Differential regulation of the mesoaccumbens dopamine circuit by serotonin2C receptors in the ventral tegmental area and the nucleus accumbens: An in vivo microdialysis study with cocaine

Stimulation of central serotonin2C receptor (5-HT_2CR) inhibits dopamine (DA)-dependent neurochemical and behavioral effects of cocaine, while 5-HT_2CRs locally expressed into the ventral tegmental area (VTA) and the nucleus accumbens (NAc) exert opposite functional control over cocaine-induced behavioral effects. Using in vivo microdialysis in halothane-anesthetized rats, we tested the hypothesis that this functionally opposite regulation of the mesoaccumbens DA pathway relies on the ability of 5-HT_2CRs in the VTA and the NAc to inhibit and enhance respectively cocaine-induced accumbal DA outflow. Intra-VTA injection of the 5-HT _2CR agonist Ro 60-0175 at 5 μg/0.2 μl, but not 1 μg/0.2 μl, attenuated the increase in accumbal DA outflow induced by the systemic administration of 10 mg/kg of cocaine. Intra-VTA injection of the 5-HT _2CR antagonist SB 242084 at either dose (0.1 or 0.5 μg/0.2 μl) did not modify the effects of cocaine. Intra-NAc application of Ro 60-0175 dose-dependently excited (0.1 μM) and inhibited (1 μM) cocaine-induced DA outflow. In contrast, intra-NAc application of SB 242084 resulted in diametrically opposite effects when applied at these concentrations. These results further support the idea that the overall action of central 5-HT _2CRs on accumbal DA output is dependent, at least in part, on the functional balance between different 5-HT_2CR populations within the NAc and within the mesoaccumbens DA pathway (VTA vs NAc).