The 5-HT2 receptor family seems to be particularly involved in anxiety because several drugs effective for the treatment of anxiety disorders interact with this type of receptor (Mora et al. 1997; Peroutka 1995). Mora et al. (1997) tested mCPP, ritanserin and trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3-(2-fluorophenyl) propen-1-yl]phenol hemifumarate (SR-463496A), a selective 5-HT2A/2C receptor antagonist (Rinaldi-Carmona et al. 1992) on two types of fear. The authors used a paradigm in which the same rat in one experimental session was exposed to two types of fear, in an elevated T-maze with the perpendicular arm closed and the other with arms open. By placing the animal in the closed arm, the training of inhibitory passive avoidance is evaluated by measurement of the time that the animal takes to leave the closed arm during three consecutive trials. This inhibitory avoidance task is assumed to represent conditioned fear. The same animal is placed in the open arm in a one-way escape task, which is assumed to represent unconditioned fear (Graeff et al. 1993). Using this task, Mora et al. (1997) observed a facilitatory effect of TFMPP on inhibitory avoidance, which was evident in an increase in the latency to leave the closed arm, whereas the latency to leave the open arm was increased in rats receiving 0.2 mg/kg IP Thus, the drug impaired the one-way escape task. Similarly, mCPP increased the avoidance latency in a dose-dependent manner, while it tended to impair one-way escape. SB 200646A, a 5-HT2C receptor antagonist, dose-dependently decreased the avoidance latency. However, the one-way escape task was not affected by the drug. Inhibitory avoidance was also impaired by the selective 5-HT2C antagonist (+)-cii-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7-bC)(2,6) naphthyridine (SER-082; 0.1-1.0 mg/kg). Thus, the conditioned fear seems to be tonically facilitated through 5-HT2C receptor stimulation, whereas unconditioned fear might be phasically inhibited by activation of 5-HT2C receptors (Graeff et al. 1993).
Jones et al. (2002) evaluated the 5-HT2C receptor participation in unconditioned escape behavior using an unstable elevated exposed plus maze. Based on the evidence that mCPP induces panic in humans and increases the unconditioned escape behavior in a dose-dependent manner in the rat, the 5-HT2C antagonist SB 242084 was administered to rats previously treated with mCPP, and a dose-dependent inhibition of the increase in escape and hypolocomotor effects was observed. Moreover, Martin et al. (2002) tested the anxiolytic effects of SB 242084 administered in rats at doses that reverse the mCPP-induced hypolocomotor effect and observed that the 5-HT2C antagonist is able to cause anxiolytic effects as determined by the elevated plus maze task.
In other studies, local administration of TFMPP (0.75 and 1.5 mg) in the ventral hippocampus produced a reduction in the open arm exploration by rats exposed to the elevated plus maze, without effects on the number of entries in the closed arm, indicating a selective anxiogenic profile. A higher dose of TFMPP (3.0 mg) reduced both open and closed arm entries, suggesting hypolocomotion. Similar results were observed after application of MK-212, suggesting anxiogenic effects due to 5-HT2C agonism (Alves et al. 2004).
Moreover, in other studies in rats, it was observed that chronic unpredictable mild stress facilitates 5-HT2C receptor function, whereas antidepressant treatments reduced 5-HT2C receptor function (Jenck et al. 1993). The pharmacological characterization of the effects of the 5-HT2C agonist mCPP led to the hypothesis that activation of 5-HT2C receptors may mediate anxiety in humans and in rodents (Kantor et al. 2005). Earlier, it was suggested that the anxiety produced in rodents and possibly in humans after the administration of a selective serotonin reuptake inhibitor (SSRI), antidepressants, or mCPP could be mediated by activation of 5-HT2C receptors (Bagdy et al. 2001; Kennett et al. 1989). In addition, the 5-HT2C receptor antagonist SB 242084 has shown anxiolytic effects in several anxiety tests (Martin et al. 2002; Kennett et al. 1997).
