Emerging roles of striatal dopamine D2 receptors in motivated behaviour: Implications for psychiatric disorders

Abstract

Impaired motivation has been a long recognized negative symptom of schizophrenia, as well as a common feature of non-psychotic psychiatric disorders, responsible for a significant share of functional burden, and with limited treatment options. The striatum and dopamine signalling system play a central role in extracting motivationally relevant information from the environment, selecting which behavioural direction the animal should follow, and the vigour with which to engage it. Much of this function relies on striatal projection neurons, known as medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2Rs), or D2-MSNs. However, determining the precise nature of D2-MSNs in regulating motivated behaviour in both healthy individuals and experimental manipulations of D2-MSN function has at times yielded a somewhat confusing picture since their activity has been linked to either enhancement or dampening of motivation in animal models. In this MiniReview, we describe the latest data from rodent studies that investigated how D2Rs exert their modulatory effect on motivated behaviour by regulating striatal indirect pathway neuronal activity. We will include a discussion about how functional selectivity of D2Rs towards G protein–dependent or β-arrestin–dependent signalling differentially affects motivated behaviour. Lastly, we will describe a recent preclinical attempt to improve motivation by exploiting serotonin receptor–mediated modulation of dopamine transmission in the striatum.

1 |. INTRODUCTION

The ability to generate and sustain effort to achieve distant goals, such as finding food or mates, building shelter, and escaping threats, is a common thread across animal species. In human beings, persistent efforts can range in timescale from seconds to years. Impaired motivation is a prominent feature of several psychiatric syndromes, including major depressive disorder (MDD) and schizophrenia, being responsible for a significant portion of the overall functional deficit experienced by patients.^1–4 In schizophrenia, motivational deficit is a stronger predictor of poor functional outcome than positive symptoms such as hallucinations and delusions because while the latter symptoms respond to antipsychotic medications, motivation deficit does not.^3,5 Although non-pharmacological strategies to treat cognitive deficits in schizophrenia, such as cognitive behavioural therapy (CBT) for executive functioning and cognitive remediation, have been shown to improve occupational function, specific treatment options for motivational deficits remain very limited.^6–9

The importance of dopamine and striatal dopamine D2 receptors (D2Rs) in schizophrenia was first recognized by the discovery that the clinical response to antipsychotic medication correlates with the degree of D2R antagonism.^10,11 Abnormal striatal dopamine signalling has also been implicated in the aetiology of schizophrenia by seminal human PET imaging studies that reproducibly showed higher occupancy and availability of D2Rs, as well as increased amphetamine-induced dopamine release, in the striatum of drug-free patients with schizophrenia compared to healthy individuals.^12–15 Specifically, increased dopamine release capacity in the associative region of the striatum positively correlates with hallucinations and delusions and with the efficacy of D2R receptor antagonists to treat those symptoms.^16–18 In contrast, the severity of negative symptoms including motivational deficit negatively correlates with DA in the ventral region of the striatum.¹⁹ This complex aetiology may explain why D2R antagonists effectively treat positive symptoms but not motivational deficits.^20,21 In fact, given acutely, these drugs decrease motivation in healthy individuals ^22,23 and in preclinical animal models.²⁴

Animal studies using advanced molecular and electrophysiological techniques are being used to functionally dissect the conserved neural pathways and receptors involved in regulating motivated behaviour. Dopamine D2 receptors (D2Rs) present on striatal indirect pathway neurons have received significant attention, and recent reports provide contradictory ideas about the nature of indirect pathway neurons in regulating motivated behaviour. In this MiniReview, we describe rodent models of D2 receptor overexpression and other pathway-specific manipulations, with a focus on their effects on motivation and what can be inferred from neurocircuitry analysis and attempt to reconcile the seemingly divergent data where possible. We also discuss novel indirect methods of regulating dopamine function as a promising avenue for developing pharmacological treatments for motivational deficits. This includes serotonin receptor–mediated regulation of dopamine release and D2R ligands with functional selectivity for recruitment of distinct downstream cellular signalling pathways.

