Role of Central Serotonin in Impulsivity and Compulsivity: Comparative Studies in Experimental Animals and Humans

CHAPTER 3.8

Role of Central Serotonin in Impulsivity and Compulsivity: Comparative Studies in Experimental Animals and Humans Trevor W. Robbins* and Molly J. Crockett* Department of Experimental Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK

Abstract: The involvement of serotonin in impulsivity (the tendency to respond prematurely) and compulsivity (the tendency to perseverate) is reviewed from the joint perspective of animal and human studies. Evidence is provided to support a role for serotonin in some forms of impulsivity, but not others, and in compulsivity. However, it is difficult to accommodate these roles into a common scheme implicating behavioral inhibition. The implications for neuropsychiatric disorders such as obsessive-compulsive disorder are considered. Keywords: impulsivity, compulsivity, behavioral inhibition, striatum, prefrontal cortex, ADHD, obsessive-compulsive disorder. Whether these two contingencies actually are equivalent to receiving an aversive or appetitive reinforcer, respectively, seems somewhat dubious, although they may share some generalized emotional congruence. There is a similar confound in terms of the relationship between aversive motivation and inhibition: a punishing contingency normally results in the suppression of appetitive behavior, whereas the unconditioned response for a rodent to a pavlovian aversive reinforcer is to freeze. So a manipulation of the 5-HT system which reduces the unconditioned response to an aversive reinforcer (e.g., freezing in rodents) generally also causes increases in overall motor output, or ‘behavioral disinhibition’. The question is, which of these roles ascribed to 5-HT is primary: inhibition or aversiveness? A further complication has been the fact that different aspects of aversiveness also implicate 5-HT; thus Deakin and Graeff (1991) pointed out that increasing levels of 5-HT transmission are associated with anxiety, and decreasing levels with depression. Throughout this chapter we will observe how seemingly opposite functional effects can follow superficially similar manipulations of 5-HT neurotransmission, in a manner that almost appears bound to confound any attempt to assign a unitary function to this system. These paradoxes, however, serve to strengthen our understanding of the 5-HT system, and how its operation may depend on subtle contextual demands.

Introduction Serotonin (or 5-hydroxytryptamine, 5-HT) has been implicated in many behavioral and physiological functions, which is not surprising, given the diverse ramification of central 5-HT neurons and the existence of at least 14 distinct 5-HT receptors. However, the unitary functions most often attributed to this system have been those of aversive motivation (Wise et al., 1972; Deakin and Graeff, 1991) and behavioral inhibition (Gray, 1982; Soubrié, 1986). The latter is most relevant to theories of impulsivity and compulsivity, although 5-HT may also be linked with these constructs through its possible role in aversive motivation. This chapter will summarize the research especially relevant to the impulsivity/compulsivity theme, and will draw on work performed in this laboratory as well as others, in both experimental animals and human volunteers. As Gray (1982) himself realized, there are clear reciprocal relationships between apparently opponent appetitive and aversive systems, whereby the omission of an expected positive reinforcer (or ‘reward’) has aversive consequences, and the omission or postponement of an aversive reinforcer is perceived in a positive light. * Corresponding authors E-mail: [email protected] (T.W. Robbins); [email protected] (M.J. Crockett)

Christian Müller & Barry Jacobs (Eds.) Handbook of Behavioral Neurobiology of Serotonin ISBN 978-0-12-374634-4

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DOI: 10.1016/B978-0-12-374634-4.00025-3 Copyright 2010 Elsevier B.V. All rights reserved

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Serotonin and Behavioral Control of impulsivity, although with some overlap sufficient to encourage the notion of a unitary construct (Robinson et al., 2008a; but see also Winstanley et al., 2004a).

5-HT and impulsivity Impulsivity is generally defined as the tendency to respond prematurely without adequate foresight, sometimes with adverse consequences. This definition conceals a number of possibly distinct aspects of impulsivity which may each implicate an inhibitory process – for example, inhibition of an action or response or inhibition of the salience of an appetitive goal. Moreover, an impulsive decision can result from an altered criterion in terms of perceptual evidence sampled, or from altered processing of reinforcement contingencies. In our work with rats we employ three tests of impulsivity that capture these distinct forms; premature responding in a five-choice serial reaction time task; stop-signal inhibition; and temporal discounting of reward. These tests reveal different neural and neurochemical substrates for these distinct forms

Impulsivity in the five-choice serial reaction time task (5-CSRTT) The 5-CSRTT is a test paradigm in which rats are trained to detect brief visual targets presented randomly in five locations to earn food (Figure 1). Rats have a propensity to respond prematurely in this task, particularly as the duration of the visual target is reduced, although this behavior is punished by time-out from positive reinforcement. This tendency is quite variable between individuals, with a small proportion of rats exhibiting high degrees of impulsive responding, even after extended training.

5-choice task

hole

Food Magazine Start of a trial (rat pushes the panel of the magazine)

Stimulus (in one of the 5 holes) Correct response

Reward

Incorrect response

5 sec.

Timeout Omission

Premature respose

PREMATURE RESPONSES sham

Percent premature responses

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0.01 0.03 M100907 (mg/kg)

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Figure 1 Contrasting effects of the 5-HT2A receptor antagonist M100907 and the 5-HT2C receptor antagonist SB242084 on premature responding in the 5-choice serial reaction time task in rats with either forebrain 5-HT depletion from the forebrain or the control treatment (sham surgery). The five-choice paradigm is also shown. The figures are reproduced from Winstanley et al. (2004b) and Robbins (2002), by permission of the publishers (Springer-Verlag).