The social environment can be, among others, an important source of ethologi-cal-based stress (File and Seth 2003; Koolhaas et al. 1997). Kantor et al. (2005) evaluated the effect of the administration of SB 242084 in a social interaction anxiety test using a highlighted unfamiliar arena in which a pair of rats was placed together in order to evaluate the social interaction of each rat with an unknown, similar sized (none differing more than 15 g in weight) test partner. Both the magnitude and the time of social interaction under the effects of SB 242084 were compared with those recorded after chlordiazepoxide (CDP), a widely used benzodiazepine, administration. SB 242084 increased the time of social interaction at doses of 0.3 and 1.0 mg/kg, while the magnitude of social interaction was similar to that observed under CDP effects.
As previously discussed, 5-HT2C receptors could influence learning processing through their effect on anxiety levels. Particularly, acute inescapable stress in rats dramatically affects synaptic plasticity in the hippocampus and inhibits LTP when stress occurred prior to the induction of this electrical phenomenon (Diamond et al. 2005; Shors et al. 1989). It is known that inescapable stress led to an increase of 5-HT output in several brain areas including the hippocampus (Vahabzadeh and Fillenz 1994), and in unstressed animals, drugs increasing serotonin activity such as fluoxetine (an SSRI) and fluvoxamine inhibit the induction of LTP (Kojima et al. 2003; Shakesby et al. 2002). In stressed animals, Ryan et al. (2008) evaluated the participation of 5-HT2 receptors on the inhibition of CA1 high frequency stimulation-induced LTP, produced by unavoidable stress; they observed that fenfluramine (5 mg/kg IP) is able to reverse the stress-induced LTP inhibition, and the 5-HT2 receptor antagonist cinanserin prevented this reversal, indicating a primarily 5-HT2 effect of the fenfluramine. In addition, the preferential 5-HT2C receptor antagonist MK-212, enabled the induction of LTP in stressed rats (3 mg/kg IP). The same effect was observed after the application of a-methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine hydrochloride (BW 723C86), a 5-HT2B receptor agonist, showing that the activation of both receptor subtypes is enough to revert the stress-induced inhibition of LTP recorded from the CA1 hippocampal subfield.
Thus, besides direct influences on learning processes, 5-HT2C receptors can be involved in the modulation of other processes, like anxiety, that may in turn influence learning ability.
Forebrain serotonin depletion induced by 5,7-DHT administration increases impulsive responses in different experimental paradigms including go/no-go and differ-ential-reinforcement-of-low-rate schedule of reinforcement tasks (Fletcher 1995; Harrison et al. 1999).
Impulsiveness is defined as an action without adequate forethought; in addition, alterations in the impulse control or lack of behavioral inhibition are part of disorders such as OCD, attention deficit hyperactivity disorder (ADHD), schizophrenia, antisocial behavior, and addictive behavior (American Psychiatric Association 1994).
Five-choice serial reaction time is helpful in identifying animals with attentional deficits in conjunction with impulsiveness (Puumala et al. 1996). The task was adapted from Leonard reaction time test for humans (Wilkinson 1963) and requires a rat to detect and respond to brief flashes of light presented randomly in one of five spatial diverse locations in order to evaluate attention, impulsiveness, speed of response, and motivation (Carli et al. 1983). Puumala et al. reported that the measure of attention (percentage of correct responses) is inversely correlated with the probability of premature responses, a reflection of impulsiveness (Puumala et al. 1997). Further, Puumala and Sirvio (1998) demonstrated that poorly performing rats had a higher serotonin utilization ratio (5-HIAA/5-HT) in the frontal cortex than well-performing rats in the task. This suggests a serotonin influences against the accuracy of responses in the 5-CSRT task.
However, global serotonin depletion caused by intracerebroventricular administration of 5,7-DHT increases the number of premature responses in the 5-CSRT task in rats (Winstanley et al. 2004a). When the 5-HT2A/2C receptor agonist DOI was used, Koskinen et al. (2000a) observed that DOI decreased the number of completed trials (0.1 or 0.15 mg/kg IP), whereas only the administration of 1.0 mg/kg resulted in increase of the number of premature responses, without effect on choice accuracy.
