The serotonergic system regulates the main functions of the prefrontal cortex including emotional control, cognitive behaviors, and working memory (Buhot 1997; Williams et al. 2002). As a result, abnormalities in the serotonergic system have been implicated in the pathogenesis of mental disorders associated with prefrontal cortex dysfunction, such as depression, anxiety, obsessive-compulsive disorder (OCD), and schizophrenia (Doris et al. 1999; Gross et al. 2002; Lemonde et al. 2003). A common characteristic associated with these disorders is cognitive inflexibility, that is, an inability to spontaneously withhold, modify, or sustain adaptive behavior in response to changing situational demands. Thus, in order to study the role of the prefrontal cortex in sustaining behavioral flexibility, reversal learning tasks have been designed for humans (Fellows and Farah 2003; Murphy 2002; Rogers et al. 2000; Rolls et al. 1994), nonhuman primates (Butter et al. 1969; Clarke et al. 2004, 2005, 2007; Dias and Segraves 1996; Lee et al. 2007), and rats (Birrell and Brown 2000; Boulougouris et al. 2007; Idris et al. 2005; McAlonan and Brown 2003; van der Meulen et al. 2007). In these tasks, 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 (Boulougouris et al. 2008).
The monoamine neurotransmitter serotonin has been strongly implicated in behavioral flexibility (Boulougouris et al. 2008), possibly through its influence on the mentioned functions. In accordance with this hypothesis, selective serotonin depletions in the marmoset prefrontal cortex induced by the neurotoxin 5,7-DHT impaired performance on a serial visual discrimination reversal learning task, which was mainly involved with perseverative responses to a 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 serotonin and not dopamine depletion in the orbitofrontal cortex (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 that was reversed by the selective 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide trihydrochloride (WAY 100635) (Clarke et al. 2003). Similar deficits were observed in rats after 5HT-reduction by administration of a tryptophan-defi-cient diet and in monkeys with administration of the 5-HT3 receptor antagonist ondansetron in high doses (Barnes et al. 1990; Domeney et al. 1991).
While the involvement of 5-HT systems in reversal learning is well established, the particular 5-HT receptor subtypes that underlie these effects are not well understood.
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 (5-CSRT) task, whereas the 5-HT2A receptor antagonist MDL-100907 decreases it by the same measure (Higgins and Fletcher 2003; Winstanley et al. 2004b). In this sense, a dissociable behavioral effect of the selective 5-HT2A antagonist MDL-100907 and the 5-HT2C antagonist SB 242084 on serial spatial reversal learning has been observed (Boulougouris et al. 2008). MDL-100907 impaired initial reversal learning by increasing the number of trials (highest dose, 0.1 mg/kg IP) and incorrect responses to the criterion (two highest doses, 0.03 and 0.1 mg/kg IP). 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 (the two highest doses, 0.3 and 1.0 mg/kg). Moreover, the analysis of type of errors revealed that the opposing effects of the 5-HT2A and 5-HT2C receptor antagonists were specific to early reversal I stages (when more reversal tests were made, no effects were induced by the drugs) affecting perseverative but not learning errors (Boulougouris et al. 2008).
However, the study of the effects of 5-HT2C receptor agonists on compulsive behavior has led to contradictory results. It has been observed that 5-HT2C receptor activation induced "compulsive" grooming (Graf 2006; Graf et al. 2003) and directional persistence in spatial alternation (Tsaltas et al. 2005); whereas, in other models such as marble burying and schedule-induced polydipsia, 5-HT2C agonists attenuated compulsive behavior and blockade of 5-HT2C receptors increased compulsive drinking (in the polydipsia model) (Martin et al. 1998, 2002), though the anticompulsive effects of 5HT2C agonists have been attributed to their sedative effects (Kennett et al. 2000). On the other hand, it has been demonstrated that 5-HT2C antagonism mimics some of the effects of psychostimulant drugs such as d-amphetamine, which increases dopamine release in the nucleus accumbens (Cole and Robbins 1987, 1989); d-amphetamine causes a similar pattern of behavioral effects on the 5-CSRT tasks as SB 242084, increasing the number of premature responses (Cole and Robbins 1987; Harrison et al. 1997). Thus, there could be an interaction with dopamine modulation by 5-HT2C receptors.
Effects of 5-HT2C receptor antagonism have also been reported to enhance the stimulant effects of several drugs of abuse such as phencyclidine and MDMA (Fletcher et al. 2002a; b, 2001, Hutson et al. 2000). A number of studies attribute the proaddictive effects of 5-HT2C antagonists to an increase of the dopaminergic activity in the ventral tegmental area and the consequent increased release of dopamine in the nucleus accumbens (Gobert et al. 2000; Di Matteo et al. 1999, 2000a, b; Millan et al. 1998; Higgins and Fletcher 2003; Di Giovanni et al. 2001). In contrast, MDL-100907 neither influences the spontaneous firing rate of dopaminergic neurons nor alters basal levels of dopamine or norepinephrine (noradrenaline) release (Kehne et al. 1996), but it does attenuate amphetamine-induced hyperactivity (Sorensen et al. 1993) and amphetamine, DOI, or MDMA-induced dopamine release (Gobert and Millan 1999; Porras et al. 2002; Schmidt et al. 1994).
The finding that SB 242084 reduced perseverative responding in spatial reversal learning, a task dependent on the orbitofrontal cortex (Boulougouris et al. 2008), suggests that this facilitatory effect of 5-HT2C antagonists is possibly mediated by the orbitofrontal cortex (Boulougouris et al. 2008). Nevertheless, Clarke et al. (2007) showed that selective 5-HT depletion of the marmoset orbitofrontal cortex impaired performance of a visual serial reversal learning task; this deficit was due to a failure to inhibit responding to the previously rewarded stimulus. On the other hand, mutant mice devoid of 5-HT2C receptors display enhanced exploration of a novel environment (Rocha et al. 2002), as well as perseverative behavior, a component of OCDs. Likewise, it has been reported that 5-HT2C receptor knockout mice may display compulsive-like behavior (Chou-Green et al. 2003).
It is known that mCPP causes exacerbation of OCD symptoms in patients (Zohar and Insel 1987) and it appears that selective serotonin reuptake inhibitors produce anti-OCD effects through 5-HT2 receptors (Erzegovesi et al. 1992). Since several lines of evidence show any participation of 5-HT2A receptors in OCD, it has been suggested that the effects of mCPP on the persistence are mediated by mCPP acting via 5-HT2C receptors. Meta-chlorophenylpiperazine acts as a nonselective agonist for 5-HT1A/1B/2C receptors and antagonist of 5-HT3 receptors. Since MK-212, which has a high affinity for 5-HT1A and 5-HT2C receptor subtypes, had no effect on OCD symptom intensity, this apparently excludes the participation of 5-HT2C in OCD behavioral expression (Gross et al. 1998). However, in monkeys, compulsive whole-body scratching is produced by 8-OH-DPAT, and the effect can be fully reversed by subsequent treatment with 5-HT2C receptor agonists more potently than with fluoxetine (Martin et al. 1998).
As observed from the previous data, a complex modulation of perseveration could be occurring through 5-HT2 serotonin receptors, and the specific role of 5-HT is beginning to be elucidated.
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