Serotonin_2C receptors in the medial prefrontal cortex facilitate cocaine-induced dopamine release in the rat nucleus accumbens

A functional balance between excitatory and inhibitory control over dopamine (DA)-dependent behavioral and neurochemical effects of cocaine is afforded by the serotonin_2C receptor (5-HT_2CR) located within the ventral tegmental area and the nucleus accumbens (NAc). The 5-HT_2CR located in the medial prefrontal cortex (mPFC) has also been shown to inhibit cocaine-induced behaviors perhaps through inhibition of DA function in the NAc. Using in vivo microdialysis in halothane-anesthetized rats, we tested this hypothesis by assessing the influence of mPFC 5-HT_2CRs on cocaine-induced DA outflow in the NAc shell. Intra-mPFC injection of the 5-HT_2CR agonist Ro 60-0175 at 5 μg/0.2 μl, but not 1 μg/0.2 μl, potentiated the increase in accumbal DA outflow induced by the intraperitoneal administration of 10 mg/kg of cocaine. Conversely, cocaine-induced accumbal DA outflow was significantly reduced by the intra-mPFC injection of the selective 5-HT_2CR antagonist SB 242084 (0.5 μg/0.2 μl) or SB 243213 (0.5 and 1 μg/0.2 μl). These results show that mPFC 5-HT_2CRs exert a positive control over cocaine-induced accumbal DA outflow. Observations further support the idea that the overall action of central 5-HT_2CRs on accumbal DA output is dependent on the functional balance among different 5-HT_2CR populations located within the mesocorticoaccumbens system, and that 5-HT_2CRs can modulate DA-dependent behaviors independently of changes of accumbal DA release itself.