Role of Central Serotonin in Impulsivity and Compulsivity An early experiment showed that profound (⬎85 percent loss in most forebrain regions assayed, including neocortex and striatum) depletion of forebrain 5-HT induced by intraventricular administration of the selective neurotoxin 5,7 dihydroxytryptamine (5,7-DHT) produced significant and essentially permanent increases in premature responding (Harrison et al., 1997a). Further experiments targeting separately the dorsal and medial raphe nuclei indicated that lesions of the dorsal nucleus, which projects preferentially to the neocortex and striatum, produced higher levels of impulsive responding, sometimes in conjunction with improved accuracy (Harrison et al., 1997b). The increase in premature responses in the 5-CSRTT following intraventricular 5,7-DHT was replicated and extended by Winstanley et al. (2004b), who also demonstrated that the effect was ameliorated to some extent by systemic administration of M100907, the 5-HT2A receptor antagonist. However, the suppression of premature responses was enhanced by lower doses of M100907 in sham-operated control rats (see Figure 1). By contrast, systemic administration of the 5-HT2C receptor antagonist SB242084 exacerbated impulsivity produced by the 5-HT depletion, although again the exacerbation was obtained at lower doses in controls (Figure 1). This different pattern of effects of the 5-HT2A and 5-HT2C receptor antagonists (Figure 2) has since been reproduced following intracerebral administration into the nucleus accumbens (Robinson et al., 2008a), a structure known to be implicated in impulsivity on the 5-CSRTT, and possibly reflecting an interaction between 5-HT and mesolimbic dopamine (DA) (Berg et al., 2008). These contrasting

Contrasting effects of 5HT2A and 2C antagonists on measures of impulsive and compulsive responding in the rat IMPULSIVITY e.g. premature responses on 5CSRTT

COMPULSIVITY e.g. perseverative responses on discrimination reversal learning

5HT2A receptor antagonist (M100927)

Antagonise, remediate (ILC-PFC. N.Acc.)

Exacerbate (OFC-PFC)

5HT2C receptor antagonist (SB240804)

Exacerbate (N.Acc.)

Antagonise, remediate (OFC-PFC)

Figure 2 Contrasting effects of 5HT2A and 5-HT2C antagonists on measures of impulsive and compulsive responding in the rat. Abbreviations: OFC, orbitofrontal cortex; N. Acc., nucleus accumbens. Summary of data from Winstanley et al. (2003, 2004b) and Boulougouris et al. (2008).

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effects of 5-HT2A and 5-HT2C agents are consistent with other data on effects of 5-HT2A and 5-HT2C agonists on impulsive responding when administered systemically (Koskinen et al., 2000; Fletcher et al., 2007; Navarra et al., 2008). The opposite effects of the 5-HT2A and 5HT2C antagonist are perhaps surprising in view of their structural similarities, and commonalities in their effects on secondary messengers (Conn and Sanders-Bush, 1987), but presumably reflect their differential involvement in neuronal circuitry modulated by serotonin (see, for example, Pompeiano et al., 1994; Berg et al., 2008; Calcagno et al., 2009). Whereas ventral striatal 5-HT is implicated in impulsive responding induced on the 5-CSRTT, the involvement of cortical 5-HT is a little less clear. Previous work has established that the infralimbic (IL-) or ventromedial prefrontal cortex (PFC) is particularly implicated in the control of impulsivity, but not accuracy, of responding in the 5-CSRTT (Chudasama et al., 2003; Murphy et al., 2005). Dalley et al. (2002) actually found that the more highly impulsive rats tended to have higher levels of 5-HT in the medial prefrontal cortex (mPFC) as measured using in vivo microdialysis, seemingly in contradiction of a role for 5-HT in behavioral inhibition. This putative increase in mPFC 5-HT neurotransmission was apparently supported by findings that intra-mPFC infusions of ketanserin (a mixed 5-HT2A/C antagonist; Passetti et al., 2003) and the more selective 5-HT2A receptor antagonist M100907 (Winstanley et al., 2003) reduced premature responses on the 5-CSRTT. However, these effects were only obtained in modified versions of the task when the duration of the visual targets was reduced. With standard task parameters, Robinson et al. (2008b) found no effect of either M100907 or the 5-HT2C receptor antagonist SB242084 when infused intra-mPFC. However, Carli et al. (2006) found that intra-mPFC M100907 did antagonize the increased premature responses induced by intra-mPFC infusions of the NMDA receptor antagonist CPP, consistent with the possibility of the modulation of glutamate responses by the 5-HT2A receptor in this region. This blockading effect is also consistent with the fact that premature responses had a high baseline in the study by Winstanley et al. (2003), but a low one in the experiment of Robinson et al. (2008b). Thus, it appears that the 5-HT2A receptor does modulate impulsivity within the mPFC under some circumstances, consistent with the high density of 5-HT2A receptors in this region (Santana et al., 2004). Recent evidence suggests that there is also a balance between the influence on pyramidal cell output of 5-HT2A and 5-HT2C receptor activity in this region (Calcagno et al., 2009). Thus, in parallel with the enhanced impulsivity elicited by intra-mPFC CPP and

