title: Protracted withdrawal from cocaine self-administration flips the switch on 5-HT(1B) receptor modulation of cocaine abuse-related behaviors.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, Arizona 85287-4501, USA.
authors.forename: Nathan S
authors.initials: NS
authors.lastname: Pentkowski
authors.forename: Tim H C
authors.initials: TH
authors.lastname: Cheung
authors.forename: William A
authors.initials: WA
authors.lastname: Toy
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Adams
authors.forename: John F
authors.initials: JF
authors.lastname: Neumaier
authors.forename: Janet L
authors.initials: JL
authors.lastname: Neisewander
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003042:Cocaine / Q000378:metabolism / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000502:physiology*; D005108:Extinction, Psychological / Q000187:drug effects; D018014:Gene Transfer Techniques; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics / Q000502:physiology*; D012055:Reinforcement Schedule; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
chemical_list: D044302:Receptor, Serotonin, 5-HT1B; D003042:Cocaine