Protracted withdrawal from cocaine self-administration flips the switch on 5-HT_1B receptor modulation of cocaine abuse-related behaviors

Background: The role of serotonin-1B receptors (5-HT_1BRs) in modulating cocaine abuse-related behaviors has been controversial due to discrepancies between pharmacological and gene knockout approaches and opposite influences on cocaine self-administration versus cocaine-seeking behavior. We hypothesized that modulation of these behaviors via 5-HT_1BRs in the mesolimbic pathway may vary depending on the stage of the addiction cycle. Methods: To test this hypothesis, we examined the effects of increasing 5-HT_1BR production by microinfusing a viral vector expressing either green fluorescent protein and 5-HT_1BR or green fluorescent protein alone into the medial nucleus accumbens shell of rats either during maintenance of cocaine self-administration (i.e., active drug use) or during protracted withdrawal. Results: 5-HT_1BR receptor gene transfer during maintenance shifted the dose-response curve for cocaine self-administration upward and to the left and increased breakpoints and cocaine intake on a progressive ratio schedule, consistent with enhanced reinforcing effects of cocaine. In contrast, following 21 days of forced abstinence, 5-HT_1BR gene transfer attenuated breakpoints and cocaine intake on a progressive ratio schedule of reinforcement, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. Conclusions: This unique pattern of effects suggests that mesolimbic 5-HT_1BRs differentially modulate cocaine abuse-related behaviors, with a facilitative influence during periods of active drug use, in striking contrast to an inhibitory influence during protracted withdrawal. These findings suggest that targeting 5-HT_1BRs may lead to a novel treatment for cocaine dependence and that the therapeutic efficacy of these treatments may vary depending on the stage of the addiction cycle.