Neurochemical and behavioral effects of bupropion and mecamylamine in the presence of nicotine.
The primary mechanism of action of bupropion, a smoking cessation drug, is commonly believed to involve the dopaminergic system although evidence exists that bupropion also has effects at nicotinic acetylcholine receptors (nAChRs). This study evaluated the disruptive effects of nicotine on response rates in the presence of bupropion and the nAChR antagonist, mecamylamine, as well as the ability of these drugs to alter nicotine-stimulated nAChR function in various brain areas. Rats were trained to respond on a single lever under a variable interval 15 (VI15) schedule for food reinforcement. Initially, dose effect curves were generated for nicotine, bupropion and mecamylamine. Upon determining the dose of nicotine (1.2 mg/kg) effective in completely disrupting rates of responding, it was established that both mecamylamine and bupropion block nicotine's rate-reducing effects. This result suggests that bupropion shares behavioral effects with mecamylamine when administered in the presence of nicotine. To explore this relationship further, the effect of in vivo administration of bupropion or mecamylamine on nicotine-stimulated (86)Rb(+) efflux was studied in synaptosomes prepared from the frontal cortex, hippocampus, striatum and thalamus. Nicotine-stimulated (86)Rb(+) efflux from all brain regions was significantly reduced in rats administered 3.0 mg/kg mecamylamine (s.c.) 15 min prior to dissection compared to control rats. In contrast, a significant increase in nicotine-stimulated (86)Rb(+) efflux was observed in all brain regions from rats administered 30.0 mg/kg bupropion (s.c.) 15 min prior to dissection compared to control rats. Taken together these results demonstrate that when administered in the presence of nicotine, bupropion elicits unique pharmacological differences such that it exhibits both nAChR agonist- and antagonistic-like effects.
Vann
Robert E
RE
Department of Pharmacology, Virginia Commonwealth University, Richmond, PO Box 980613, Richmond, VA 23298-0613, USA. revann@vcu.edu
Rosecrans
John A
JA
James
John R
JR
Philibin
Scott D
SD
Robinson
Susan E
SE
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D016642:Bupropion / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology*; D009538:Nicotine / Q000037:antagonists & inhibitors*; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D012054:Reinforcement, Psychology; D012414:Rubidium Radioisotopes; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
D018765:Dopamine Uptake Inhibitors; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D012414:Rubidium Radioisotopes; D016642:Bupropion; D008464:Mecamylamine; D009538:Nicotine; D004298:Dopamine