Effects of hydroxymetabolites of bupropion on nicotine dependence behavior in mice.
Bupropion is an atypical antidepressant that also has utility as a smoking cessation aid. Hydroxybupropions are major metabolites of bupropion and are believed to contribute to antidepressant and perhaps smoking cessation activities. Because bupropion metabolism is more similar in humans and mice than in humans and rats, the present study investigated effects of hydroxybupropion enantiomers in mouse behavioral models measuring various aspects of nicotine dependence. Bupropion and (2S,3S)-hydroxybupropion, but not (2R,3R)-hydroxybupropion, significantly decreased the development of nicotine reward as measured in the conditioned place preference and withdrawal paradigm in mice. Bupropion and both of its metabolites reversed affective and somatic withdrawal signs in nicotine-dependent mice, but the (2S,3S)-hydroxymetabolite had higher potency. Bupropion and (2S,3S)-, but not (2R,3R)-hydroxybupropion, produced partial substitution for nicotine in drug discrimination tests. Our findings support the hypothesis that the effects of bupropion on measures of nicotine dependence reflect actions of bupropion itself, its hydroxymetabolites, or a combination and suggest that the (2S,3S)-hydroxy isomer is the most active principle, making it a potentially better drug candidate for smoking cessation than bupropion.
Damaj
M Imad
MI
Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA. mdamaj@vcu.edu
Grabus
Sheri D
SD
Navarro
Hernan A
HA
Vann
Robert E
RE
Warner
Jonathan A
JA
King
Lindsey S
LS
Wiley
Jenny L
JL
Blough
Bruce E
BE
Lukas
Ronald J
RJ
Carroll
F Ivy
FI
D000818:Animals; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D016642:Bupropion / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004644:Emotions / Q000187:drug effects; D006900:Hydroxylation; D006930:Hyperalgesia / Q000523:psychology; D051379:Mice; D008813:Mice, Inbred ICR; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology; D012201:Reward; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control / Q000523:psychology; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000523:psychology*
D018765:Dopamine Uptake Inhibitors; D018722:Nicotinic Agonists; D016642:Bupropion; D009538:Nicotine