Serotonin (5-hydroxytryptamine, or 5-HT) is strongly implicated in the ability to shift behavior in response to changing stimulus-reward contingencies. However, there is little information on the contribution of different 5-HT receptors in reversal learning. Thus, we investigated the effects of systemic administration of the 5-HT2A antagonist M100907 (0, 0.01, 0.03, and 0.1 mg/kg, i.p.) and the 5-HT2C antagonist SB 242084 (0, 0.1, 0.3, and 1.0 mg/kg, i.p.) on the performance of an instrumental two-lever spatial discrimination and serial spatial reversal learning task, where both levers were presented and only one was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, a series of within-session reversals was presented. Neither M100907 nor SB 242084 altered performance during spatial discrimination and retention of the previously reinforced contingencies. M100907 significantly impaired reversal learning by increasing both trials to criterion (only at the highest dose) and incorrect responses to criterion in Reversal 1, a pattern of behavior manifested as increased perseverative responding on the previously reinforced lever. In contrast, SB 242084 improved reversal learning by decreasing trials and incorrect responses to criterion in Reversal 1, with significantly fewer perseverative responses. These data support the view that 5-HT2A and 5-HT2C receptors have distinct roles in cognitive flexibility and response inhibition. The improved performance in reversal learning observed following 5-HT2C receptor antagonism suggests these receptors may offer the potential for therapeutic advances in a number of neuropsychiatric disorders where cognitive deficits are a feature, including obsessive-compulsive disorder.
Cognitive inflexibility, the inability spontaneously to withhold, modify, or sustain adaptive behavior in response to changing situational demands, is associated with various psychiatric disorders, most notably schizophrenia, depression, and obsessive-compulsive disorder (OCD). The elucidation of the underlying neurochemical mechanisms of cognitive flexibility and constituent processes including response inhibition could be of major importance for the understanding of the etiology and treatment of inflexible behavior apparent in such disorders.
The reversal learning task has been used as a measure of behavioral flexibility in humans (Rolls et al, 1994; Rogers et al, 2000; Murphy et al, 2002; Fellows and Farah, 2003), nonhuman primates (Jones and Mishkin, 1972; Butter, 1969; Dias et al, 1996; Clarke et al, 2004, 2005, 2007; Lee et al, 2007), and rats (Birrell and Brown, 2000; McAlonan and Brown, 2003; Idris et al, 2005; van der Meulen et al, 2006; Boulougouris et al, 2007). Converging evidence from a number of studies has implicated the orbitofrontal cortex (OFC) (human, Rolls et al, 1994; nonhuman primate, Settlage et al, 1948; Jones and Mishkin, 1972; Butter, 1969; Dias et al, 1996; rat, Chudasama and Robbins, 2003; McAlonan and Brown, 2003; Boulougouris et al, 2007) and the ventrolateral sector of caudate nucleus (monkey, Divac et al, 1967; rat, Dunnett and Iversen, 1980), while a recent study demonstrated that basolateral amygdala lesions abolished OFC-induced reversal learning impairments (Stalnaker et al, 2007). Efficient reversal learning calls upon specific operations such as (1) detection of the shift in contingency; (2) inhibition of a prepotent, learned response; (3) overcoming ‘learned irrelevance’; and (4) new associative learning.
Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter that has been strongly implicated in behavioral flexibility. Selective 5-HT depletions in the marmoset prefrontal cortex induced by the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) impaired performance on a serial visual discrimination reversal learning task, which was mainly due to perseverative responding to the previously rewarded stimulus (Clarke et al, 2004). Subsequent work has established that this deficit was specific to reversal learning and not attentional set shifting (Clarke et al, 2005). More recently, it has been demonstrated that this deficit in reversal learning was specific to 5-HT and not dopamine (DA) depletion in the OFC (Clarke et al, 2007). Similarly, systemic administration of the 5-HT1A receptor agonist 8-OH-DPAT impaired serial reversal learning by enhancing perseverative tendencies, an effect which was reversed by the selective 5-HT1A receptor antagonist WAY100635 (Clarke et al, 2003). Deficits were found in 5-HT-deficient rats following a tryptophan-deficient diet and monkeys with high doses of the 5-HT3 antagonist ondansetron (Barnes et al, 1990; Domeney et al, 1991). However, low doses of ondansetron (Domeney et al, 1991) and lysergic acid diethylamide (LSD) improved reversal learning (King et al, 1974), although these effects were not specific to reversal learning per se.
While the involvement of 5-HT systems in reversal learning is thus established, the particular 5-HT receptor subtypes that underlie these effects are not well understood. A growing body of evidence suggests that 5-HT2A and 5-HT2C receptors have opposing functional roles. For example, 5-HT2C receptors appear to inhibit DA release, whereas activation of 5-HT2A receptors enhances it (Millan et al, 1998; Di Matteo et al, 2001, 2002). Moreover, antagonism of 5-HT2C receptors potentiates some of the behavioral effects of cocaine, whereas antagonism of 5-HT2A receptors attenuates both cocaine-induced hypermotility and reinstatement of cocaine-seeking (Cunningham et al, 1992; Fletcher et al, 2002). Decreasing 5-HT transmission through blockade of 5-HT2C receptors could therefore have opposing effects on behavior to those obtained through antagonizing 5-HT2A receptors. With respect to inhibitory response control, recent reports indicate that the 5-HT2C receptor antagonist SB 242084 increases premature responding on the five-choice serial reaction time task (5CSRTT), whereas 5-HT2A receptor antagonist M100907 decreases the same measure (Higgins et al, 2003; Winstanley et al, 2004). In conclusion, although 5-HT2A and 5-HT2C receptors share similar pharmacological profiles with the highest degree of sequence homology (about 50% overall sequence identity), the apparently different behavioral actions elicited by antagonism at these receptors may be attributable to fundamental differences in signal transduction pathways of the two receptor subtypes (Berg et al, 1994, 1998).
The aim of the present study was to investigate the contribution of 5-HT2A and 5-HT2C receptors on the performance of rats in the instrumental two-lever spatial discrimination and serial reversal learning task through systemic administration of the selective 5-HT2A receptor antagonist M100907 (Kehne et al, 1996) and the selective 5-HT2C receptor antagonist SB 242084 (Kennett et al, 1997) to provide a direct comparison of these two 5-HT receptor subtypes on ‘cognitive flexibility’ and constituent processes including response inhibition.
MATERIALS AND METHODS
Sixty-eight experimentally naive adult male Lister Hooded rats (Charles River, UK) weighting 280–320 g at the start of experiments were pair-housed under a reversed light cycle (lights on from 1900 to 0700 hours). Prior to the beginning of training, rats were handled for ≈5 min daily for 5 days and were put on to a food-restriction schedule (18 g of Purina lab chow per day). Water was available ad libitum and testing took place between 1300 and 1600 hours 7 days per week. One animal was excluded due to computer failure during testing. The work was carried out under a UK Home Office Project license (PPL 80/1767) in accordance with the UK Animals (Scientific Procedures) Act 1986.