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its reversal by M100907, the enhanced glutamate release following intra-mPFC CPP by M100907 was blocked by concurrent administration of a 5-HT2C receptor antagonist. Furthermore, Calcagno et al. (2009) have found that the enhanced impulsivity produced by intra-IL-PFC CPP can be blocked by a 5-HT2C agonist. The functional interaction between 5-HT2A and 5-HT2C receptors may be mediated by their neuronal effects at pyramidal cells, and on parvalbumin-containing GABA neurons, respectively (see Liu et al., 2007; Calcagno et al., 2009). This series of studies has shown that the involvement of 5-HT in one form of impulsivity, premature responding in the 5-CSRTT, is quite complex, with behavioral disinhibition certainly being the outcome of global forebrain 5-HT loss. However, there is evidence that the effects of two subtypes of the 5-HT2 receptor are reciprocally involved in the regulation of impulsivity. This reciprocity is also expressed within the nucleus accumbens and the mPFC, as well as other possible neural sites. A further question is, what form of impulsivity is captured by the premature responding measure in the 5-CSRTT? It quite possibly reflects perceptual and motivational, as well as motor, aspects.

Response inhibition: stop signal inhibition and Go/ NoGo paradigms As will be seen below, there are several ways of inferring effects of 5-HT manipulations on motor inhibition, which lead to a surprising, but informative, conclusion (Table 1). In this section, we also compare studies performed in the same paradigm with human as well as animal subjects. Although it is feasible to manipulate 5-HT function in humans, there is a relative dearth of means for doing this. Some of the most often used methods are shown in Box 1.

Stop-signal reaction time task (SSRTT) Logan’s stop-signal reaction time task was devised originally for human subjects with applications especially to patients with attention deficit hyperactivity disorder (ADHD) (Logan et al., 1984). Simply speaking, the SSRTT measures the speed with which an initiated action can be cancelled or inhibited (see Eagle and Robbins, 2008a, for a full theoretical description). Recently, it has

Table 1 Summary of reviewed findings of serotoninergic manipulations on measures of response inhibition Reference

Manipulation

Task

Is response inhibition before or after response selection?

Effect on response inhibition

Rats Harrison et al., 1997b Harrison et al., 1999 Eagle et al., 2008a Bari et al., 2009 Eagle et al., 2008b Eagle et al., 2008b Harrison et al., 1999

5,7 DHT Dorsal raphe lesion Acute SSRI Acute SSRI 5,7 DHT 5,7 DHT 5,7 DHT

5CSRTT 5CSRTT SSRTT SSRTT SSRTT SSRTT with waiting period GNG

Before Before After After After ? Before

Impaired Impaired No effect No effect No effect Impaired Impaired

Humans Chamberlain et al., 2006 Clark et al., 2005 Crean et al., 2002

Acute SSRI ATD ATD

SSRTT SSRTT SSRTT

After After After

Walderhaug et al., 2002 Walderhaug et al., 2007

ATD ATD

CPT CPT

Before Before

LeMarquand et al., 1999

ATD

GNG

Before

Evers et al., 2006 Crockett et al., 2008 Scholes et al., 2006 Evers et al., 2006

ATD ATD ATD ATD

GNG GNG Stroop Stroop

Before Before Before Before

No effect No effect Impaired in FH⫹ males; improved in FH⫺ males Impaired Impaired in males; improved in females Impaired in FH⫹ males; no effect in FH⫺ males No effect No effect Enhanced Enhanced

Abbreviations: 5,7 DHT: neurotoxic lesions to 5-HT-releasing neurons; 5CSRTT: 5-choice serial reaction time task; SSRTT: Stop signal reaction time task; GNG: Go/NoGo task; ATD: Acute tryptophan depletion; FH⫹: family history of alcoholism; FH⫺: no family history of alcoholism; CPT: Continuous performance task.

Role of Central Serotonin in Impulsivity and Compulsivity

Common methods for manipulating 5-HT in humans Acute tryptophan depletion (ATD) ATD induces a transient 5-HT deficit in the CNS (Carpenter et al., 1998). In the ATD procedure, participants ingest an amino acid load via a drink that contains all of the large neutral amino acids (LNAAs) except for tryptophan, which is the chemical precursor of 5-HT. Tryptophan competes with other LNAAs for access via the blood–brain barrier through the LNAA transporter. Lowering the tryptophan:LNAA ratio almost completely halts tryptophan transport into the brain. Microdialysis in rats has shown that ATD attenuates 5-HT release in frontal cortex and midbrain raphe nuclei (Bel and Artigas, 1996). In human subjects, plasma and CSF tryptophan levels reach nadir 5 hours after the administration of the amino acid mixture (Carpenter et al., 1998). Tryptophan supplementation and loading Tryptophan supplementation and loading are thought to enhance 5-HT function by increasing availability of tryptophan. Tryptophan loading involves a similar procedure to ATD, but the amino acid load contains a large amount of tryptophan. In the tryptophan supplementation procedure, participants take daily supplements of tryptophan in tablet form, often for several weeks. Both procedures increase tryptophan availability to levels that saturate tryptophan hydroxylase, the rate-limiting enzyme that converts tryptophan to 5-HT (Young and Gauthier, 1981). Acute vs chronic SSRI administration Selective serotonin reuptake inhibitors (SSRIs) increase the concentration of 5-HT in the synapse by blocking its presynaptic reuptake. They do so by blocking the presynaptic active transport mechanism in the 5-HT transporter (5-HTT). Consequently, the action of 5-HT on postsynaptic receptors is enhanced (Spinks and Spinks, 2002). The onset of an SSRI’s clinical effects can be delayed 1 or 2 weeks from the start of treatment (Taylor et al., 2006), despite the fact that these drugs inhibit 5-HT reuptake within hours of administration (Bymaster et al., 2002). The underlying mechanisms of this effect are presumed to involve the presynaptic 5-HT1A autoreceptors. When released 5-HT activates these receptors, potassium channels are opened, leading to hyperpolarization of the cell and inhibition of cell firing, which results in decreased 5-HT release (Blier et al., 1998).

