory effect on subsequent alcohol drinking in adults (Gill et al., 2014). Also, a recent series of studies in an established rat model for ADHD (SHR strain) demonstrated enhanced cocaine self-administration in adults after methylphenidate treatment during adolescence (reviewed in Kantak and Dwoskin, 2016). Moreover, as mentioned before, several previous studies in “normal” rats showed that, similar to repeated pretreatment with other psychostimulants (Vezina, 2004), repeated pretreatment with methylphenidate alone (i.p.) can facilitate subsequent acquisition of cocaine seeking and taking in the cocaine self-administration model [pretreatment in peri/adolescents (Brandon et al., 2001; Crawford et al., 2011) or adults (Schenk and Izenwasser, 2002)] (but see Gill et al., 2012, for an extended release formulation). As described in Section 5, we also found facilitated cocaine self-administration after a 4-week chronic oral methylphenidate-only pretreatment in adolescents (Senior et al., 2023), but not after a short i.p. pretreatment in adults (Lamoureux et al., 2023) (however, besides the different pretreatment doses/durations and age at treatment, this comparison is also confounded by different cocaine doses during cocaine self-administration). Overall, these findings suggest that methylphenidate-only pretreatment can increase the abuse/addiction risk, as determined by the cocaine self-administration paradigm (O’Connor et al., 2011), at least under certain circumstances.

Less is known regarding the impact of methylphenidate plus fluoxetine pretreatments in the cocaine self-administration model. As far as we know, our three studies (Lamoureux et al., 2023; Senior et al., 2023; Lamoureux et al., 2024) are the first to determine the effects on cocaine seeking and taking in this model. As described in Section 5, our studies showed that methylphenidate plus fluoxetine pretreatment facilitated subsequent cocaine self-administration after a short i.p. pretreatment (in a subpopulation; Lamoureux et al., 2023) and a long oral pretreatment (Senior et al., 2023), and enhanced reinstatement after i.p. pretreatment (Lamoureux et al., 2024). These findings suggest a (further) increased abuse/addiction liability for cocaine after exposure to combinations of methylphenidate plus prototypical SSRIs.

Importantly, in contrast to combinations that included the prototypical SSRI fluoxetine, the combination of methylphenidate plus vilazodone, the novel SSRI with 5-HT1A agonist properties, did not produce potentiated addiction-associated gene regulation in the striatum (Hrabak et al., 2024; Hrabak et al., 2025; Section 6). The potential for vilazodone to enhance cocaine place preference conditioning was assessed in the CPP paradigm, a behavioral model often used to determine reinforcing effects of a drug and thus with a bearing on its abuse/addiction liability (Tzschentke, 2007). In contrast to fluoxetine, pretreatment with vilazodone did not enhance subsequent cocaine place preference conditioning, suggesting a lower (or no) impact of vilazodone, compared with fluoxetine, on the reinforcing properities of cocaine. Whether/how pretreatment with vilazodone affects subsequent cocaine self-administration remains to be determined. In summary, both our molecular and behavioral findings with vilazodone are consistent with a reduced or no facilitating effect of this SSRI/5-HT1A partial agonist on the dopamine transmission (see Section 7) and the resulting abuse/addiction liability of psychostimulants.

Finally, while the focus of this discussion has been on behavioral changes relevant for drug abuse/addiction, it should be noted that adverse effects of combined methylphenidate plus fluoxetine treatment may not be limited to drug abuse/addiction (Steiner et al., 2014). The study by Warren et al. (2011) showed that, in addition to the enhanced reinforcing effects of cocaine (see above), the methylphenidate plus fluoxetine-pretreated rats also displayed an enhanced sensitivity to natural reward (sucrose), a finding that was confirmed after oral pretreatment with methylphenidate plus fluoxetine (Thanos et al., 2023). Moreover, other findings indicative of deficits in mood-related behaviors and reactivity to stress were also obtained in both studies (Warren et al., 2011; Thanos et al., 2023).