The behavioral apparatus consisted of eight operant conditioning chambers (30 × 24 × 30 cm; Med Associates, Georgia, VT), each enclosed within a sound-attenuating wooden box fitted with a fan for ventilation and masking of extraneous noise. Each chamber was fitted with two retractable levers located on either side of a centrally positioned food magazine, into which an external pellet dispenser could deliver 45 mg sucrose pellets (Noyes dustless pellets; Sandown Scientific, Middlesex, UK), a light-emitting diode (LED), which was positioned centrally above each lever, a magazine light, and a houselight. Magazine entry was detected by an infrared photocell beam located horizontally across the entrance. The apparatus was controlled by Whisker control software (www.whiskercontrol.com) and the task was programmed in Visual C++ (v.6).
Rats were trained on the instrumental two-lever spatial discrimination and serial reversal learning task as described and illustrated previously (Boulougouris et al, 2007). Briefly, rats were initially trained to nose poke in the central magazine to trigger presentation of the retractable levers and to respond on them under a fixed ratio 3 (FR-3) schedule for food delivery (pretraining). The FR-3 schedule was used to preclude the possibility of reinforcing single, accidental presses on the correct lever.
Acquisition of spatial discrimination
Training continued with the acquisition of a two-lever discrimination task. Now both levers were presented at trial onset and the rat had to learn that three lever presses on only one of these levers would result in reward.
Each session lasted 20 min and consisted of a maximum of five 10-trial blocks. Each trial began with the presentation of both levers and a visual stimulus (a lit LED). The lit LED was used as a distractor and its location (left/right) varied from trial to trial according to a pseudorandom schedule so that the light was presented an equal number of times on each side for the session. Thus, the only stimulus with informational value for the discrimination at this phase was the spatial position of the retractable levers. Throughout the session, three lever presses on one lever (lever A) would produce a single pellet reward and the retraction of both levers, whereas three responses on lever B would result in lever retraction without reward delivery. The position of the reinforced lever (left or right) was kept constant for each rat but was counterbalanced between subjects.
Each rat had one training session per day and was trained to a criterion of nine correct responses in one block of 10 trials (binomial distribution p<0.01, likelihood of attaining criterion in a 10-trial block). Once this criterion was reached, this initial discrimination phase was considered complete, and the animal was returned to the home cage. If the criterion was not achieved this phase was repeated the next day till criterion attainment (Figure 1).
Within-session serial reversal learning task
In the next training session, reversal learning was introduced. By definition, reversal learning presupposes retention of a previously acquired discrimination. In serial reversals, in the first instance this would involve recall of the initially acquired discrimination described above. In subsequent reversals it would involve retention of the preceding reversal phase.
Accordingly, in the reversal session, animals were again exposed to the initial discrimination task described above (with the same lever rewarded as before: discrimination retention in the first instance, latest reversal retention in subsequent runs). This initial retention phase preceding reversal also comprised a maximum of five 10-trial blocks and once the criterion of nine correct responses in a 10-trial block was achieved, the position of the reinforced lever was reversed (reversal phase). The reversal phase also consisted of a maximum of five 10-trial blocks. The learning criterion was the same as in the initial phase (nine correct responses in a 10-trial block). Animals required more than one session to reach criterion on reversal phase. Thus, they received multiple, separate training sessions that were summed together to produce the final results. During these sessions the initial contingency was determined by retention fluency. For example:
All rats always achieved criterion in the initial retention phase preceding reversal.
A series of three reversals was given. Between successive reversals, animals were always given a single intervening day session of up to five 10-trial blocks where they were required to show retention of the previous reversal phase by reaching the 9 of 10 correct criterion in one 10-trial block (retention phase without reversal: same procedure as acquisition of spatial discrimination described above; Figure 1).
M100907 and SB 242084 (Solvay, Weesp, The Netherlands) were tested in two different experiments. Prior to drug administration, animals were divided into four groups for each experiment, matched for their performance during the acquisition of the spatial discrimination. Each group received i.p. injections of either M100907 (0, 0.01, 0.03, and 0.1 mg/kg; Experiment 1) or SB 242084 (0, 0.1, 0.3, and 1.0 mg/kg; Experiment 2). All drugs were administered daily 20 min prior to the start of the behavioral task. Following initiation of drug testing, animals required 8–11 days to achieve criterion in Reversals 1–3.
M100907 was dissolved in saline and the pH adjusted to 6.25 using 0.1 M NaOH and 0.1 M HCl. SB 242084 was dissolved in 25 mM citric acid in 8% cyclodextrine in 0.9% saline, and the pH adjusted to 6.4 using 0.1 M NaOH. Systemic injections of drug were given in a volume of 1 ml/kg. Determination of doses was based on previous studies using the same drugs (Jones et al, 2002; Winstanley et al, 2004).
The main measures of the animals' ability to learn the discrimination and reversals were: (1) the number of trials to criterion, (2) the total number of incorrect responses to criterion on completed (correct and incorrect) trials, and (3) the total number of errors (ie incorrect trials) to criterion. Type of errors were further analyzed as described previously (Boulougouris et al, 2007) according to the method of Dias et al (1996) and Bussey et al (1997), modified from Jones and Mishkin (1972). In this analysis, errors during reversal learning were broken down into two learning stages: errors committed before the attainment of chance level performance (<50% correct trials) and errors committed above chance (⩾50% correct trials). Jones and Mishkin regarded errors made during the first stage of learning as indicative of perseverative responses to the previously reinforced stimulus. Thus, stage 1 errors are termed ‘perseverative errors’ whereas stage 2 errors are termed ‘learning errors’. Additional secondary measures recorded for each trial were (3) the latency to respond, (4) the latency to collect the reward, (5) the number of omissions, and (6) the number of extra responses (ie incorrect responses in a trial scored as correct).
Data for each variable were subjected to a repeated-measures ANOVA. Where significant interactions were detected, they were further explored through separate ANOVAs or planned comparisons (contrast testing) to establish simple effects. For all comparisons, significant difference was assumed at p<0.05. The between-subject factor was Drug (four levels: three different doses of drug plus vehicle) and the within-subject factors were either Retention phase without reversal occurring (three levels: retention of spatial discrimination, retention of Reversals 1–2), or Retention phase preceding reversal (three levels: retention of spatial discrimination, retention of Reversals 1–2), or Reversal phase (three levels: Reversals 1–3).
Prior to drug administration, the groups did not differ in the number of incorrect responses to reach the performance criterion on the acquisition of spatial discrimination (M100907: F3,30=1.10, p=0.37; SB 242084: F3,29=0.295, p=0.83; data not shown).