1.1 |. Striatal circuitry of motivation

Motivation is defined as the process by which animals energize behaviour in the pursuit of a goal. Because striatal activity regulates the initiation, termination and selection of motor actions, as well as stimulus-reward processing, the striatum is critically involved in motivated behaviour. Striatal dysfunction is implicated not only in schizophrenia but also Huntington’s and Parkinson’s diseases, and substance use disorders. The striatum is the main input station of the basal ganglia for excitatory glutamatergic cortical afferents while receiving major neuromodulatory dopaminergic inputs from the midbrain’s substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). The majority (95%) of neurons in the striatum are GABAergic medium spiny neurons (MSNs) that are grouped into anatomically semi-segregated pathways with largely opposing effects on thalamo-cortical activity: direct pathway MSNs which predominantly express dopamine D1 receptors (D1R) and D2R-expressing “indirect” pathway MSNs.^25,26 Dopamine receptors are classified according to the primary G-protein type to which they are coupled. D1-like receptors (D1R, D5R) signal via Gα_s and Gα_olf and are thought to cause cellular depolarization. D2-like receptors (D2R, D3R, D4R) signal via Gα_i/o or via the G protein–independent β-arrestin pathway and regulate corticostriatal plasticity and synaptic transmission at axonal terminals.^27–34

In the dorsal striatum (dSTR), direct pathway MSNs project monosynaptically to inhibit the basal ganglia output nuclei, the internal segment of globus pallidus (GPi) and substantia nigra pars reticulata (SNr). In the classical model of basal ganglia circuitry, inhibition of GPi/SNr facilitates initiation of motor activity.²⁵ Conversely, indirect pathway neurons of the dorsal striatum project to the external segment of the globus pallidus (GPe), which in turn projects to the GPi/SNr and inhibits initiation of motor activity.²⁵ This is supported by artificial inhibition of direct and indirect pathway, where recent reports indicate that activation of direct pathway D1-MSNs facilitates positive reinforcement learning and sensitization and enhances locomotor activity. In contrast, activation of the indirect pathway promotes learning about negative/aversive stimuli and decreases locomotor activity.^35–38 However, this dichotomous view of striatal pathway effects on motor actions has been challenged by Ca²⁺ imaging and optogenetic studies in mice demonstrating that both pathways can contribute to the initiation, execution and termination of motor actions.^39–41

An analogous picture has been described in the ventral striatum, or nucleus accumbens (NAc), where indirect D2-MSNs predominantly project to the ventral pallidum (VP) and D1-MSNs synapse onto the midbrain.²⁵ Classically, D1-MSNs in NAc have been associated with positive reinforcement, while negative reinforcement and aversion require activation of D2-MSNs.^42–44 It is important to note that the anatomical segregation between D1R-expressing “direct” and D2R-expressing “indirect” MSNs is not absolute and D1-MSNs have been found to project to the indirect GPe.^37,45 This is especially true in the NAc, where the degree of D1-MSNs projecting to the pallidum is more pronounced relative to the dorsal striatum, prompting the suggestion of abolishing the use of “direct” and “indirect” pathway terminology in the NAc.⁴⁶ In a similar vein, the prevailing view that assigns distinct and opposing roles to D1 and D2 receptors on accumbal-related behaviours (eg stimulus-reward processing) has been challenged by optogenetic studies suggesting both types of receptors are activated during reward-based operant tasks.⁴⁷

D2Rs are also found in striatal cholinergic interneurons (CINs), where they regulate corticostriatal plasticity,⁴⁸ and on pre-synaptic dopaminergic terminals, where they regulate dopamine release.³³ The presence of D2Rs in non-MSN cell types complicates the interpretation of pharmacological effects on striatal function since at least three different cell populations can be simultaneously affected.^25,33 However, targeting specific neuronal populations by combining transgenic mouse lines with more recent technologies, such as optogenetics, chemogenetics or D2R up- or down-regulation, has allowed for a finer dissection of the individual circuit components and their contribution to motivated behaviour in rodents.

