title: Examination of the metabolite hydroxybupropion in the reinforcing and aversive stimulus effects of nicotine in rats.
abstract: BACKGROUND
  Preclinical studies with bupropion in rodent models of nicotine dependence have generated equivocal findings with regard to translating the clinical efficacy of the antidepressant as a smoking cessation agent.
  
  
  OBJECTIVE
  Given that rats are poor metabolizers of bupropion, the present experiments examined (2S,3S)-hydroxybupropion, the major active metabolite, on the positive reinforcing and aversive stimulus properties of nicotine in rats.
  
  
  METHODS
  In male hooded Lister rats, (2S,3S)-hydroxybupropion (1.0-10.0 mg/kg IP) was tested on intravenous nicotine (0.03 mg/kg/inf) self-administration behaviour for three sessions (n = 8), and in another experiment, the same doses of (2S,3S)-hydroxybupropion were tested in a conditioned taste aversion procedure to assess the aversive stimulus properties of nicotine, a function implicated in the regulation of nicotine intake.
  
  
  RESULTS
  (2S,3S)-hydroxybupropion attenuated nicotine intake in a manner similar to that produced by mecamylamine pretreatment (1.0 mg/kg SC). This effect on nicotine-taking was specific since these doses had no effect on responding maintained by sucrose presented orally (200 μl of 5 % w/v). (2S,3S)-hydroxybupropion (1, 3 and 10 mg/kg IP) pretreatment failed to modify the aversive effects produced by a small dose of nicotine (0.1 mg/kg SC).
  
  
  CONCLUSIONS
  These results demonstrate this metabolite to specifically modify the positive reinforcing effects of nicotine without affecting its aversive motivational effects. We propose that the clinical efficacy of bupropion may be due to a combination of effects produced by bupropion and/or its active metabolite (2S,3S)-hydroxybupropion involving the inhibition of reuptake of dopamine and noradrenaline in reward centres of the brain and the noncompetitive antagonism of neuronal nicotinic receptors.
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle, NE2 4HH, UK.
authors.forename: E
authors.initials: E
authors.lastname: Malcolm
authors.forename: F I
authors.initials: FI
authors.lastname: Carroll
authors.forename: B
authors.initials: B
authors.lastname: Blough
authors.forename: M I
authors.initials: MI
authors.lastname: Damaj
authors.forename: M
authors.initials: M
authors.lastname: Shoaib
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D001362:Avoidance Learning / Q000187:drug effects; D016642:Bupropion / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009538:Nicotine / Q000008:administration & dosage*; D051381:Rats; D011978:Receptors, Nicotinic / Q000502:physiology*; D012201:Reward; D012646:Self Administration; D016540:Smoking Cessation; D014029:Tobacco Use Disorder
chemical_list: D000928:Antidepressive Agents; D011978:Receptors, Nicotinic; C580748:hydroxybupropion; D016642:Bupropion; D009538:Nicotine