M100907 had no significant effects, at any dose, on retention (with or without reversal occurring) of the drug-free spatial discrimination or the previously acquired reversals, as indicated by a lack of effect on the number of trials to reach criterion (Figure 2a) or the number of incorrect responses (Figure 3a). However, rats treated with M100907 at the two highest doses (0.03 and 0.1 mg/kg) exhibited significant impairment of performance in reversal learning. Specifically, M100907 (0.1 mg/kg) significantly increased trials to criterion in reversal phase 1 (reversal 1—vehicle vs 0.1 mg/kg contrast: F1,30=15.80, p=0.0004; Figure 2b), whereas both doses of 0.03 and 0.1 mg/kg significantly increased incorrect responses to criterion (reversal 1—vehicle vs 0.03 mg/kg contrast: F1,30=4.93, p=0.03; vehicle vs 0.1 mg/kg contrast: F1,30=19.81, p<0.001; Figure 3b). Animals treated with the two highest doses of M100907 made significantly more perseverative errors (ie <50% correct) than controls in reversal 1 phase (reversal 1—vehicle vs 0.03 mg/kg: F1,30=6.75, p=0.014; vehicle vs 0.1 mg/kg: F1,30=18.75, p<0.001; Figure 4). No differences were noted in learning errors (Figure 4).
In contrast, although SB 242084 did not alter significantly either the number of trials to reach criterion (Figure 5a) or the number of incorrect responses (Figure 6a) during retention (with or without reversal occurring) of the drug-free spatial discrimination or the previously acquired reversals, it facilitated reversal learning. Specifically, SB 242084 significantly decreased trials to criterion in reversal phase 1 at all doses (reversal 1—vehicle vs 0.1 mg/kg contrast: F1,29=4.65, p=0.039; vehicle vs 0.3 mg/kg contrast: F1,29=6.13, p=0.019; vehicle vs 1.0 mg/kg contrast: F1,29=11.0, p=0.002; Figure 5b), while the two highest doses of the drug decreased both number of incorrect responses (reversal 1—vehicle vs 0.3 mg/kg contrast: F1,29=5.71, p=0.024; vehicle vs 1.0 mg/kg contrast: F1,29=8.37, p=0.007; Figure 6b) and perseverative errors (reversal 1—vehicle vs 0.3 mg/kg: F1,29=5.17, p=0.03; vehicle vs 1.0 mg/kg: F1,29=8.05, p=0.008; Figure 7). No differences were noted in learning errors (Figure 7).
Neither M100907- nor SB 242084-treated animals omitted more trials compared with vehicle-treated controls (Table 1) and there were no effects of either drug on the latencies to make a respond at any stage of the experiment (Table 2). Finally, no significant differences were noted between the groups in number of extra responses on the incorrect lever during correct scored trials (p-values>0.05; data not shown).
It should be noted here that M100907 vehicle-treated rats performed better in Reversal 1 than SB 242084 vehicle-treated controls in the measures of incorrect responses and perseverative errors, though not in terms of number of trials. Current as well as previous (Boulougouris et al, 2007) work has defined the range of variation in control groups to be about 225±26 for incorrect responses and 57±17 for perseverative errors in Reversal 1. While not significantly outside the typical range of responding expected in this task (SB 242084 vs M100907; incorrect responses, 256±19.08 vs 196±15.26; perseverative errors, 74.45±6.51 vs 51.18±0.62), baseline differences even smaller than those reported here could influence drug response, a fact that should be kept in mind when interpreting these results.
We have demonstrated dissociable behavioral effects of the selective 5-HT2A antagonist M100907 and the 5-HT2C antagonist SB 242084 on serial spatial reversal learning. M100907 impaired initial reversal learning by increasing number of trials (highest dose only) and incorrect responses to criterion (two highest doses). This impairment, perseverative in nature, occurred in the absence of significant effects on retention of previous stimulus-reward contingencies. In contrast, SB 242084 improved reversal learning by decreasing the same measures (two highest doses). Our findings indicate that 5-HT2A and 5-HT2C receptors influence distinct aspects of behavioral flexibility. These dissociable effects were observed during Reversal 1 only. Failure of the drugs to affect Reversals 2 and 3 may be due to several reasons: (1) tolerance to the drug effects after repeated administration (effects of chronic administration of these drugs has not been reported); (2) Reversal 1 may be more drug sensitive, possibly due to its novelty; or (3) because it requires a large number of trials to criterion compared with Reversals 2 and 3; this reveals a possible learning set component specific to Reversal 1, which could be expected to benefit future reversals. It is noteworthy that OFC lesions (marmoset, Dias et al, 1996; rat, Boulougouris et al, 2007) also impaired the first reversal only. The single study reporting impaired first, second, and third reversals of odor discriminations after OFC lesions (McAlonan and Brown, 2003) employed a task where reversal sessions are not true serial reversals, as they occur with novel stimuli for each reversal.
In the present study, analysis of type of errors revealed that the opposing effects of the 5-HT2A and 5-HT2C receptor antagonists were specific to early Reversal 1 stages, affecting perseverative but not learning errors. Perseverative responding may have been modified as a result of changes either in prepotent response inhibition, or in the ability to detect contingency changes. We believe the perseverative deficit we noted reflects a selective influence on inhibitory response control: the alternative explanation, deficient detection of contingency changes, should have resulted in significant differences in (1) omissions and/or (2) number of incorrect responses until the stage where animals score their first correct trial during reversal (ie experience contingency shift). No such differences were observed.
Experiment 1: Effects of M100907 on Reversal Learning
M100907 affected neither rats' ability to perform a spatial discrimination learned prior to drug administration nor the late phases (ie ‘learning’ phases) of reversal learning. However, it significantly increased perseverative errors in the early stage of reversal learning. This finding is reminiscent of the effects of dietary tryptophan depletion in humans (Park et al, 1994) or selective (5,7-DHT) destruction of the ascending serotonergic projections in animals (Clarke et al, 2004, 2005, 2007). This perseverative deficit is likely to be mediated by orbitofrontal circuitry and its serotonergic innervation, which have previously been shown to play a critical role in response reversal. Specifically, we have previously demonstrated that bilateral excitotoxic lesions of the rat OFC (but not infralimbic or prelimbic cortex) impair reversal learning, a deficit manifested as increased perseverative responding to the previously reinforced lever (Boulougouris et al, 2007). Moreover, Clarke et al (2007) showed that selective 5-HT depletion of the marmoset OFC markedly impaired performance of a visual serial reversal learning task and this deficit was due to a failure to inhibit responding to the previously rewarded stimulus.
Previous studies have shown that 5-HT2A receptor antagonism produces a functional enhancement of D2 receptor antagonism under certain conditions. Selective blockade of 5-HT2A receptors, for example, enhances the effect of D2 receptor blockade on ventral midbrain DA cell firing (Olijslagers et al, 2004, 2005) and on limbic DA release (Bonaccorso et al, 2002; Liegeois et al, 2002). In reversal learning, there is evidence for an involvement of the DA system. Ridley et al (1981) demonstrated impaired reversal after the D2 receptor antagonist haloperidol, while Lee et al (2007) showed that the selective D2/D3 receptor antagonist, raclopride, impairs reversal learning in monkeys. Furthermore, Floresco et al (2006) showed that administration of the D2/D3 subtype selective antagonist eticlopride potently impaired animals' ability to change their behavior in response to a conditional change of rule in a set-shifting task. Finally, selective blockade of D2 receptor gene in knockout mice impaired reversal learning of an odor discrimination (Kruzich and Grandy, 2004).