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SSRI-induced increases in synaptic 5-HT are thus countered by negative feedback on serotonergic release caused by 5-HT binding to autoreceptors, which may explain why SSRIs do not show clinical effects immediately after administration. The effects of acute administration of SSRIs may therefore mirror those of serotonin depletions, such as ATD (Carpenter et al., 19981). The lower acute doses used in research in human volunteers are particularly likely to have autoreceptor effects to decrease extracellular 5-HT levels. Chronic administration of SSRIs, however, is thought to enhance serotonergic neurotransmission, as autoreceptors desensitize with repeated drug administration and firing of 5HT neurons is restored (Blier et al., 1998). Pharmacological fMRI All of the above methods can be combined with functional magnetic resonance imaging (fMRI) to probe the effects of altered 5-HT neurotransmission on the neural correlates of behavior. Interpreting the effects of 5-HT manipulations on neural activity is not straightforward, however, and must be approached with caution when the manipulation does not produce effects on behavior. When 5-HT manipulation does affect fMRI results, it is not yet possible to determine the underlying mechanism; for example, enhanced neural activity could reflect increased neurotransmission due to greater efficiency, or the need to recruit more neurons due to impaired efficiency (Anderson et al., 2008).

proven possible to configure this task appropriately for monkeys and rodents (Eagle and Robbins, 2003; Eagle et al., 2008a) allowing for comparisons to be made across species. Performance in the SSRTT appears to involve structures other than the nucleus accumbens in the rat; in fact, an orbitofrontal cortex (OFC)–medial striatal– subthalamic nucleus system has been implicated, which may overlap with the neural network engaged during performance of the task in an fMRI paradigm in humans (Aron and Poldrack, 2006). So far, manipulations of the central 5-HT system have shown few effects on performance of the SSRTT. The selective serotonin reuptake inhibitor (SSRI) citalopram has no effect on performance in rats (Eagle et al., 2008a; Bari et al., 2009) on acute administration. More strikingly, global forebrain 5-HT depletion in rats also has no effect on the SSRTT, which contrasts markedly with its effects to induce impulsive responding in the 5-CSRTT or in the Go/NoGo paradigm (Eagle et al., 2008b). However,

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if the period for which a response has to be inhibited on the SSRTT is prolonged, then 5-HT depletion in the rat does produce behavioral disinhibition; there is a deficit in ‘waiting’ but not ‘stopping’ itself (Eagle et al., 2008b). The effects of 5-HT manipulations in humans on SSRTT performance for the most part parallel the findings in rats, with a few complications (Table 1). Acute tryptophan depletion (ATD) had no effect on response inhibition in the SSRTT (Clark et al., 2005), and neither did acute administration of the SSRI citalopram (Chamberlain et al., 2006). However, another study found that ATD impaired SSRTT performance in males with a family history of alcoholism, but improved performance in males without a family history of alcoholism (Crean et al., 2002). Whether these more complex findings reflect the release by ATD of contrasting underlying individual tendencies, or differential individual responses to the ATD procedure, remains unclear.

Go/NoGo discrimination Go/NoGo discrimination is another paradigm used to measure response inhibition. In this task, inhibition has to be exerted in the response selection phase, whereas in the SSRTT, response selection has already occurred but the performance of the response has to be curtailed. Considerable evidence links a reduction of 5-HT to behavioral disinhibition in Go/NoGo paradigms, including classical findings reviewed by Soubrié (1986). The interpretation of such data is generally along the lines that impaired 5-HT function results in a reduction of response inhibition, and hence the increase in non-reinforced or even punished NoGo responding. An alternative account is that the aversive consequences of responding on NoGo trials are reduced by 5-HT depletion. The latter hypothesis is difficult to refute, but we have attempted to address it by studying in parallel two similar tasks. In the first of these, acquiring a Go/NoGo discrimination depended on responding differentially to a fast-flashing or slowflashing visual stimulus (counterbalanced across rats). Global 5-HT depletion actually completely prevented the acquisition of this discrimination, as the depleted rats failed to inhibit responding to the NoGo stimulus (regardless of whether it was fast or slow), although withholding the response, like performing the Go response, was symmetrically reinforced with food. If rats were pre-trained to solve the discrimination, 5-HT depletion impaired performance by inducing inappropriate responding on NoGo trials – though not to the extent of the complete behavioral disinhibition observed during acquisition (Harrison et al., 1999). In a complementary experiment, rats were trained in a conditional Go/Go discrimination based on similar fast

