Protracted withdrawal from cocaine self-administration flips the switch on 5-HT(1B) receptor modulation of cocaine abuse-related behaviors

• Published in: Biological psychiatry (1969) 2012-09, Vol.72 (5), p.396
• Main Authors: Pentkowski, Nathan S, Cheung, Tim H C, Toy, William A, Adams, Matthew D, Neumaier, John F, Neisewander, Janet L
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Cocaine - metabolism; Cocaine - pharmacology; Cocaine-Related Disorders - physiopathology; Conditioning, Operant - drug effects; Dose-Response Relationship, Drug; Drug-Seeking Behavior - physiology; Extinction, Psychological - drug effects; Gene Transfer Techniques; Male; Nucleus Accumbens - drug effects; Nucleus Accumbens - physiology; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1B - genetics; Receptor, Serotonin, 5-HT1B - physiology; Reinforcement Schedule; Self Administration; Substance Withdrawal Syndrome - physiopathology
• ISSN: 1873-2402
• DOI: 10.1016/j.biopsych.2012.03.024

The role of serotonin-1B receptors (5-HT(1B)Rs) 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(1B)Rs in the mesolimbic pathway may vary depending on the stage of the addiction cycle. To test this hypothesis, we examined the effects of increasing 5-HT(1B)R production by microinfusing a viral vector expressing either green fluorescent protein and 5-HT(1B)R 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. 5-HT(1B)R 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(1B)R 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. This unique pattern of effects suggests that mesolimbic 5-HT(1B)Rs 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(1B)Rs 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.