It is worth noting that the results reported here reveal a dissociation between anticipatory responding in the 5CSRTT and reversal learning (ie impulsivity vs compulsivity). Specifically, studies utilizing the 5CSRTT have shown that M100907 decreases premature but not perseverative responses (Winstanley et al, 2003). These authors suggested that the latter measure does not represent perseverative responding at the aperture associated with reward but perseverative nose-poke activity at the array that is not punished. In another study (Carli et al, 2006), infusions of M100907 in the medial prefrontal cortex (mPFC) counteracted the loss of executive control (impulsivity increase induced by the competitive NMDA receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-propyl-1-phosphonic acid), while the selective 5-HT1A receptor agonist 8-OH-DPAT decreased compulsive perseveration. Given the suggestion that perseveration in a response associated with reward delivery may be related to both impulsive and compulsive behavior, particularly when such an action is punished or not rewarded (Soubrié, 1986; Hollander and Rosen, 2000), these findings suggest that perseverative and premature responses in the 5CSRTT are differentially regulated by the 5-HT system. This lends support to the view that different aspects of impulsivity/compulsivity have distinct neurobiological substrates.
Experiment 2: Effects of SB 242084 on Reversal Learning
In contrast to M100907, SB 242084 actually improved serial spatial reversal learning by reducing the number of trials and incorrect responses to criterion in Reversal 1 compared to vehicle controls. Perseverative, but not learning, errors were also reduced.
5-HT2C antagonism has previously been shown to mimic some of the effects of psychostimulant drugs such as D-amphetamine which increases DA release in the nucleus accumbens (Cole and Robbins, 1987, 1989): D-amphetamine causes a similar pattern of behavioral effects on the 5CSRTT as SB 242084, increasing the number of premature responses (Cole and Robbins, 1987; Harrison et al, 1997). Moreover, it has been shown to impair reversal-test performance (Ridley et al, 1998; Bensadoun et al, 2004; Idris et al, 2005). However, other studies have reported D-amphetamine facilitation of reversal learning in a two-choice simultaneous brightness discrimination (Weiner et al, 1986; Weiner and Feldon, 1986) and enhanced switching behavior (Evenden and Robbins, 1983; van den Bos and Cools, 1989). The present finding that SB 242084 decreased number of trials and incorrect (perseverative) responses may be consistent with these findings.
To our knowledge, this is the first demonstration of 5-HT2C receptor involvement in reversal learning. Results on the effects of 5-HT2C receptor agonists on compulsive behavior are equivocal. 5-HT2C receptor activation induced ‘compulsive’ grooming (Graf et al, 2003; Graf, 2006) and directional persistence in spatial alternation (Tsaltas et al, 2005), while in other models 5-HT2C agonists attenuated compulsive behavior (marble burying and schedule-induced polydipsia; Martin et al, 1998a). It should be noted that the anticompulsive effects of 5-HT2C agonists have been attributed to their sedative effects (Kennett et al, 2000). On the other hand, blockade of 5-HT2C receptors increased compulsive drinking in the polydipsia model (Martin et al, 2002), whereas E Tsaltas et al (unpublished observations) have shown that SB 242084 protected against meta-chlorophenylpiperazine (mCPP; a nonselective serotonin agonist)-induced directional persistence in the spatial alternation model of OCD. Finally, systemic administration of the 5-HT2C receptor antagonist RS 10221 selectively decreased ‘surplus’ lever-pressing in the signal attenuation model (Flaisher-Grinberg et al, unpublished observations).
Effects of 5-HT2C receptor antagonism have also been reported to enhance the stimulant effects (eg suppression of motivated behavior, locomotor activity, etc) of several drugs of abuse (phencyclidine, 3,4-methylenedioxymethamphetamine (MDMA); Hutson et al, 2000; Fletcher et al, 2001, 2002a, 2002b). Given that addiction and compulsivity seem to share underlying neural substrates such as the OFC and the DA system (Stein et al, 1995; Jentsch and Taylor, 1999; Everitt and Robbins, 2005; Kalivas and Volkow, 2005), the present finding that SB 242084 reduced perseverative responding suggests that 5-HT2C receptors of distinct brain areas may be involved in compulsivity vs drug addiction. Accumulating evidence attributes the proaddictive effects of 5-HT2C antagonists to increase of burst firing of dopaminergic neurons in the ventral tegmental area (VTA), leading to increased release of DA in the nucleus accumbens (Millan et al, 1998; Di Matteo et al, 1999, 2000a, 2000b, 2001, 2002; Gobert et al, 2000; Di Giovanni et al, 2001; Higgins and Fletcher, 2003). The finding that SB 242084 reduced perseverative responding in spatial reversal learning, a task dependent on the OFC (Boulougouris et al, 2007), suggests that this facilitatory effect of 5-HT2C antagonists is possibly mediated by the OFC.
Pharmacological Specificity of the Drugs and 5-HT/DA Neurotransmission
5-HT2C receptors are located in a variety of forebrain structures, including the neocortex, amygdala, hippocampus, dorsal, and ventral (including nucleus accumbens) striatal regions, as well as in monoaminergic cell body-rich areas such as the locus coeruleus, substantia nigra, and VTA (Pompeiano et al, 1994; Abramowski et al, 1995; Eberle-Wang et al, 1997). Eberle-Wang et al (1997) demonstrated the presence of 5-HT2C mRNA within inhibitory GABAergic interneurons making direct synaptic contact with dopaminergic cell bodies in both the VTA and substantia nigra. The 5-HT2A receptors are particularly prominent in cortical areas but are also found in DA-rich areas such as the striatum, substantia nigra, and VTA (Pompeiano et al, 1994; Lopez-Gimenez et al, 1997; Doherty and Pickel, 2000).
