title: Methamphetamine-like discriminative stimulus effects of bupropion and its two hydroxy metabolites in male rhesus monkeys.
abstract: The dopamine transporter (DAT) inhibitor and nicotinic acetylcholine (nACh) receptor antagonist bupropion is being investigated as a candidate 'agonist' medication for methamphetamine addiction. In addition to its complex pharmacology, bupropion also has two distinct pharmacologically active metabolites. However, the mechanism by which bupropion produces methamphetamine-like 'agonist' effects remains unknown. The aim of the present study was to determine the role of DAT inhibition, nACh receptor antagonism, and the hydroxybupropion metabolites in the methamphetamine-like discriminative stimulus effects of bupropion in rhesus monkeys. In addition, varenicline, a partial agonist at the nACh receptor, and risperidone, a dopamine antagonist, were tested as controls. Monkeys (n=4) were trained to discriminate 0.18 mg/kg intramuscular methamphetamine from saline in a two-key food-reinforced discrimination procedure. The potency and time course of methamphetamine-like discriminative stimulus effects were determined for all compounds. Bupropion, methylphenidate, and 2S,3S-hydroxybupropion produced full, at least 90%, methamphetamine-like effects. 2R,3R-Hydroxybupropion, mecamylamine, and nicotine also produced full methamphetamine-like effects, but drug potency was more variable between monkeys. Varenicline produced partial methamphetamine-like effects, whereas risperidone did not. Overall, these results suggest DAT inhibition as the major mechanism of the methamphetamine-like 'agonist' effects of bupropion, although nACh receptor antagonism appeared, at least partially, to contribute. Furthermore, the contribution of the 2S,3S-hydroxybupropion metabolite could not be completely ruled out.
authors.affiliation: aDepartment of Pharmacology and Toxicology bInstitute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia cCenter for Drug Discovery, Research Triangle Institute, Research Triangle Park, North Carolina, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Smith
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000378:metabolism / Q000494:pharmacology*; D016642:Bupropion / Q000378:metabolism* / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008253:Macaca mulatta; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D012054:Reinforcement, Psychology; D018967:Risperidone / Q000494:pharmacology; D013997:Time Factors; D000068580:Varenicline / Q000494:pharmacology
chemical_list: D018687:Antidepressive Agents, Second-Generation; D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D018722:Nicotinic Agonists; D016642:Bupropion; D008694:Methamphetamine; D009538:Nicotine; D018967:Risperidone; D000068580:Varenicline