Role of serotonin2C receptor (5-HT2CR) in expression of cocaine-induced conditioned hyperactivity

Environmental cues can become classically conditioned to cocaine exposure and are known to contribute to drug craving and relapse in addicts. The 5-HT2C receptor (5-HT2CR) has been shown to modulate the behavioral effects of acute cocaine administration and, in the present study, we investigated the role of this receptor in the expression of cocaine-induced conditioned hyperactivity. We first test the hypothesis that the 5-HT2CR ligands alter expression of cocaine-induced conditioned hyperactivity. Rats received repeated pairings of a distinct test environment with either saline or cocaine for 7 days. In a drug-free test 2 days after the last pairing, expression of conditioned hyperactivity was seen in the rats previously exposed to cocaine in the test environment. The 5-HT2CR agonist MK 212 significantly decreased, while the 5-HT2CR antagonist SB 242084 enhanced, expression of cocaine-induced conditioned hyperactivity. The effective doses of MK 212 and SB 242084 did not alter basal activity during the test session. These results suggest that the 5-HT2CR controls expression of cocaine-induced conditioned hyperactivity. In order to begin to localize the site of action whereby the 5-HT2CR modulates expression of cocaine-induced conditioned hyperactivity, we also investigated alteration of expression of cocaine-induced conditioned hyperactivity following microinjection of MK212 into the prelimbic cortex (PrL), a subarea of the medial prefrontal cortex (mPFC). We found that MK 212 at 0.15 ìg/0.2ìl/site inhibited expression of cocaine-induced conditioned hyperactivity while not affecting basal activity. Since activation of the 5-HT2CR in the mPFC inhibited expression of cocaine-induced conditioned hyperactivity, we investigated the location of the 5-HT2CR in the mPFC. About half of neurons with 5-HT2CR-IR expressed glutamic acid decarboxylase (GAD) 67-IR, a marker of GABA interneurons. Among subpopulations of GABA interneurons, a significantly higher percentage of neurons expressing parvalbumin-IR also expressed 5-HT2CR-IR compared to other subpopulations. Since parvalbumin is located in GABA interneurons projecting to the cell body and initial segment of axon of pyramidal cells, these results raise the possibility that the 5-HT2CR in the mPFC affects the parvalbumin-positive GABAergic interneurons to regulate the output of the pyramidal cells and therefore control expression of cocaine-induced conditioned hyperactivity.