It has been shown that the 5-HT2 receptor subtypes are differentially activated by 5-HT in vivo. M100907 does not influence the spontaneous firing rate of dopaminergic neurons or alter basal levels of DA or norepinephrine (noradrenaline, NA) release (Kehne et al, 1996), but attenuates amphetamine-induced hyperactivity (Sorensen et al, 1993) and amphetamine or DOI or MDMA-induced DA release (Schmidt et al, 1994; Gobert and Millan, 1999; Porras et al, 2002). In contrast, administration of 5-HT2C receptor antagonists, including SB 242084, increases DA and NA release (Millan et al, 1998; Di Matteo et al, 2000a; Gobert et al, 2000) as well as VTA cell firing in the nucleus accumbens (Di Matteo et al, 1999). Moreover, SB 242084 produces behavioral effects in 5-HT-depleted animals (Winstanley et al, 2004), indicating that the 5-HT2C receptors are tonically activated and that 5-HT2C receptors are likely to be active under conditions of low-5-HT tone. Alternatively, these data may suggest that SB 242084 effects are not due to its actions at 5-HT receptors. However, SB 242084 is a high-affinity antagonist for the 5-HT2C receptor (pKi 9.0), 100-fold, 158-fold selectivity over the 5-HT2B and 5-HT2A receptors, respectively, and also has over 100-fold selectivity for the 5-HT2C receptor over a range of other serotonergic, dopaminergic, and adrenergic receptors (Kennett et al, 1997). It seems unlikely that such marked behavioral effects known to be sensitive to manipulations of the 5-HT system are caused through the drug's actions at non-serotonergic receptors. Moreover, there is a debate whether SB 242084 acts as an inverse agonist at 5-HT2C receptors rather than as a neutral antagonist (Barker et al, 1994), but there is no evidence to date supporting this possibility. In contrast, M100907 has been shown to exert its behavioral effects (reduced hyperactivity after NMDA receptor antagonism) under conditions of increased 5-HT release, while low-5-HT tone abolishes these effects (Martin et al, 1998b; Ceglia et al, 2004). This differentiation between 5-HT2A and 5-HT2C receptors may be attributed to the lower affinity of M100907 for the 5-HT2A receptor than that of SB 242084 for the 5-HT2C receptor, or to differences in selectivity of 5-HT for 5-HT2C over 5-HT2A receptors. However, these explanations seem unlikely (Winstanley et al, 2004) as the pKi of M100907 for the 5-HT2A receptor is 9.4 and the pKi of SB 242084 for the 5-HT2C receptor is 9.0 (Barnes and Sharp, 1999).
Obsessive-Compulsive Disorder and Reversal Learning
The present findings may be relevant to various neuropsychiatric disorders where inflexible behavior is a feature. Although OCD patients are not markedly impaired on simple reversal learning, they have impairments in other tasks sensitive to OFC function such as alternation learning, a task related to reversal learning (Freedman et al, 1998). They also show impairments on laboratory tests of frontal lobe function involving response shifting and inhibitory processing that correlate with the severity of their symptoms (Veale et al, 1996; Rosenberg et al, 1997; Schmidtke et al, 1998; Hollander and Rosen, 2000). The serotonergic system is also implicated in OCD, for example, via the therapeutic effects of specific serotonin reuptake inhibitors (SSRIs) (Baumgarten and Grozdanovic, 1998; El Mansari and Blier, 2006). Further investigation has implicated 5-HT2 receptor families in the pathophysiology of OCD and in the mediation of the antiobsessive effects of SRIs. Treatment with psychedelic drugs possessing potent 5-HT2A/2C agonist action properties appears to have favorable results on OCD patients (Moreno and Delgado, 1997; Delgado and Moreno 1998a, 1998b; Delgado, 2000), and 5-HT2C receptor antagonism has been suggested to play a role in the generation of obsessive-compulsive symptoms in patients with comorbid psychiatric disorder, although this effect was not reported in patients suffering from primary/pure OCD (Khullar et al, 2001; see Sareen et al, 2004 for review). Furthermore, the 5-HT2 antagonist ritanserin reversed the therapeutic effect of fluvoxamine (Erzegovesi et al, 1992), while studies which assessed the behavioral response to mCPP following chronic treatment with SSRIs have shown attenuated response to mCPP suggesting that chronic treatment with SSRIs leads to desensitization of 5-HT2C receptors (Kennedy et al, 1993; Kennett et al, 1994; Maj et al, 1996; Yamauchi et al, 2004). This latter hypothesis has been strengthened from reports on 5-HT2C downregulation following chronic treatment with SSRIs (van Oekelen et al, 2003; Serretti et al, 2004). Based on this line of evidence, the results presented here may be relevant to the pathophysiology of OCD, suggesting a potential role for 5-HT2A and 5-HT2C receptors when considering possible treatment strategies for this disorder.
Abramowski D, Rigo M, Duc D, Hoyer D, Staufenbiel M (1995). Localization of the 5-hydroxytryptamine2C receptor protein in human and rat brain using specific antisera. Neuropharmacology 34: 1635–1645.
Barker EL, Westphal RS, Schmidt D, Sanders-Bush E (1994). Constitutively active 5-hydroxytryptamine2C receptors reveal novel inverse agonist activity of receptor ligands. J Biol Chem 269: 833–835.
Barnes JM, Costall B, Coughlan J, Domeney AM, Gerrard PA, Kelly ME et al (1990). The effects of ondansetron, a 5-HT3 receptor antagonist, on cognition in rodents and primates. Pharmacol Biochem Behav 35: 955–962.
Barnes NM, Sharp T (1999). A review of central 5-HT receptors and their function. Neuropharmacology 38: 1083–1152.
Baumgarten HG, Grozdanovic Z (1998). Role of serotonin in obsessive-compulsive disorder. Br J Psychiatry 35 (Suppl): 13–20.
Bensadoun JC, Brooks SP, Dunnett SB (2004). Free operant and discrete trial performance of mice in the nine-hole box apparatus: validation using amphetamine and scopolamine. Psychopharmacology 174: 396–405.
Berg KA, Clarke WP, Sailstad C, Saltzman A, Maayani S (1994). Signal transduction differences between 5-hydroxytryptamine type 2A and type 2C receptor systems. Mol Pharmacol 46: 477–484.
Berg KA, Maayani S, Goldfarb J, Scaramellini C, Leff P, Clarke WP (1998). Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol Pharmacol 54: 94–104.
Birrell JM, Brown VJ (2000). Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci 20: 4320–4324.
Bonaccorso S, Meltzer HY, Li Z, Dai J, Alboszta AR, Ichikawa J (2002). SR46349-B, a 5-HT(2A/2C) receptor antagonist, potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens. Neuropsychopharmacology 27: 430–441.
Boulougouris V, Dalley JW, Robbins TW (2007). Effects of orbitofrontal, infralimbic and prelimbic cortical lesions on serial spatial reversal learning in the rat. Behav Brain Res 179: 219–228.
Bussey TJ, Muir JL, Everitt BJ, Robbins TW (1997). Triple dissociation of anterior cingulate, posterior cingulate, and medial frontal cortices on visual discrimination tasks using a touchscreen testing procedure for the rat. Behav Neurosci 111: 920–936.
Butter CM (1969). Impairments in selective attention to visual stimuli in monkeys with inferotemporal and lateral striate lesions. Brain Res 12: 374–383.
Carli M, Baviera M, Invernizzi RW, Balducci C (2006). Dissociable contribution of 5-HT1A and 5-HT2A receptors in the medial prefrontal cortex to different aspects of executive control such as impulsivity and compulsive perseveration in rats. Neuropsychopharmacology 314: 757–767.
Ceglia I, Carli M, Baviera M, Renoldi G, Calcagno E, Invernizzi RW (2004). The 5-HT receptor antagonist M100,907 prevents extracellular glutamate rising in response to NMDA receptor blockade in mPFC. J Neurochem 91: 189–199.