Taken together, our findings in animal studies suggest a potentially increased abuse/addiction liability and possibly a risk for other behavioral dysfunction for such methylphenidate plus fluoxetine combination treatments. Clinical studies are needed to evaluate these potential risks.

9. Conclusions

Our studies demonstrate that prototypical SSRIs such as fluoxetine potentiate gene regulation induced by the medical psychostimulant methylphenidate in the striatum in rats. This altered gene regulation is wide-spread, affecting limbic, associative and sensorimotor domains, and preferentially occurs in neurons of the direct striatal output pathway (D1-MSNs). These molecular changes are associated with various behavioral dysregulations, including facilitated acquisition of cocaine self-administration. Together, these findings suggest that these methylphenidate plus SSRI combinations increase the risk for psychostimulant abuse/addiction after these treatments. Our further studies identified 5-HT receptor subtypes, 5-HT1A and 5-HT1B, that may be useful to attenuate these neuronal changes. Importantly, our findings also show that vilazodone, a novel SSRI/5-HT1A partial agonist, in contrast to the prototypical SSRI fluoxetine, does appear to have reduced or no effects on methylphenidate-induced gene regulation, suggesting that this SSRI may have less psychostimulant abuse/addiction-facilitating properties than fluoxetine. Vilazodone may thus serve as an improved adjunct SSRI for combinations with methylphenidate.

Highlights.

Serotonin receptors regulate dopamine input to striatum
Serotonin enhances dopamine effects in rat models of psychostimulant addiction
Methylphenidate (Ritalin) plus SSRI antidepressants facilitate cocaine self-administration
Methylphenidate plus fluoxetine exposure triggers relapse to cocaine seeking
SSRI antidepressants potentiate methylphenidate-induced gene regulation in striatum

Acknowledgments

This work was supported by the National Institutes of Health Grant DA046794. We would like to thank Prof. Tony West for many stimulating discussions (as well as good fishing) over the years.

Funding:

This work was supported by the National Institutes of Health Grant DA046794.

Footnotes

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PERMALINK

Serotonin-dopamine interactions in psychostimulant-induced gene regulation: SSRI antidepressants potentiate gene regulation by methylphenidate (Ritalin) in the striatum and enhance behavioral profile indicative of addiction liability in rodents

Heinz Steiner

Michael Hrabak

Carlos A Bolaños-Guzmán

Abstract

1. Introduction

2. Approach to measure gene expression

Fig. 1.

3. High-dose, intermittent (“abuse”) treatment: effects on gene regulation

3.1. Acute treatment

Fig. 2.

3.2. Repeated treatment

Fig. 3.

4. Chronic oral (“clinical”) treatment: effects on gene regulation

Fig. 4.

5. Behavioral changes after methylphenidate plus fluoxetine treatment

5.1. Methylphenidate plus fluoxetine-induced behavior

5.2. Cocaine-induced behavior after methylphenidate plus fluoxetine pretreatment

5.2.1. Locomotion and stereotypies

Fig. 5.

5.2.2. Cocaine self-administration

6. Mechanisms for serotonin-dopamine interactions in striatal gene regulation

6.1. Role of 5-HT1B receptor

Fig. 6.

6.2. Role of 5-HT1A receptor

6.2.1. Effects of 5-HT1A receptor agonist vilazodone on methylphenidate-induced gene regulation

Fig. 7.

6.2.2. Effects of repeated vilazodone treatment on subsequent abuse/addiction-related behavior

Fig. 8.

7. Functional considerations

7.1. Potentially involved anatomical circuits

Fig. 9.

7.2. Psychostimulant-induced gene regulation in the different functional domains of the striatum: Effects in limbic vs. associative vs. sensorimotor domains

7.3. Psychostimulant-induced gene regulation in striatal neurons: Potential impact of altered dynorphin signaling

8. Enhanced Abuse/Addiction Liability?

9. Conclusions

Highlights.

Acknowledgments

Funding:

Footnotes

References

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