The serotonin (5-HT) 2C receptor (5-HT2CR) and its downstream signaling components: Distinct adaptations in cortical circuits associated with cocaine exposure
Repeated intermittent cocaine administration results in a progressive augmentation of motor stimulant responses to subsequent drug challenge. Neuronal adaptations underlying this enduring behavioral transformation, known as behavioral sensitization, have been proposed to mediate the incentive motivational effects of cocaine that contribute to increased anxiety, craving and paranoia observed in cocaine addicts. Neuroadaptations in the serotonin (5 HT)2C receptor (5-HT2CR) system, which exerts an inhibitory influence over the limbic-corticostriatal circuitry and has been implicated in modulating cocaine-evoked behaviors, may play a key role in the development and maintenance of behavioral sensitization. However, the sensitivity of 5-HT2CR is diminished after withdrawal from a sensitizing cocaine regimen, suggesting that 5-HT2CR function or its downstream signaling components are significantly altered. Cortical brain areas, including motor cortex and prefrontal cortex (PFC), are important sites of action for 5-HT2CR control of cocaine-induced behaviors and are strongly implicated in cocaine-craving and cocaine-seeking behaviors. We investigated changes in four neuroadaptations that could contribute to functional 5-HT2CR subsensitivity following repeated cocaine administration: 1) 5 HT2CR protein expression and subcellular localization; 2) 5-HT2CR mRNA editing; 3) expression and subcellular localization of postsynaptic-density (PSD) protein-95 (PSD-95); and 4) phosphorylation of p44/p42-mitogen-activated protein kinases (p44/p42-MAPK), which influences activity of molecules involved in 5 HT2CR trafficking. We found decreased 5 HT2CR protein expression in total homogenate and PSD compartment of motor cortex and an apparent shift in edited 5 HT2CR mRNA isoforms in the PFC at day 3 of withdrawal from a repeated cocaine regimen. Acute cocaine administration resulted in redistribution of PSD-95 and p42-MAPK to the PSD in motor cortex, but not in PFC. Cocaine challenge following a sensitizing cocaine regimen increased phospho-p42-MAPK in total homogenate only in motor cortex. Our results suggest distinct regulatory mechanisms for 5 HT2CR function in motor cortex and PFC, with motor cortex being more responsive to the pharmacological effects of cocaine. The combination of these neuroadaptations could strengthen the cortico-striatal circuit and activate the reward pathway, exacerbating the behavioral effects of cocaine and contributing to the expression of sensitization, which could parallel the tendency for cocaine use to escalate to addiction in humans.