Chudasama Y, Robbins TW (2003). Dissociable contributions of the orbitofrontal and infralimbic cortex to pavlovian autoshaping and discrimination reversal learning: further evidence for the functional heterogeneity of the rodent frontal cortex. J Neurosci 23: 8771–8780.
Clarke H, Walker S, Dalley J, Robbins T, Roberts A (2007). Cognitive inflexibility after prefrontal depletion is behaviorally and neurochemically specific. Cereb Cortex 17: 18–27.
Clarke HF, Dalley JW, Crofts HS, Robbins TW, Roberts AC (2003). Prefrontal serotonin and serial reversal learning: the effects of serotonin depletion and serotonin 1A receptor manipulation. Presentation at EBPS, Antwerp, Belgium.
Clarke HF, Dalley JW, Crofts HS, Robbins TW, Roberts AC (2004). Cognitive inflexibility following prefrontal serotonin depletion. Science 304: 878–880.
Clarke HF, Walker SC, Crofts HS, Dalley JW, Robbins TW, Roberts AC (2005). Prefrontal serotonin depletion affects reversal learning but not attentional set shifting. J Neurosci 25: 532–538.
Cole BJ, Robbins TW (1987). Amphetamine impairs the discriminative performance of rats with dorsal noradrenergic bundle lesions on a 5-choice serial reaction time task: new evidence for central dopaminergic-noradrenergic interactions. Psychopharmacology 91: 458–466.
Cole BJ, Robbins TW (1989). Effects of 6-hydroxydopamine lesions of the nucleus accumbens septi on performance of a 5-choice serial reaction time task in rats: implications for theories of selective attention and arousal. Behav Brain Res 33: 165–179.
Cunningham KA, Paris JM, Goeders NE (1992). Serotonin neurotransmission in cocaine sensitization. Ann NY Acad Sci 654: 117–127.
Delgado PL (2000). Future pharmacotherapy for obsessive-compulsive disorder: 5-HT2 agonists and beyond. In: Maj M, Sartorius N, Okasha A, Zohar J (eds). Obsessive-Compulsive Disorder. WPA Series Evidence and Experience in Psychiatry, vol. 4. John Wiley: New York. pp 68–70.
Delgado PL, Moreno FA (1998a). Different roles for serotonin in anti-obsessional drug action and the pathophysiology of obsessive-compulsive disorder. Br J Psychiatry 35 (Suppl): 21–25.
Delgado PL, Moreno FA (1998b). Halluciogens, serotonin and obsessive-compulsive disorder. J Psychoactive Drugs 30: 359–366.
Di Giovanni G, Di Matteo V, La Grutta V, Esposito E (2001). m-Chlorophenylpiperazine excites non-dopaminergic neurons in the rat substantia nigra and ventral tegmental area by activating serotonin-2C receptors. Neuroscience 103: 111–116.
Di Matteo V, Cacchio M, Di Giulio C, Esposito E (2002). Role of serotonin(2C) receptors in the control of brain dopaminergic function. Pharmacol Biochem Behav 71: 727–734.
Di Matteo V, De Blasi A, Di Giulio C, Esposito E (2001). Role of 5-HT(2C) receptors in the control of central dopamine function. Trends Pharmacol Sci 22: 229–232.
Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E (1999). SB 242084, a selective serotonin2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system. Neuropharmacology 38: 1195–1205.
Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E (2000a). Biochemical and electrophysiological evidence that RO 60-0175 inhibits mesolimbic dopaminergic function through serotonin(2C) receptors. Brain Res 865: 85–90.
Di Matteo V, Di Giovanni G, Esposito E (2000b). SB 242084: a selective 5-HT(2C) receptor antagonist. CNS Drug Rev 6: 195–205.
Dias R, Robbins TW, Roberts AC (1996). Dissociation in prefrontal cortex of affective and attentional shifts. Nature 380: 69–72.
Divac I, Rosvold HE, Szwarcbart MK (1967). Behavioral effects of selective ablation of the caudate nucleus. J Comp Physiol Psychol 63: 184–190.
Doherty MD, Pickel VM (2000). Ultrastructural localization of the serotonin 2A receptor in dopaminergic neurons in the ventral tegmental area. Brain Res 864: 176–185.
Domeney AM, Costall B, Gerrard PA, Jones DN, Naylor RJ, Tyers MB (1991). The effect of ondansetron on cognitive performance in the marmoset. Pharmacol Biochem Behav 38: 169–175.
Dunnett SB, Iversen SD (1980). Regulatory impairments following selective kainic acid lesions of the neostriatum. Behav Brain Res 1: 497–506.
Eberle-Wang K, Mikeladze Z, Uryu K, Chesselet MF (1997). Pattern of expression of the serotonin2C receptor messenger RNA in the basal ganglia of adult rats. J Comp Neurol 384: 233–247.
El Mansari M, Blier P (2006). Mechanisms of action of current and potential pharmacotherapies of obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 30: 362–373.
Erzegovesi S, Ronchi P, Smeraldi E (1992). 5-HT2 receptor and fluvoxamine effect in obsessive-compulsive disorder. Hum Psychopharmacol 7: 287–289.
Evenden JL, Robbins TW (1983). Increased response switching, perseveration and perseverative switching following d-amphetamine in the rat. Psychopharmacology 80: 67–73.
Everitt BJ, Robbins TW (2005). Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 8: 1481–1489.
Fellows LK, Farah MJ (2003). Ventromedial frontal cortex mediates affective shifting in humans: evidence from a reversal learning paradigm. Brain 126: 1830–1837.
Fletcher PJ, Grottick AJ, Higgins GA (2001). Differential effects of the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2C) receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding. Soc Neurosci Abs 27: 441.15.
Fletcher PJ, Grottick AJ, Higgins GA (2002a). Differential effects of the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2C) receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding. Neuropsychopharmacology 27: 576–586.
Fletcher PJ, Korth KM, Robinson SR, Baker GB (2002). Multiple 5-HT receptors are involved in the effects of acute MDMA treatment: studies on locomotor activity and responding for conditioned reinforcement. Psychopharmacology (Berl) 162: 282–291.
Fletcher PJ, Korth KM, Robinson SR, Baker GB (2002b). Multiple 5-HT receptors are involved in the effects of acute MDMA treatment: studies on locomotor activity and responding for conditioned reinforcement. Psychopharmacology (Berl) 162: 282–291.
Floresco SB, Magyar O, Ghods-Sharifi S, Vexelman C, Tse MT (2006). Multiple dopamine receptor subtypes in the medial prefrontal cortex of the rat regulate set-shifting. Neuropsychopharmacology 31: 297–309.
Freedman M, Black S, Ebert P, Binns M (1998). Orbitofrontal function, object alternation and perseveration. Cereb Cortex 8: 18–27.
Gobert A, Millan MJ (1999). Serotonin (5-HT)2A receptor activation enhances dialysate levels of dopamine and noradrenaline, but not 5-HT, in the frontal cortex of freely-moving rats. Neuropharmacology 38: 315–317.