1.2 |. Developmental overexpression of D2Rs in striatum: Low motivation phenotype

To model the higher striatal D2R occupancy observed in patients with schizophrenia, Kellendonk, Simpson and colleagues developed a transgenic mouse (D2R-OE_dev mouse) that selectively overexpresses D2Rs in striatal MSNs throughout development by 15%, thus comparable to the elevation reported in patients. D2R-OE_dev mice display deficits in working memory, cognitive flexibility and motivation, mirroring some of the cognitive and negative symptoms of schizophrenia.^49–51 Expression of the transgenic D2Rs is driven by a tetracycline-responsive transcriptional activator and can therefore be switched off by providing the tetracycline analogue doxycycline in the diet. Switching off the transgene partially ameliorates some, but not all, of the cognitive deficits, suggesting a neurodevelopmental effect.^51,52 In contrast, motivational deficits are completely rescued by switching off the D2R transgene. Partial rescue of the cognitive deficits demonstrates the complex interactions between cognition and incentive motivation, where deficits in the latter can negatively affect the former. Conversely, some of the cognitive deficits in D2R-OE_dev mice can be partially rescued by behavioural and pharmacological interventions that increase motivation.^51–54 While shutting off D2R overexpression increases motivation, chronic D2 receptor antagonism with haloperidol does not.⁵⁵ However, systemic haloperidol treatment will block not only the additional receptors on MSNs, but also receptors on other neuron populations within or outside of the striatum.⁵⁵

To identify the molecular processes mediating motivation deficit in D2R-OE_dev mice, Simpson et al used an unbiased gene chip approach that revealed an up-regulation of serotonin 5-HT2C receptors in the striatum of D2R-OE_dev mice that was reversed after turning the D2R transgene off with doxycycline. Acute systemic treatment with a functionally selective 5-HT2C antagonist rescued motivation as measured by performance on a progressive ratio (PR) schedule of reward in which the number of responses required to earn a reward progressively increased during a test session. These results imply that 5-HT2C receptors might be a therapeutic target for motivational deficits in schizophrenia and other disorders where motivation is affected.⁵⁵

Further behavioural testing revealed that while D2R-OE_dev mice display normal hedonic reaction to reinforcers like sucrose and milk, they are less willing to work to obtain reinforcement.⁵⁶ In tasks designed to independently assess the impact of reward value or task effort on cost-benefit decisions, the motivational deficit of D2-OE_dev mice was associated with a negative shift in dopaminergic encoding of cost, but not reward value.⁵⁷ Collectively, these results demonstrate that increasing the expression of D2 receptors in the striatum of mice by a similar amount to that observed in human patients with schizophrenia is sufficient to recapitulate behavioural and cognitive deficits with striking similarity to patient symptoms. One important limitation of the D2R-OE_dev mouse is that in the 33% of MSNs that overexpress D2Rs, 40% of are indirect and 26% are direct MSNs,^58,59 making it difficult to determine the specific contributions of each striatal pathway to different aspects of motivated behaviour. In addition, overexpression of D2 receptors is observed across the entire striatum, thus precluding further conclusions about the contributions of specific striatal regions to the D2R-OE_dev behavioural phenotypes.^{37,49,50,55,58}

Despite these limitations, the D2R-OE_dev mouse has provided useful insights into the structural and functional downstream effects of altering D2Rs function, which may contribute to cognitive and motivational deficits. Specifically, chronic D2R overexpression in MSNs altered the anatomy and functional balance of the striatal output pathways, decreasing dendritic complexity and causing hyperexcitability by down-regulating the expression of inward rectifying potassium (Kir2.1/2.3) channels.⁵⁸ Expressing a dominant negative Kir2 channel in wild-type indirect (D2-expressing) MSNs via viral gene delivery was sufficient to recapitulate the phenotype, and enhancing wild-type Kir2.1 expression in D2R-OE mice reversed the structural and functional deficits observed in D2R-OE_dev.^37,58

