Role of the Serotonin (5-HT) 5-HT2C Receptor (5-HT2CR) in Cocaine Cue Reactivity


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Cocaine use disorder is a chronic brain disorder characterized by high relapse rates and poor treatment outcomes; one variable known to engender relapse is exposure to environmental and discrete cues previously associated with drug-taking (cue reactivity). Human drug users experience an increase in craving elicited by drug-paired cues over time, and in rodent models, a time-dependent increase in cue reactivity (‘incubation”) is observed during forced abstinence from drug self-administration. Neuroplasticity in the mesocorticolimbic neurocircuitry mediates the incubation of cue reactivity, and a greater understanding of the mechanisms underlying incubation phenomena is needed to improve treatment outcomes and extend abstinence. Serotonin (5-HT) neurotransmitter systems play an important role in the behavioral effects of cocaine particularly through the 5-HT2C receptor (5-HT2CR), however, the involvement of this system in incubation of cue reactivity during abstinence from cocaine self-administration has not been investigated. The 5-HT2CR is expressed throughout reward neurocircuitry, but exploration of the region-dependent role of 5-HT2CR function to modulate cocaine-related behaviors, including cue reactivity, has been limited. The present studies aimed to explore the 5-HT2CR localized to nodes of the mesocorticolimbic pathway as a potential neuroregulator of cue reactivity assessed during forced abstinence from cocaine self-administration. Prolonged vs. early forced abstinence from cocaine self-administration was associated with elevated cue reactivity, a lower potency of the selective 5-HT2CR agonist WAY163909 to suppress cue reactivity, and an altered subcellular distribution profile of the 5-HT2CR in the medial prefrontal cortex. Levels of cue reactivity and 5-HT2CR protein expression levels within specific nodes (medial prefrontal cortex, ventral tegmental area) of the mesocorticoaccumbens pathway were inversely correlated. A definitive role for the 5-HT2CR in the VTA as a driver of cocaine-related behaviors could not be determined in the present study due to technical limitations in virally-mediated gene transfer experiments. Collectively, these studies illuminate the 5-HT2CR as a potential contributor to the incubation of cue reactivity associated with abstinence from cocaine self-administration. These data shed new light on the involvement of pathway-specific regulation of the 5-HT2CR in a key phenotype associated with relapse suggest new pharmacotherapeutic strategies to curb cue reactivity and prevent relapse to cocaine.



cocaine cue reactivity, serotonin 5-HT2C receptor