and slow-flashing visual stimuli. In this situation, 5-HT depletion actually improved acquisition of the discrimination. Therefore, it is difficult to argue that 5-HT depletion reduced the impact of reward omission, as this would presumably also have impaired trial-and-error discrimination learning. The more parsimonious hypothesis is that it impaired response inhibition in the Go/NoGo procedure, but this deficit was largely irrelevant to the Go/Go task (Ward et al., 1999). Note that these findings also approximate the effect of forebrain 5-HT loss on performance on the 5-CSRTT, where again premature responding was enhanced, but visual discrimination was unaffected or even enhanced (Harrison et al., 1997a, 1997b). In humans, the effects of 5-HT manipulations on Go/ NoGo discrimination are more complex. Paralleling the findings in rats, Walderhaug et al. (2002) reported increased impulsivity or disinhibition following ATD in a continuous performance task requiring Go/NoGo discrimination. However, several other findings are less straightforward (Table 1). A later study using the same continuous performance task showed that ATD increased impulsivity in males, but decreased impulsivity in females (Walderhaug et al., 2007). LeMarquand et al. (1999) found that ATD increased impulsive responses in the Go/ NoGo task in males with a family history of alcoholism, but not in males without a family history of alcoholism. Two more recent studies found no effect of ATD on Go/NoGo discrimination in male and female healthy volunteers (Evers et al., 2006; Crockett et al., 2008). Furthermore, it could be argued that performance on the Stroop task involves inhibitory control in the response selection phase, and thus taps into the same mechanisms of the Go/NoGo task. However, two studies have found that ATD enhances performance on the Stroop task (Evers et al., 2006; Scholes et al., 2006). Thus, in humans the effects of ATD on Go/NoGo discrimination are not straightforward and appear to depend to a certain extent on individual vulnerability factors, such as gender or family history of psychopathology. Researchers have used fMRI to investigate whether 5-HT manipulations modulate brain activity during Go/ NoGo discrimination. One study found that ATD attenuated activity in the right inferior frontal gyrus (rIFG) during the Go/NoGo task (Rubia et al., 2005); another study reported no effect of ATD on neural activity during the Go/NoGo task (Evers et al., 2006). A third study found enhanced rIFG activity during the Go/NoGo task following acute pre-treatment with the SSRI citalopram (Del-Ben et al., 2005). These findings provide some evidence for serotonergic modulation of the neural correlates of response inhibition, but it is important to note that none of these studies found effects of ATD on behavioral measures of response inhibition.

Role of Central Serotonin in Impulsivity and Compulsivity One potential explanation for these mixed results is that the behavioral tasks typically used to measure response inhibition in humans are non-reinforced: subjects do not receive rewarding or punishing feedback for their responses. But the 5-HT-inhibition hypothesis was based on animal work that employed reinforced tasks (Soubrié, 1986). This suggests that the results obtained in animal studies could be due to the involvement of 5-HT in reinforcement processing. 5-HT has indeed been linked with behavioral and neural indices of reinforcement processing in a variety of paradigms. In summary, 5-HT manipulations have strikingly different effects on performance in two different tasks designed to measure response (including motor) inhibition. When response selection is involved prior to response initiation, 5-HT appears to have an important role in suppressing impulsive NoGo responding. This parallels the effects of 5-HT depletion on premature responding in the 5-CSRTT. In contrast, after a response has been initiated, 5-HT appears to no longer play a role in motor inhibition. Behavioral manipulations suggest that the predominant effect of 5-HT loss is to induce deficits in the capacity to wait rather than stop (Table 1). Clearly, this distinction goes beyond a simple theory of 5-HT involvement in behavioral inhibition; response inhibition may be involved in both circumstances, but the 5-HT system appears to be implicated only in one of them.

Temporal discounting of reward: impulsive choice This refers to the choice between small immediate rewards and large delayed ones – an elemental form of decision-making. Other versions of temporal discounting or ‘inter-temporal choice’ may pit the choice between small immediate rewards and avoidance of large delayed punishment, as may occur in several decisions involving personal health choices, such as those involved in addiction. Previous work has suggested that down-regulating 5-HT function in rats by combined dorsal and median raphe 5,7-DHT increases impulsive choice (see, for example, Mobini et al., 2000). However, using the same intraventricular treatment with 5,7-DHT as previously, we found no effect on temporal discounting in an operant procedure in which hungry rats responded for either immediate single food pellets, or for four pellets presented at varying delays culminating in 60 s. The resulting choice behavior could readily be fit by a hyperbolic discounting function, but there was no effect on temporal discounting following profound forebrain 5-HT loss. However, such 5-HT depletion did have effects on temporal discounting affected by systemic d-amphetamine. The latter treatment (repeated three times) dose-dependently reduced impulsive

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choice, inducing rats to respond on the lever associated with the large, delayed reward. This effect was only significant, however, for those rats with initially steep discounting functions – i.e., in rats showing impulsive choice. Intriguingly, given that d-amphetamine is an indirect catecholamine agonist, its effects to reduce impulsive choice were blocked by 5-HT depletion. The effects of d-amphetamine could also be blocked by the mixed D1/ D2 receptor blocker α-flupenthixol, but only in 5-HTdepleted rats, suggesting that they were mediated by an interaction between DA and 5-HT systems. Further evidence for such an interaction comes from the fact that mesolimbic DA depletion achieved by intra-accumbens 6-hydroxydopamine failed by itself to block the antiimpulsive effect of d-amphetamine. Furthermore, the 5-HT1A receptor antagonist WAY 100635 enhanced the action of d-amphetamine to reduce impulsive choice (Winstanley et al., 2005). The most likely site of action for these interactions is the nucleus accumbens, core region, as excitotoxic lesions of this structure have been found to cause impulsive choice in the same paradigm (Cardinal et al., 2001). 5-HT1A receptors are known to be located on DA cells in the ventral tegmental area that projects to the nucleus accumbens (as well as within the nucleus accumbens itself). Acute, systemic treatment with the 5-HT1A agonist 8-OH-DPAT elicits strong impulsive choice, an effect which is blocked by a 5-HT1A receptor antagonist, but which is not blocked by 5-HT depletion, suggesting that it is postsynaptic in origin. In contrast, such impulsivity is blocked by 6-OHDA lesions of the nucleus accumbens, which deplete dopamine there (Figure 3). At the dose used to induce impulsive choice, 8-OH-DPAT may thus induce impulsive responding by facilitating release of DA in the nucleus accumbens. These findings again highlight the intimate interactions of DA and 5-HT in the control of impulsive behavior. An in vivo microdialysis study of delayed discounting by Winstanley et al. (2006) found elevated extracellular 5-HT within the mPFC specifically related to an instrumental choice condition, independent of the effects in separate groups of passive reward presentation, or of instrumental behavior without choice. This contrasted with findings for DA in mPFC which was elevated following passive reward presentation or during instrumental behavior, as well as during impulsive choice. Within the OFC, however, DA was more reliably associated with impulsive choice behavior. The relationship between low or impaired 5-HT and ‘impulsive’ inter-temporal choice described above has been extended to humans. An early study found no effect of ATD on a temporal discounting of reward task (Crean et al., 2002). The authors suggested that the