These results suggested that inhibiting indirect pathway transmission would be sufficient to rescue the motivational deficit of D2R-OE_dev mice.⁵⁸ To test this hypothesis, Carvalho-Poyraz et al⁶⁰ virally expressed the inhibitory Designer Receptor Exclusively Activated by Designer Drug (DREADD) receptor hM4Di, in indirect MSNs of adult D2R-OE_dev mice. The effects of acute CNO/hM4D-induced D2-MSN inhibition on motivated behaviour were tested in dorsal and ventral striatum (NAc) separately, and strikingly, inhibition of either location reversed the motivational deficit in D2R-OE_dev mice and enhanced performance in wild-type mice.⁶⁰

1.3 |. Adult D2 receptor overexpression: Enhanced motivation?

The experimental evidence from the D2R-OE_dev mouse model shows that up-regulation of D2Rs impairs motivation. However, lesioning and pharmacological manipulations of the NAc that disrupt normal dopaminergic signalling also impair motivation.^61,62 It has been suggested that this response in the adult is mediated by the role of the NAc core in regulating effortful responses.⁶³ To test this, Trifilieff et al used a non–cell-type-specific viral strategy to overexpress D2 receptors in the NAc of adult mice and found motivation was, in fact, enhanced, the opposite of what was observed in D2R-OE_dev mice and consistent with the acute hM4Di inhibition experiments in the adult animal.^60,64

The opposing effects of increasing striatal D2Rs in adulthood compared to the D2R-OE_dev model suggest that overexpressing D2Rs during early development might alter the developmental trajectory of striatal circuitry and how MSNs respond to dopamine transmission. In fact, developmental inhibition of direct or indirect MSNs by pathway-specific conditional knockout of VGAT (Slc32a1) respectively altered the strength of corticostriatal synapses in the opposite directions. In the case of VGAT-null indirect D2-MSNs, an increase in spontaneous excitatory currents was observed in both types of MSNs at P15, suggesting a general shift towards increased corticostriatal inputs when the indirect pathway is inhibited developmentally. This circuit-level effect was accompanied by increased open-field locomotion at P15, respectively. Moreover, direct hM4D-mediated developmental (P8–15) inhibition of corticostriatal synaptic activity was associated with persistent circuit changes as shown by a decrease in the number of MSN excitatory synapses 10 days after the manipulation (P25–28).⁶⁵ Although hM4D-mediated corticostriatal synaptic inhibition did not alter open-field locomotion at P15 in the same way VGAT deletion of indirect striatal neurons did, the authors did not test locomotion or reward-based learning at later ages, leaving open the possibility that corticostriatal circuit alterations initiated early in development could leave a lasting imprint on adult motivational phenotypes.⁶⁵ These data show the complexity of comparing animal models of D2R up-regulation that differ in the temporal onset (late embryogenesis vs adult), the area of expression (entire striatum vs NAc core) and the degree of up-regulation (20% vs 10-fold). Manipulating D2-MSNs during discrete developmental windows and examining the consequences for adult behaviour would shed light on the neurodevelopmental contributions of D2Rs in setting up basal ganglia circuit function.

To determine the consequences of D2R up-regulation when restricted to the indirect pathway, a virus containing a Cre-dependent form of Drd2 was injected into the NAc of adult D2-Cre mice (D2R-OE_NacInd mice).^66,67 This technique resulted in a 3-fold increase in D2Rs and avoided the expression of D2Rs in direct MSNs that occurred in the D2R-OE_dev mice and other non–cell-type-specific virus-mediated up-regulation.^58,64 D2R-OE_NacInd mice exhibited hyperlocomotion in the open field and enhanced responding in a progressive ratio (PR) schedule of food (milk) reinforcement.⁶⁶ D2R-OE_NacInd mice also showed an increased rate of lever pressing for a preferred food (milk) when less preferred home cage chow was available for no effort. Combined, these results indicate that increased D2Rs in NAc indirect MSNs increase locomotor activity, including in situations incentivized by preferred food.⁶⁷ Motivation for all types of reinforcement was not altered as alcohol consumption and cocaine place preference were not affected by this intervention.⁶⁶

