Serotonin 5-HT_2C receptors in nucleus accumbens regulate expression of the hyperlocomotive and discriminative stimulus effects of cocaine

The serotonin 5-HT_2C receptor (5-HT_2CR) is abundant in the nucleus accumbens (NAc) shell and is considered an important target for 5-HT to modulate the dopamine (DA) mesoaccumbens circuit, which plays a prominent role in the behavioral effects of cocaine. The present study analyzed the ability of intra-NAc shell infusions of the 5-HT_2CR agonists, MK 212 and RO 60-0175, or the 5-HT_2CR antagonist, RS 102221, to alter either spontaneous or cocaine-evoked activity as well as the discriminative stimulus properties of cocaine. In male Sprague-Dawley rats implanted with bilateral cannulae aimed at the NAc shell, locally injected MK 212 (0.05-0.5 μg/side) or RO 60-0175 (0.5-5 μg/side) did not alter spontaneous activity, but dose-dependently enhanced hyperactivity evoked by cocaine (10 mg/kg ip). In rats trained to discriminate cocaine (10 mg/kg ip) from saline (ip) in a two-lever, water-reinforced FR 20 task, intra-NAc microinfusion of MK 212 (0.05 μg/side) or RO 60-0175 (0.5 μg/side) evoked 37% or 48% cocaine lever responding, respectively. Both MK 212 (0.05 μg/side) and RO 60-0175 (0.5 μg/side) enhanced the discriminability of submaximal doses of cocaine (0.625-2.5 mg/kg). Moreover, intra-NAc infusion of RS 102221 (0.05-1.5 μg/side) dose-dependently attenuated the stimulus effects of cocaine. These data reinforce the hypothesis that 5-HT_2CR plays a role in the regulatory neurochemistry of the NAc shell that is important to the full expression of the behaviors evoked by cocaine.