Gobert A, Rivet JM, Lejeune F, Newman-Tancredi A, Adhumeau-Auclair A, Nicolas JP et al (2000). Serotonin(2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse 36: 205–221.
Graf M (2006). 5-HT2c receptor activation induces grooming behaviour in rats: possible correlations with obsessive-compulsive disorder. Neuropsychopharmacol Hung 8: 23–28.
Graf M, Kantor S, Anheuer ZE, Modos EA, Bagdy G (2003). m-CPP-induced self-grooming is mediated by 5-HT2C receptors. Behav Brain Res 142: 175–179.
Harrison AA, Everitt BJ, Robbins TW (1997). Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms. Psychopharmacology 133: 329–342.
Higgins GA, Enderlin M, Haman M, Fletcher PJ (2003). The 5-HT2A receptor antagonist M100,907 attenuates motor and ‘impulsive-type’ behaviours produced by NMDA receptor antagonism. Psychopharmacology (Berl) 170: 309–319.
Higgins GA, Fletcher PJ (2003). Serotonin and drug reward: focus on 5-HT2C receptors. Eur J Pharmacol 480: 151–162.
Hollander E, Rosen J (2000). Impulsivity. J Psychopharmacol 14: S39–S44.
Hutson PH, Barton CL, Jay M, Blurton P, Burkamp F, Clarkson R et al (2000). Activation of mesolimbic dopamine function by phencyclidine is enhanced by 5-HT(2C/2B) receptor antagonists: neurochemical and behavioural studies. Neuropharmacology 39: 2318–2328.
Idris NF, Repeto P, Neill JC, Large CH (2005). Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and D-amphetamine in the rat. Psychopharmacology 179: 336–348.
Jentsch JD, Taylor JR (1999). Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology 146: 373–390.
Jones B, Mishkin M (1972). Limbic lesions and the problem of stimulus—reinforcement associations. Exp Neurol 36: 362–377.
Jones N, Duxon MS, King SM (2002). 5-HT2C receptor mediation of unconditioned escape behaviour in the unstable elevated exposed plus maze. Psychopharmacology (Berl) 164: 214–220.
Kalivas PW, Volkow ND (2005). The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162: 1403–1413.
Kehne JH, Baron BM, Carr AA, Chaney SF, Elands J, Feldman DJ et al (1996). Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100,907 as a potent 5-HT2A antagonist with a favorable CNS safety profile. J Pharmacol Exp Ther 277: 968–981.
Kennedy AJ, Gibson EL, O'Connell MT, Curzon G (1993). Effects of housing, restraint and chronic treatments with mCPP and sertraline on behavioural responses to mCPP. Psychopharmacology 113: 262–268.
Kennett G, Lightowler S, Trail B, Bright F, Bromidge S (2000). Effects of RO 60 0175, a 5-HT(2C) receptor agonist, in three animal models of anxiety. Eur J Pharmacol 387: 197–204.
Kennett GA, Lightowler S, de Biasi V, Stevens NC, Wood MD, Tulloch IF et al (1994). Effect of chronic administration of selective 5-hydroxytryptamine and noradrenaline uptake inhibitors on a putative index of 5-HT2C/2B receptor function. Neuropharmacology 33: 1581–1588.
Kennett GA, Wood MD, Bright F, Trail B, Riley G, Holland V et al (1997). SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist. Neuropharmacology 36: 609–620.
Khullar A, Chue P, Tibbo P (2001). Quetiapine and obsessive-compulsive symptoms (OCS): case report and review of atypical antipsychotic-induced OCS. J Psychiatry Neurosci 26: 55–59.
King AR, Martin IL, Melville KA (1974). Reversal learning enhanced by lysergic acid diethylamide (LSD): concomitant rise in brain 5-hydroxytryptamine levels. Br J Pharmacol 52: 419–426.
Kruzich PJ, Grandy DK (2004). Dopamine D2 receptors mediate two-odor discrimination and reversal learning in C57BL/6 mice. BMC Neurosci 5: 12.
Lee B, Groman S, London ED, Jentsch JD (2007). Dopamine D(2)/D(3) receptors play a specific role in the reversal of a learned visual discrimination in monkeys. Neuropsychopharmacology, print copy in press (originally published online 14 February 2007; doi:10.1038/sj.npp.1301337).
Liegeois JF, Ichikawa J, Meltzer HY (2002). 5-HT(2A) receptor antagonism potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and inhibits that in the nucleus accumbens in a dose-dependent manner. Brain Res 947: 157–165.
Lopez-Gimenez JF, Mengod G, Palacios JM, Vilaro MT (1997). Selective visualization of rat brain 5-HT2A receptors by autoradiography with [3H]MDL 100,907. Naunyn Schmiedebergs Arch Pharmacol 356: 446–454.
Maj J, Bijak M, Dziedzicka-Wasylewska M, Rogoz R, Rogz Z, Skuza G et al (1996). The effects of paraxetine given repeatedly on the 5-HT receptor subpopulations in the rat brain. Psychopharmacology 127: 73–82.
Martin JR, Ballard TM, Higgins GA (2002). Influence of the 5-HT2C receptor antagonist, SB-242084, in tests of anxiety. Pharmacol Biochem Behav 71: 615–625.
Martin JR, Bos M, Jenck F, Moreau J, Mutel V, Sleight AJ et al (1998a). 5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential. J Pharmacol Exp Ther 286: 913–924.
Martin P, Carlsson ML, Hjorth S (1998b). Systemic PCP treatment elevates brain extracellular 5-HT: a microdialysis study in awake rats. Neuroreport 9: 2985–2988.
McAlonan K, Brown VJ (2003). Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat. Behav Brain Res 146: 97–103.
Millan MJ, Dekeyne A, Gobert A (1998). Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5-HT, release in the frontal cortex in vivo. Neuropharmacology 37: 953–955.
Moreno FA, Delgado PL (1997). Hallucinogen-induced relief of obsessions and compulsions. Am J Psychiatry 154: 1037–1038.
Murphy FC, Smith KA, Cowen PJ, Robbins TW, Sahakian BJ (2002). The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers. Psychopharmacology 163: 42–53.
Olijslagers JE, Perlstein B, Werkman TR, McCreary AC, Siarey R, Kruse CG et al (2005). The role of 5-HT(2A) receptor antagonism in amphetamine-induced inhibition of A10 dopamine neurons in vitro. Eur J Pharmacol 520: 77–85.
Olijslagers JE, Werkman TR, McCreary AC, Siarey R, Kruse CG, Wadman WJ (2004). 5-HT2 receptors differentially modulate dopamine-mediated auto-inhibition in A9 and A10 midbrain areas of the rat. Neuropharmacology 46: 504–510.
Park SB, Coull JT, McShane RH, Young AH, Sahakian BJ, Robbins TW et al (1994). Tryptophan depletion in normal volunteers produces selective impairments in learning and memory. Neuropharmacology 33: 575–588.
Pompeiano M, Palacios JM, Mengod G (1994). Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors. Brain Res Mol Brain Res 23: 163–178.