D2Rs affect D2-MSN function via regulating corticostriatal plasticity and inhibiting synaptic transmission at indirect pathway terminals.^25,34 In line with this, the selective up-regulation of D2Rs in indirect MSNs by Gallo and colleagues had two main circuit-level effects. While it decreased synaptic transmission at indirect-to-direct MSN collaterals, it also decreased baseline transmission to the ventral pallidum (VP).⁶⁷ Therefore, the motivational enhancement could be explained by disinhibition of the direct pathway via collaterals, or by inhibition of indirect pathway transmission to the VP. The first possibility was ruled out by in vivo Ca²⁺ imaging experiments that showed no change in the activity of D1-MSNs in D2R-OE_NacInd mice.⁶⁷ In contrast, chemogenetically inhibiting synaptic transmission from the NAc to the VP using localized hM4D activation in NAc to VP terminals enhanced PR performance, indicating that D2R overexpression in NAc indirect MSNs increases incentive motivation by disinhibiting the neurons of the ventral pallidum (VP; Figure 1).⁶⁷

FIGURE 1.

Proposed mechanisms of how D2 receptor overexpression in indirect pathway might enhance motivation in D2R-OE_NacInd mice. A, Schematic drawing of a sagittal mouse brain highlighting inputs from the prefrontal cortex (PFC) to the ventral striatum and ventral pallidum (VP), indirect pathway projections from the nucleus accumbens (NAc) to the VP, and the efferent projections from VP to medial dorsal thalamic nucleus (MD), subthalamic nucleus (STN) and the ventral tegmental area (VTA). STN efferents synapse onto the main output nuclei of the basal ganglia, the globus pallidus pars interna (GPi) and the substantia nigra pars reticulata (SNr). Green arrows denote glutamatergic synapses and red arrows inhibitory GABAergic synapses. B, Proposed possible downstream circuit alterations in response to selective indirect pathway D2R overexpression (↑D2R) in adult mice. Dashed lines denote inhibited synaptic output, whereas thickened lines show enhanced output. D2R overexpression inhibits activity of indirect pathway projecting neurons into the VP. The three main outputs out of the VP could contribute to the motivation enhancement observed in Gallo et al.⁶⁷ Abbreviations: CPu, caudate-putamen; D2R, dopamine D2 receptor; GPe, globus pallidus pars externa

1.4 |. Indirect pathway: Inhibition or facilitation of motivation?

The work from Gallo et al and Carvalho-Poyraz et al suggests that inhibition of indirect pathway transmission from the adult NAc core to the VP, either by virus-mediated D2R up-regulation or by chemogenetic inhibition, enhances motivation.^60,67 However, other studies combining Ca²⁺ fibre photometry and optogenetics suggest that both D1- and D2-MSNs promote motivated behaviour during a cue-based progressive ratio task. In these studies, optogenetic inhibition or stimulation was performed in the lateral shell of the NAc which is adjacent to the NAc core and at specific time-points during the operant task, instead of during the entire trial.⁶⁸ When applied at trial initiation (when the chamber light was turned off), optogenetic inhibition of either D1- or D2-MSNs decreased PR performance. However, when applied after the first lever press, only D1-MSN inhibition appeared to negatively affect PR performance. These data suggest that D2-MSN activity itself can have opposing effects on PR performance, depending on the exact timing of activation during the reward-oriented behavioural task.⁶⁸

There is further evidence implicating both D1- and D2-MSNs of medial shell and core of the NAc in enhancing progressive ratio performance.⁴⁷ Using a Cre-inducible channelrhodopsin 2 (ChR2) to specifically activate D1- or D2-MSNs in the NAc of adult mice, the authors submitted mice to a progressive ratio schedule where a cue light indicated the active lever at the start of each PR trial. Application of a brief, 1-second optogenetic stimulation of either pathway during the cue light, which signalled the start of a PR trial, enhanced performace on the task. In contrast, optogenetic inhibition of indirect D2-MSNs during the cue exposure was associated with decreased PR performance.^47,69 Taken together, these experiments argue against an antagonistic relationship between the two pathways in the regulation of PR performance and suggest that synaptic inhibition of the ventral pallidum by D2-MSNs promotes motivation.^47,69