Serotonin plays a role in OCD, a relatively common anxiety disorder characterized by recurrent intrusive thoughts and repetitive time-consuming behaviors (Antony et al. 1998). Thus, an effect on learning processes could arise in the ability to modulate perseveration in rats, that could be an opposing effect in learning tests in which the animals must learn to act depending on information provided and to inhibit perseverative responses.
Higgins and Fletcher (2003) reported that the 5-HT2C receptor antagonist SB 242084 increases premature responding on the 5-CSRT task, as well as decreases the latency for correct responses. Using this task, Winstanley and colleagues administered the 5-HT2C receptor antagonist SB 242084 to rats previously lesioned with 5,7-DHT and control rats. They reported an increase in premature responding both in control and in serotonin-depleted animals, antagonist treated. However, there was no effect on the accuracy of responses (Winstanley et al. 2004b). Talpos et al. (2006) compared the effects of ketanserin (5-HT2A/C receptor antagonist) and SER-082 (5-HT2C/2B receptor antagonist) by means of two tests of impulsiveness, the 5-SCRT task and the delayed reward task. The authors observed a decrease in premature (impulsive) responding after ketanserin administration in the 5-CSRT task, as was previously described (Koskinen et al. 2000b; Passetti et al. 2003), although no effect was caused by the treatment in the delayed reward task. SER-082 had no effect on the 5-CSRT task, whereas impulsive responding decreased in the delayed reward task. The authors explained the results of this work by considering the properties of SB 242084 as an antagonist, an inverse agonist, or as a weak agonist. However, similarly, the accuracy of responses as reported previously was not affected in any of the tests.
Fletcher et al. (2007) applied different compounds to rats and evaluated the animals using the 5-SCRT task. They observed that ketanserin (1.0 mg/kg IP) and the 5-HT2A receptor antagonist MDL100197 (0.01, 0.1, and 0.5 mg/kg IP) decreased the number of premature responses, using an intertrial interval (ITI) of 5 and 9 s, whereas the 5-HT2B receptor antagonist 6-chloro-5-methyl-1-(5-quinolylcarbam-oyl)indoline (SB 215505) had no effect, and the 5-HT2C receptor antagonist SB 242084 increased the number of premature responses (0.1 and 0.5 mg/kg IP) with an ITI of both 5 and 9 s. DOI (0.3 and 0.6 mg/kg) reduced the accuracy of responding, increased the number of omissions, and increased the latencies of responses and reinforcer collections, whereas it did not affect premature responding. The 5-HT2C receptor agonist Ro 60-0175 increased only the proportion of omitted trials, the latency to respond, and the latency to collect the reinforcer (0.6 mg/kg). The results replicate the extended result that 5-HT2A receptor blockade reduces and 5-HT2C blockade enhances premature responding (impulsiveness). In another study, Quarta et al. (2007) analyzed the modulation of 5-HT2C on behavioral nicotine effects and evaluated the influence of the 5-HT2C receptor agonist Ro 60-0175 on responses to nicotine in the 5-CSRT task. Nicotine positively affected the response indices as response latencies and omission errors and produced anticipatory responding. Ro 60-175 counteracted the effects of nicotine, increasing the response latencies and omission errors, but it had little effect on response accuracy.
It appears that 5-HT2C receptors actively participate in the regulation of impulsiveness, because the administration of antagonists increases the impulsiveness measured as an increase in premature responses. However, this increase in the impulsiveness does not act in detriment to the accuracy of responses and may be limited to a motor influence of 5-HT2C. In accordance with this, the application of 5-HT2C agonists induces hypolocomotion as was mentioned previously.
Thus, both direct and indirect effects of 5-HT2C receptors activation or inactiva-tion in learning process have been observed. It seems that several neurotransmitter systems (e.g.,dopaminergic, cholinergic, glutamatergic) and several cerebral systems
(striatum, prefrontal cortex, and hippocampus) are involved as the neural substrate sustaining this modulation. Until now, the principal restraint in the experimental approach of 5-HT2C receptors is the unavailability of selective compounds that allow attribution of specific effects on learning processes to 5-HT2C receptors. Nevertheless, the results summarized in the review show that these receptors are important in learning modulation.
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