title: Tranylcypromine enhancement of nicotine self-administration.
abstract: Tobacco use has one of the highest rates of addiction of any abused drug. Paradoxically, in animal models, nicotine appears to be a weak reinforcer. We report here that the inhibition of monoamine oxidase (MAO), a major effect of tobacco smoke, increases the reinforcing effect of nicotine. Rats (aged postnatal day 27 and 90) were tested for self-administration, without prior response training, in five daily 3-h sessions. Whereas control rats did not self-administer nicotine, low doses of nicotine (2.5 to 21 microg/kg/injection) were avidly self-administered following a pretreatment with tranylcypromine (3 mg/kg), an irreversible and non-selective MAO inhibitor. Tranylcypromine-enhanced nicotine (10 microg/kg/injection, i.v.) self-administration was reduced by systemic injection of a D1-dopaminergic receptor antagonist, SCH23390 (0.02 mg/kg). Moreover, an increase in extracellular dopamine in the nucleus accumbens was detected, using microdialysis, following nicotine (60 microg/kg) injection in tranylcypromine pre-treated rats. Depending on the time of tranylcypromine pretreatment (20 or 1 h), MAO activity was decreased by 72% and 99% and nicotine intake at day 5 was increased by 619 and 997%, respectively. Taken together, these results indicate that in a stringent self-administration acquisition test, MAO inhibition increases the rewarding effect of low doses of nicotine, possibly via a dopamine-dependent mechanism.
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Irvine, CA 92697, USA. avillegi@uci.edu
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Villégier
authors.forename: Shahrdad
authors.initials: S
authors.lastname: Lotfipour
authors.forename: Susan C
authors.initials: SC
authors.lastname: McQuown
authors.forename: James D
authors.initials: JD
authors.lastname: Belluzzi
authors.forename: Frances M
authors.initials: FM
authors.lastname: Leslie
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000375:Aging / Q000502:physiology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry; D006207:Half-Life; D008297:Male; D017551:Microdialysis; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D012201:Reward; D012646:Self Administration; D014191:Tranylcypromine / Q000494:pharmacology*
chemical_list: D001552:Benzazepines; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D008996:Monoamine Oxidase Inhibitors; D018722:Nicotinic Agonists; D017447:Receptors, Dopamine D1; D015102:3,4-Dihydroxyphenylacetic Acid; D014191:Tranylcypromine; D009538:Nicotine; D003042:Cocaine; D004298:Dopamine