The optogenetic studies described above appear at odds with the findings of Gallo et al (2018) and Carvalho-Poyraz et al (2014).^60,67 However, although all studies utilized progressive ratio as the main readout of motivation, there are important experimental differences that might explain the seemingly diverging results. Firstly, the use of a visual cue to indicate the beginning of a trial introduces an additional stimulus to the task which could enhance motivation via VTA/dopamine-driven Pavlovian-instrumental transfer mechanism where the animal interprets the cue as an indication of increased chance of reward.⁷⁰

Secondly, the duration of the D2-MSN inhibition could have a significant impact on the outcome of the PR task. A brief inhibition of D2-MSNs limited to the trial onset cue might interfere with the integration of the visual cue information by the motivation circuit, but otherwise leave the rest of the circuit intact. Meanwhile, the chronic, viral-mediated overexpression of D2Rs (or activation of hM4D) spanning the length of the PR schedule inhibited indirect D2-MSNs (and disinhibited the VP) during the entire trial.⁶⁷ Therefore, under these circumstances, inhibition of accumbal D2-MSN activity appears to be required for the sustained level of work in the task.⁶⁷ Consistent with this, brief optogenetic activation of D2-MSNs was shown to increase VTA dopaminergic activity that could account for the motivational enhancement,⁶⁹ whereas the more chronic nature of chemogenetic manipulation may not lead to the same increase in dopaminergic transmission. Thirdly, the site of striatal inhibition (unilateral vs bilateral; medial shell, lateral shell and core of the NAc) could be an important factor explaining the different outcomes. In conclusion, the interpretation of activity by D2-MSNs in promoting or curbing motivated behaviour is highly dependent on the behavioural task design, as well as the timing and site of the manipulation.

1.5 |. D2 receptor functional selectivity and behavioural correlates

The discovery of GPCR signalling through G protein–independent mechanisms, as well as preferential coupling to specific Gα subunits, has spurred new avenues of research that offer a more nuanced view of how D2 receptors may generate sub–cell-type specificity to drive different responses to midbrain dopamine with distinct behavioural consequences.^71–74 Using exogenous GIRK channels expressed in indirect D2-MSNs in the NAc or dorsal striatum to obtain functional readouts of D2R activity, Marcott and colleagues revealed regional differences in how dopamine signals via D2 receptors. Cellular responses to dopamine in the NAc exhibited slower kinetics and less sensitivity to dopamine compared to D2-MSNs in the dorsal striatum. These differences were driven by D2R preferential coupling to Gα_o as opposed to Gα_i subunits in the NAc.⁷¹ How regional D2R functional selectivity with respect to G proteins affects D2R-dependent behaviours, including motivation, remains to be determined.

In addition to the canonical G-protein signalling, dopamine D2 receptors signal through β-arrestin 2 (β-Arr2). As scaffolding proteins, β-arrestins allow the coupling of AP-2 and clathrin, which mediate receptor endocytosis.⁷⁵ Experiments using functionally biased ligands that preferentially engage G protein–dependent vs β-arrestin–dependent signalling cascades, as well as D2 receptor variants that signal exclusively through one transduction pathway, have shown that some D2R-dependent behaviours can be primarily driven by β-Arr2 or G-protein signalling. Relying on a viral expression strategy to replace deleted endogenous striatal D2Rs with variants whose signalling transduction was restricted to either G-protein or β-Arr2 pathways, Rose et al⁷⁶ were able to show that while nestlet shredding was sensitive to G-protein signalling, locomotor activity level depended on both G protein and β-Arr2.