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Mean number of choices of large reward

Shams

6-OHDA NAC lesions

10

10

8

8

6

6

4

4

2

2 0

0 0

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Delay (s) saline 0.1mg/kg 8-OH-DPAT 0.3mg/kg 8-OH-DPAT 1.0mg/kg 8-OH-DPAT saline + 0.1mg/kg WAY 100635 1.0mg/kg 8-OH-DPAT + 0.1mg/kg WAY 100635

Figure 3 Hyperbolic temporal discounting in the rat as affected by an acute dose of the 5-HT1A receptor agonist 8-OHDPAT. The steeper discounting (i.e., impulsive responding) produced by this drug is abolished by prior dopamine depletion in the nucleus accumbens, which by itself has no effect. Reproduced from Winstanley et al. (2005).

inter-temporal choice task, which was questionnairebased, was perhaps insufficiently sensitive to detect effects of altered 5-HT. A later study used an inter-temporal choice task with experiential delays (as are used in the animal studies reviewed above), and found that ATD increased choices for the smaller, sooner reward, paralleling at least some of the complex findings from rat studies (Schweighofer et al., 2008). An fMRI study using the same task suggested that ATD increases impulsive intertemporal choice by enhancing activity in the ventral striatum during short-term reward prediction (Tanaka et al., 2007). In the same study, augmenting 5-HT function with tryptophan supplementation enhanced activity in the dorsal striatum during long-term reward prediction. It will be interesting to see if these data can be confirmed in animal studies. In summary, as in the case of the premature responding in the 5-CSRTT, impulsive behavior was modulated by 5-HT mechanisms. Although the relevant brain regions still have not been fully elucidated, available data again point to a cortico-striatal mediation, as well as to complex interactions with dopamine, probably at both a cortical and striatal level. Evidence for a strong version of the 5HT hypothesis of behavioral inhibition is lacking. Instead, the effects of 5-HT manipulations on impulsive choice appear to be more related to altered representations of instrumental outcomes.

5-HT and decision-making cognition Representing reward and punishment contingencies of decision outcomes is of critical importance in gambling and risk-taking tasks, where subjects must weigh the relative potential costs and benefits of different response options. An early study with the Cambridge Gamble Task found that ATD reduced choices for the most probable outcome (i.e., the outcome with the highest expected value) (Rogers et al., 1999a), suggesting that 5-HT is important for integrating information about the value and likelihood of choice outcomes. However, a subsequent study using the same task found the opposite effect; ATD increased choices for the most probable outcome (Talbot et al., 2006). Either way, these results imply that 5-HT modulates the influence of reinforcement contingencies on choice. This process may be supported by a serotonergic modulation of the representation of reward magnitudes. Supporting this view, Rogers et al. (2003) reported that ATD reduced discrimination between magnitudes of expected rewards associated with different choice outcomes in a risk-taking task. Enhancing 5-HT function with tryptophan supplementation did not improve reward discrimination, however. Instead, tryptophan supplementation reduced framing effects in the loss domain – following tryptophan supplementation; subjects chose certain small losses over uncertain larger losses significantly more

Role of Central Serotonin in Impulsivity and Compulsivity frequently than the placebo group (Murphy et al., 2009). The authors interpreted this finding as evidence that tryptophan supplementation reduced loss aversion, which fits with other work linking reduced 5-HT to enhanced punishment processing. The neural correlates of these behavioral effects remain unclear, and it is still not well understood how 5-HT modulates the impact of expected rewards and punishments on decision-making cognition. Social decision-making also involves weighing shortterm desires against long-term goals (e.g., compliance with social norms). To investigate decision-making cognition in social contexts, researchers typically set up games with multiple players. In these games, subjects must decide whether or not to cooperate with, trust, or retaliate against their partner. Social decision-making has been linked to 5-HT function. Chronic (2-week) pre-treatment with the SSRI citalopram enhanced cooperative decisions in the Prisoner’s Dilemma game (Tse and Bond, 2002); ATD had the opposite effect (Wood et al., 2006). In the Ultimatum Game, ATD increased retaliation against unfair treatment (Crockett et al., 2008). Notably, the effects of ATD on Ultimatum Game decision-making mirror the effects of lesions to the ventromedial prefrontal cortex (Koenigs and Tranel, 2007), suggesting a role for 5-HT in modulating decision-making cognition in this brain region.