Porras G, Di Matteo V, Fracasso C, Lucas G, De Deurwaerdere P, Caccia S et al (2002). 5-HT2A and 5-HT2C/2B receptor subtypes modulate dopamine release induced in vivo by amphetamine and morphine in both the rat nucleus accumbens and striatum. Neuropsychopharmacology 26: 311–324.
Ridley RM, Baker HF, Frith CD, Dowdy J, Crow TJ (1998). Stereotyped responding on a two-choice guessing task by marmosets and humans treated with amphetamine. Psychopharmacology 95: 560–564.
Ridley RM, Haystead TA, Baker HF (1981). An analysis of visual object reversal learning in the marmoset after amphetamine and haloperidol. Pharmacol Biochem Behav 14: 345–351.
Rogers RD, Andrews TC, Grasby PM, Brooks DJ, Robbins TW (2000). Contrasting cortical and subcortical activations produced by attentional-set shifting and reversal learning in humans. J Cogn Neurosci 12: 142–162.
Rolls ET, Hornak J, Wade D, McGrath J (1994). Emotion-related learning in patients with social and emotional changes associated with frontal lobe damage. J Neurol Neurosurg Psychiatry 57: 1518–1524.
Rosenberg DR, Dick EL, O'Hearn KM, Sweeney JA (1997). Response-inhibition deficits in obsessive-compulsive disorder: an indicator of dysfunction in frontostriatal circuits. J Psychiatry Neurosci 22: 29–38.
Sareen J, Kirshner A, Lander M, Kjernisted KD, Eleff MK, Reiss JP (2004). Do antipsychotics ameliorate or exacerbate obsessive compulsive disorder symptoms? A systematic review. J Affect Disord 82: 167–174.
Schmidt CJ, Sullivan CK, Fadayel GM (1994). Blockade of striatal 5-hydroxytryptamine2 receptors reduces the increase in extracellular concentrations of dopamine produced by the amphetamine analogue 3,4-methylenedioxymethamphetamine. J Neurochem 62: 1382–1389.
Schmidtke K, Schorb A, Winkelmann G, Hohagen F (1998). Cognitive frontal lobe dysfunction in obsessive-compulsive disorder. Biol Psychiatry 43: 666–673.
Serretti A, Artioli P, De Ronchi D (2004). The 5-HT2C receptor as a target for mood disorders. Exper Opin Ther Targets 8: 15–23.
Settlage P, Zable M, Harlow HF (1948). Problem solution by monkeys following bilateral removal of the prefrontal areas. VI. Performance on tests requiring contradictory reactions to similar and to identical stimuli. J Exp Psychol 38: 50–63.
Sorensen SM, Kehne JH, Fadayel GM, Humphreys TM, Ketteler HJ, Sullivan CK et al (1993). Characterization of the 5-HT2 receptor antagonist MDL 100907 as a putative atypical antipsychotic: behavioral, electrophysiological and neurochemical studies. J Pharmacol Exp Ther 266: 684–691.
Soubrié P (1986). Serotonergic neurons and behaviour. J Pharmacol 17: 107–112.
Stalnaker TA, Franz TM, Singh T, Schoenbaum G (2007). Basolateral amygdala lesions abolish orbitofrontal-dependent reversal impairments. Neuron 54: 51–58.
Stein DJ, Spadaccini E, Hollander E (1995). Meta-analysis of pharmacotherapy trials for obsessive-compulsive disorder. Int Clin Psychopharmacol 10: 11–18.
Tsaltas E, Kontis D, Chrysikakou S, Giannou H, Biba A, Pallidi S et al (2005). Reinforced spatial alternation as an animal model of obsessive-compulsive disorder (OCD): investigation of 5-HT2C and 5-HT1D receptor involvement in OCD pathophysiology. Biol Psychiatry 57: 1176–1185.
van den Bos R, Cools AR (1989). The involvement of the nucleus accumbens in the ability of rats to switch to cue-directed behaviours. Life Sci 44: 1697–1704.
van der Meulen JA, Joosten RN, de Bruin JP, Feenstra MG (2006). Dopamine and noradrenaline efflux in the medial prefrontal cortex during serial reversals and extinction of instrumental goal-directed behavior. Cereb Cortex, print copy in press (originally published online on 18 August 2007; doi:10.1093/cercor/bhl057).
Van Oekelen D, Luyten WH, Leysen JE (2003). 5-HT2A and 5-HT2C receptors and their atypical regulation properties. Life Sci 72: 2429–2449.
Veale DM, Sahakian BJ, Owen AM, Marks IM (1996). Specific cognitive deficits in tests sensitive to frontal lobe dysfunction in obsessive-compulsive disorder. Psychol Med 26: 1261–1269.
Weiner I, Feldon J (1986). Reversal and nonreversal shifts under amphetamine. Psychopharmacology 89: 355–359.
Weiner I, Feldon J, Ben-Shahar O (1986). Simultaneous brightness discrimination and reversal: the effects of amphetamine administration in the two stages. Pharmacol Biochem Behav 25: 939–942.
Winstanley CA, Chudasama Y, Dalley JW, Theobald DE, Glennon JC, Robbins TW (2003). Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats. Psychopharmacology 167: 304–314.
Winstanley CA, Theobald DE, Dalley JW, Glennon JC, Robbins TW (2004). 5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion. Psychopharmacology (Berl) 176: 376–385.
Yamauchi M, Tatebayashi T, Nagase K, Kojima M, Imanishi T (2004). Chronic treatment with fluvoxamine desensitizes 5-HT2C receptor-mediated hypolocomotion in rats. Pharmacol Biochem Behav 78: 683–689.
This work was supported by a Programme Grant from the Wellcome Trust to TWR. The BCNI is funded by a joint award from the Medical Research Council and the Wellcome Trust. VB is supported by the Domestic Research Studentship, the Cambridge European Trusts, the Bakalas Foundation Scholarship, and the Oon Khye Beng Ch'ia Tsio Studentship from Downing College. We thank Dr Jeffrey W Dalley for helpful discussion of these studies and for his comments on the manuscript as well as David Theobald for preparing the drugs.
JCG declares his part employment at Solvay Pharmaceuticals, Weesp, Netherlands. TWR would like to state his consultancy for GlaxoSmithKline and an honorarium for a talk at Solvay. VB has no conflicts of interest, financial or otherwise, to declare.
About this article
Cite this article
Boulougouris, V., Glennon, J. & Robbins, T. Dissociable Effects of Selective 5-HT2A and 5-HT2C Receptor Antagonists on Serial Spatial Reversal Learning in Rats. Neuropsychopharmacol 33, 2007–2019 (2008). https://doi.org/10.1038/sj.npp.1301584
This article is cited by
Adverse maternal environment affects hippocampal HTR2c variant expression and epigenetic characteristics in mouse offspring
Pediatric Research (2022)
Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder
Translational Psychiatry (2021)
Animal Cognition (2020)
The relationship between monoaminergic gene expression, learning, and optimism in red junglefowl chicks
Animal Cognition (2020)