Hyperlocomotive and discriminative stimulus effects of cocaine are under the control of serotonin_2C (5-HT_2C) receptors in rat prefrontal cortex

The serotonin_2C (5-hydroxytryptamine_2C; 5-HT_2C) receptor (5-HT_2CR) is found in abundance in dopamine (DA) mesocorticolimbic pathways and is one of the important target proteins that modulates the behavioral effects of cocaine. In the present study, the hypothesis was tested that the 5-HT_2CR in the prefrontal cortex (PFC) may control either spontaneous or cocaine-evoked locomotor activity as well as the discriminative stimulus properties of cocaine. In male Sprague-Dawley rats implanted with bilateral cannulae aimed at the PFC, local microinjections of the preferential 5-HT_2CR agonist 6-chloro-2-(1-piperazinyl)pyrazine hydrochloride (MK 212) (0.05-0.5 μg/side) did not alter spontaneous activity, but dose-dependently decreased horizontal hyperactivity evoked by cocaine (10 mg/kg i.p.). Given alone, the selective 5-HT_2CR antagonist 8-[5-(2,4-dimethoxy-5-(4-trifluorophenylsulfonamido)phenyl-5-oxopentyl]-1, 3,8-triazo-spiro[4.5]decane-2,4-dione hydrochloride (RS 102221) (5 μg/side) increased basal locomotor activity of rats expressed in the vertical plane. Microinjections of RS 102221 (5 μg/side, but not 0.15-1.5 μg/side) significantly enhanced the horizontal activity induced by cocaine (10 mg/kg). In rats trained to discriminate cocaine (10 mg/kg i.p.) from saline (i.p.) in a two-lever, water- reinforced fixed ratio 20 task, intra-PFC microinjections of MK 212 (0.05 and 0.5 μg/side) did not substitute for cocaine, but attenuated the stimulus effects of cocaine. However, intra-PFC microinjections of RS 102221 (1.5 and 5 μg/side) evoked 13 and 40% cocaine-lever responding when tested alone and enhanced the recognition of cocaine. These data indicate that the PFC is a brain site at which the 5-HT_2CR exerts an inhibitory control over the hyperactive and discriminative stimulus effects of cocaine known to be dependent upon activation of the DA mesoaccumbens circuit.