5-HT and compulsivity A clinical distinction is often made between impulsivity and compulsivity (Hollander and Rosen, 2000). In the latter case, we may define this as the inappropriate perseveration of responding, despite adverse consequences. Whereas ADHD is perhaps the most characteristic clinical example of impulsivity, obsessive-compulsive disorder is the paradigmatic example of compulsivity. Like impulsivity, compulsivity can be measured in a variety of ways and is probably not a unitary construct. For example, compulsivity can be measured in some sense by a failure to stop responding, and so the SSRTT may have an ambiguous position in this respect. However, perseveration in tasks in which altered reinforcement contingencies dictate that it is appropriate to switch responding are generally used to characterize compulsivity. The simplest version of this is extinction (reinforcement omission); increased resistance to extinction can be taken as an example of perseverative responding likely to involve inhibitory processes, given that modern conceptions of extinction suggest that it involves an active inhibitory process that suppresses stimulus–reward or action–outcome contingencies. Another measure is provided by discrimination reversal learning, in which previous associations between one stimulus and a rewarding outcome, and the other and reward omission

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or punishment, are reversed, so that the animal has to adapt appropriately to the altered environmental situation. Failure to reverse may in part occur because of a failure to learn the new stimulus–response associations; this learning is prevented if the animal persists in responding to the previously reinforced stimulus.

Reversal learning and 5-HT Reversal learning is known to depend on an OFC-striatal system in monkeys and rats. Fiber-sparing lesions of the OFC impair reversal learning, whether between visual objects in rhesus monkeys, marmosets (Dias et al., 1996) or rats (Chudasama and Robbins, 2003), or between spatial locations in the rat (Boulougouris et al., 2007). Part of the deficit in each case appears to be a tendency to perseverate in the previously reinforced response. In the past few years, it has become apparent that the ascending 5-HT systems powerfully modulate reversal learning at the level of the OFC. Thus, in marmoset monkeys, depletion of 5-HT selectively from the PFC produces striking deficits in reversal learning, particularly in serial reversal, where the contingencies are continually reversed upon attainment of the learning criterion (Clarke et al., 2004, 2005). Microanalysis of responding during the reversal stage shows that the deficit is at least partly because of a perseveration of responding to the previously rewarded stimulus immediately following contingency reversal, implicating the failure of a response inhibitory control process. A further experiment has shown that the deficit is clearly perseverative in the sense that the 5-HT-depleted monkeys do not disengage from a previously reinforced stimulus; if it is removed and replaced by a novel stimulus, discrimination learning is normal (Clarke et al., 2007). However, it is apparent that the ‘perseverative’ deficit again is more specific than would be expected of a global disinhibitory problem. First, performance on another type of shifting task, the extra-dimensional shift, which is more dependent on the lateral PFC, is not impaired by PFC 5-HT depletion (Clarke et al., 2005). Second, an obvious way of explaining the perseveration is in terms of retarded resistance to extinction. However, a recent experiment has ruled out this mechanism, as OFC 5-HT depletion failed to affect extinction of a single (nondiscriminated) rewarded response – although OFC DA loss did produce massive resistance to extinction (Walker et al., 2008). A subsequent experiment on how PFC 5-HT loss affects the acquisition of control over behavior by conditioned stimuli (i.e., conditioned reinforcers) has indicated that the 5-HT loss appears to produce a ‘bias’ towards some aspects of the stimulus which can retard acquisition of new responding – this again contrasts with the effects of OFC DA loss which is associated with no such bias.

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In more general terms, the link of 5-HT to reversal learning has been strikingly confirmed by other studies in primates – for example, linking the short-armed alleles of the 5-HT transporter polymorphism to inferior reversal learning (Izquierdo et al., 2007). In humans, ATD slows response times (Murphy et al., 2002) and increases errors to criterion during reversal learning (Park et al., 1994; Rogers et al., 1999b; Murphy et al., 2002). Talbot et al. (2006) failed to find any significant effects of tryptophan depletion on reversal learning, but this may simply highlight possible heterogeneity of response due to genetic variation in response to low tryptophan. One challenge that arises in studying reversal learning in humans is that simple versions of the task (such as those used with rats and marmosets) are typically not sufficiently difficult to be sensitive to drug manipulations. To address this issue, a probabilistic version of the reversal learning task was developed. In the probabilistic reversal task, subjects receive misleading feedback on 20 percent of trials. The behavioral and neural effects of 5-HT manipulations on probabilistic reversal learning in humans appear to be somewhat distinct from the effects of global prefrontal 5-HT depletion on classic reversal learning in rats and marmosets. A neuroimaging study of reversal learning in humans did not observe any effects of ATD on perseverative responding or OFC activity (Evers et al., 2005). Instead, the authors found that ATD enhanced activity in the dorsomedial PFC in response to negative feedback throughout the task. Another study using the same task showed that acute SSRI (citalopram) administration impaired performance by increasing the tendency to switch following misleading negative feedback, which fits with the hypothesis that low 5-HT heightens responding to negative feedback (Chamberlain et al., 2006). Similar behavioral and neural responses have been observed in depressed patients, and this mechanism is thought to underlie the ‘catastrophic response to perceived failure’ seen in depression (Taylor Tavares et al., 2008). In summary, 5-HT in the OFC appears responsible for biasing responding to particular aspects of the stimulus without necessarily being involved in control of the vigor of responding during extinction, whereas OFC DA has the opposite role. This dissociation may, of course, not hold for subcortical structures to which the OFC projects, such as the medial striatum, which is, however, also implicated in reversal learning (Clarke et al., 2008). Thus far, we have been unable to examine which 5-HT receptors are implicated in these behavioral effects in marmosets. However, we have begun such experiments in the rat, by using a simple spatial reversal paradigm which is also sensitive to OFC lesions (Boulougouris et al., 2007). Systemic administration of the 5-HT2A receptor antagonist M100907 impairs reversal on this task, whereas the

