Place Conditioning

Place conditioning is a paradigm that involves the preference of a place in which the animal had received any reinforcement (or rewarding stimulus). Using the 5-HT2C receptor agonist 8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]qui-noxalin-5(6#)-one (WAY 161503), Mosher et al. (2005) evaluated place conditioning and did not find any evidence of conditioning either for WAY 161503 (3.0 mg/kg SC) or TFMPP (3.0 mg/kg SC), but found a decrease in locomotor activity that was blocked by the 5-HT2C receptor antagonist SB 242084. Hayes et al. (2009) evaluated the role of 5-HT2C receptors in nicotine-induced place conditioning through the administration of the 5-HT2C receptor agonist WAY 161503 (1.0 and 3.0 mg/kg) and the 5-HT2C receptor antagonist SB 242084 (1 mg/kg). WAY 161530 had no effects on place conditioning, although it decreased basal and nicotine-induced locomotor activity and the effect was blocked by SB 242084.

From the preceding data, it can be observed that agonists having affinity for 5-HT2C receptors produce deficits in passive avoidance learning, whereas antagonists reverted the effects because the activation of 5-HT2C receptors apparently causes amnesic effects in the retention test (24 h after training). Thus, serotonin, through this receptor, may modulate the passive avoidance learning process. Until now, a detrimental effect by activation and improvement by inactivation of 5-HT2C receptors in striatal-dependent learning appeared to occur. It is known that mesocorti-colimbic dopamine activity also plays a central role in mediating motivation- and reward-related behavior (Ikemoto and Wise 2004) and that dopamine is a principal neurotransmitter accounting for the organization of striatal-related learning (Badgaiyan et al. 2007); thus, the effects observed in those learning processes sustained by the striatum after serotonin 5-HT2C manipulations could be related to modulation of dopamine release or utilization in this cerebral region. Systemic application of 5-HT2C receptor agonists (such as Ro 60-0175) does not significantly decrease basal firing of substantia nigra pars compacta neurons (Di Giovanni et al. 2000), though it decreases the dopamine efflux in the striatum (Alex et al. 2005). By contrast, the administration of 5-HT2C receptor antagonists (SB 242084) or inverse agonists (SB 206553) result in increase of dopamine efflux in this region (De Deurwaerdere et al. 2004). This effect could be related to the impairment of striatal-dependent learning observed after administration of compounds acting as 5-HT2C receptor agonists because striatal dopamine plays a relevant role in all learning processes sustained by this memory system (White et al. 1993). However, more complex neurochemical mechanisms could underlie these cognitive functions in view of the results obtained in DRL-72 and in auto-shaping learning tests, where a specific 5-HT2C receptor agonist produces improvement of learning (see Table 24.1).

It seems that reaching of a better understanding of the complex interaction of 5-HT receptors in general and 5-HT2C receptors in particular in the regulation of this learning process requires further research through experimental designs including highly specific 5-HT2C receptor agonists and antagonists.

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