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

摘要

Stimulation of central serotonin2C receptor (5-HT2CR) inhibits dopamine (DA)-dependent neurochemical and behavioral effects of cocaine, while 5-HT2CRs 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-HT2CRs in the VTA and the NAc to inhibit and enhance respectively cocaine-induced accumbal DA outflow. Intra-VTA injection of the 5-HT2CR 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-HT2CR 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-HT2CRs on accumbal DA output is dependent, at least in part, on the functional balance between different 5-HT2CR populations within the NAc and within the mesoaccumbens DA pathway (VTA vs NAc).