Serotonin2C 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(2C)R) located within the ventral tegmental area and the nucleus accumbens (NAc). The 5-HT(2C)R 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(2C)Rs on cocaine-induced DA outflow in the NAc shell. Intra-mPFC injection of the 5-HT(2C)R agonist Ro 60-0175 at 5 microg/0.2 microl, but not 1 microg/0.2 microl, 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(2C)R antagonist SB 242084 (0.5 microg/0.2 microl) or SB 243213 (0.5 and 1 microg/0.2 microl). These results show that mPFC 5-HT(2C)Rs exert a positive control over cocaine-induced accumbal DA outflow. Observations further support the idea that the overall action of central 5-HT(2C)Rs on accumbal DA output is dependent on the functional balance among different 5-HT(2C)R populations located within the mesocorticoaccumbens system, and that 5-HT(2C)Rs can modulate DA-dependent behaviors independently of changes of accumbal DA release itself.