In a similar approach to study the effect of distinct D2R signalling pathways on behaviour, Donthamsetti et al injected virus expressing either wild-type D2R or a variant of D2R that is arrestin-biased into the NAc of D2R KO mice. The arrestin-biased D2R variant was incapable of coupling to G proteins but strikingly resulted in the same level of cocaine-induced locomotor activation as the wild-type D2R. In contrast, the enhancement in motivation observed in the progressive ratio task after viral up-regulation of wild-type receptors was not observed after up-regulation of the arrestin-biased receptors.⁷² This dissociation suggests that non–goal-directed locomotion and motivated, goal-directed, reward-driven activity are regulated by neuronal mechanisms that involve different signalling machineries downstream of D2Rs. For example, it is possible that arrestin signalling may mainly affect corticostriatal plasticity whereas G-protein signalling is responsible for inhibiting synaptic transmission to the ventral pallidum. Alternatively, it is not the rewarding component that is differentially regulated, but it is the higher effort to perform the progressive ratio that requires G-protein signalling. Collectively, these data highlight a promising pathway for developing therapeutic strategies that could “fine-tune” D2R downstream signalling and avoid some of the undesirable side effects including amotivation.

1.6 |. Serotonin 2C receptor antagonism: Enhancement of dopamine release and motivation

Given that direct manipulation of the dopamine system is liable to create undesirable side effects including motor impairment and addiction, until we understand how to finely regulate components of dopamine signalling, indirect pharmacological approaches may be fruitful. Recent studies have explored the potentially therapeutic effect of serotonergic modulation of dopamine signalling with results suggesting a pro-motivational role for the G_q-coupled serotonin receptor 5-HT2C, which is known to inhibit pre-synaptic dopamine release in the striatum.⁷⁷ Taking advantage of this, investigators have tested the effects of a functionally selective (biased) ligand of the 5-HT2C receptor, SB242084, which acts as an inverse agonist on phospholipase A2 and produces agonist effects on phospholipase C.⁷⁷ The effect of SB242084 on various behavioural tasks designed to evaluate goal-directed motivated behaviour has been tested in WT mice and in D2R-OE_dev mice as a model of motivational deficit. The authors previously showed that striatal D2 receptor overexpression was associated with 5-HT2C up-regulation and that acute intraperitoneal injections of SB242084 were sufficient to reverse the motivational deficit displayed by these mice.⁵⁵ Pre-treatment of D2R-OE_dev or wild-type mice with SB242084 20 minutes prior to a progressive ratio task resulted in significantly higher response vigour, as reflected in lever pressing rates and willingness to continue pressing the lever on trials with increasing demand, compared to vehicle treatment. Similarly, motivation-enhancing effects were observed during an effort-based food choice task.⁷⁸ The authors determined that the effect of SB242084 was not simply due to a generalized hyperactivity because when the press requirement on a progressive schedule was length of time the lever was held down, rather than number of lever presses, SB242084 still enhanced performance. There was no desensitization to repeated treatment with SB242084 because acute enhancement of motivation could be reinstated after repeated injections of SB242084.⁷⁸ The motivational enhancement by inhibiting 5-HT2C was associated with tonic elevation of extracellular dopamine in the dorsomedial striatum, while no changes in tonic or phasic dopamine signal were observed in the NAc after SB242084 treatment.⁷⁹ Future studies should address the mechanism by which 5-HT2C activity regulates dopamine release and test the efficacy of this strategy in other models of dopamine dysregulation associated with motivational deficit.

2 |. CONCLUSION

Motivational deficit is a prominent feature shared by several psychiatric disorders, associated with abnormal striatal dopamine transmission, including schizophrenia, where D2 dopamine receptors play an important, albeit poorly understood, role. Associated with poor functional outcome, lack of motivation does not respond to existing pharmacological treatment currently available. The last decade has witnessed a blossoming of research efforts aiming to functionally dissect the striatal circuit into individual components that can account for the different aspects of motivated behaviour. The combination of long-established techniques, such as genetically modified mice, with more recent technical advances of opto- and chemogenetic tools or selective D2R overexpression have allowed the manipulation of D2-MSNs with greater cell-type specificity, regional accuracy and temporal control. This led to a far more nuanced view of how activity by D2-MSNs regulates motivation. The long-term goal is to use this knowledge for the development of better therapeutic strategies to enhance motivated behaviour without inducing side effects such as exaggerating psychotic symptoms.