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 present aim 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. Potency and time course of methamphetamine-like discriminative stimulus effects were determined for all compounds. Bupropion, methylphenidate, and 2S,3S-hydroxybupropion produced full, ≥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.

Comparison of In Vitro Stereoselective Metabolism of Bupropion in Human, Monkey, Rat, and Mouse Liver Microsomes

“…Based simply on the close genetic homology of NHPs to humans [59], it is reasonable to expect they would be a superior translational model to understand bupropion CNS disposition and ensuing central effects in humans. However, in vitro metabolite kinetics, and 15 in vivo metabolite disposition in NHPs is limited [51,[60][61][62], and reports of stereoselective analysis are absent. We found that the total percentage of hydroxybupropion, threohydrobupropion, erythrohydrobupropion in marmoset monkey liver microsomes (62%, 23%,14%, respectively) is in good agreement with a previously published report (62%,28%,10%) in baboon hepatic microsomes [60].…”