5-HT2C receptor antagonist SB-242084 again had the opposite effect, in this case of facilitation of reversal learning – and in both cases, the effects appear to be mediated, at least in part, by perseverative responding (Boulougouris et al., 2008). These findings may be theoretically important, as they appear to provide problems for the hypothesis that 5-HT is implicated in behavioral inhibition. As Figure 2 shows, whereas the 5-HT2A receptor antagonist ameliorates impulsive behavior, it induces perseverative responding during reversal. By contrast, the 5-HT2C receptor antagonist exacerbates impulsive responding, but facilitates reversal learning. It is difficult to see how a unitary response inhibition mechanism could account for this. Either there is a common effect on another mediating variable (e.g., anxiety or enhanced aversiveness) which accounts for both effects, or they are controlled by separate neuronal circuitries with differing involvement of 5-HT receptors. Given the involvement of an OFC-medial striatal circuitry in aspects of compulsive behavior, and the IL-PFC-nucleus accumbens in impulsive responding, this does appear plausible. A clear conclusion, however, is that impulsivity and compulsivity do appear to be distinct behavioral constructs, and probably have separate if interactive roles in the explanation of such syndromes as OCD and ADHD, and also substance abuse.

Conclusions We have reviewed studies in experimental animals and humans, mainly from the perspective of our own studies, on the role of 5-HT in inhibitory control and reinforcement processing, relevant to such constructs as impulsivity, compulsivity and anxiety. Progress has clearly been made with respect to theories of central 5-HT function, although, as initially admitted, it is very difficult to arrive at a unitary role for such a complex system. Nevertheless, a few generalizations can be made. The functions of 5-HT in global behavioral inhibition are increasingly questioned; however, 5-HT depletion may especially ‘disinhibit’ responding in situations in which ‘waiting’ is required, perhaps through an exaggeration of the negative aversive qualities of the waiting period. A comparison of effects of 5-HT manipulations on paradigms tapping ‘impulsivity’ and ‘compulsivity’ suggests again that a behavioral construct such as ‘inhibition’ cannot adequately account for the findings. The effects of 5-HT loss on perseveration in monkeys also argue against a simple inhibitory account, in favor of one suggesting a modulation of the OFC in the control of stimulus preference. This theme that manipulations of 5-HT can bias the emotional processing of salient stimuli is consistent with many of the effects of 5-HT manipulations in humans, where, for example, mild and

Role of Central Serotonin in Impulsivity and Compulsivity transient 5-HT loss leads to a bias to respond to negative feedback and to exhibit heightened aversive responses to emotional stimuli. We have also raised the possibility of specific effects of 5-HT manipulations on higher cognitive processes such as decision-making cognition, suggesting specific functions for this neurotransmitter in brain regions such as the prefrontal cortex. Here, the question is whether such effects ultimately derive from actions of 5-HT in lower level processes. The resolution of these paradoxes has been part and parcel of research on 5-HT functions in health and disease over the past 50 years or so. We assume that this will be possible as we understand the impact of current manipulations in more detail in the context of those neural systems on which they impinge, as new methods for studying the role of 5-HT emerge, and as knowledge about the precise functions of the different neural systems modulated by 5-HT accrues. Acknowledgements This work was mainly supported by a Wellcome Trust Programme Grant awarded to T.W. Robbins, B.J. Everitt, A.C. Roberts and B.J. Sahakian, and completed within the Behavioural and Clinical Neuroscience Institute supported by a joint grant from the MRC UK and the Wellcome Trust. Molly Crockett is a Gates Scholar. References Anderson, I.M., Mckie, S., Elliott, R., Williams, S.R. and Deakin, J.F.W. (2008) Assessing human 5-HT function in vivo with pharmacoMRI. Neuropharmacology, 55: 1029–1037. Aron, A.R. and Poldrack, R.A. (2006) Cortical and subcortical contributions to Stop signal response inhibition: role of the subthalamic nucleus. J. Neurosci., 26: 2424–2433. Bari, A., Eagle, D.M., Mar, A.C., Robinson, E.S.J. and Robbins, T.W. (2009) Dissociable effects of noadrenaline, dopamine and serotonin uptake blockade on stop task performance in rats. Psychopharmacology, 205; 273–283. Bel, N. and Artigas, F. (1996) Reduction of serotonergic function in rat brain by tryptophan depletion: effects in control and fluvoxamine-treated rats. J. Neurochem., 67: 669–676. Berg, K.A., Clarke, W.P. and Cunningham, K.A. (2008) Finetuning serotonin 2C receptor function in the brain: molecular and functional implications. Neuropsychopharmacology, 55: 969–976. Blier, P., Pineyro, G., El Mansari, M., Bergeron, R. and De Montigny, C. (1998) Role of somatodendritic 5-HT autoreceptors in modulating 5- HT neurotransmission. Ann. NY Acad. Sci., 861: 204–216. Boulougouris, V., Dalley, J.W. and Robbins, T.W. (2007) Effects of orbitofrontal, infralimbic and prelimbic cortical lesions on serial spatial reversal learning in the rat. Behav. Brain Res., 179: 219–228. Boulougouris, V., Glennon, J.C. and Robbins, T.W. (2008) Dissociable effect of selective 5-HT2A and 5-HT2C receptor

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