Bupropion enhances brain reward function and reverses the affective and somatic aspects of nicotine withdrawal in the rat.
BACKGROUND
Bupropion is an atypical antidepressant and the only non-nicotine-based therapy approved for smoking cessation. Its use has raised much debate as to how a non-nicotine-based agent can aid in smoking cessation.


OBJECTIVE
We assessed the effects of bupropion on brain reward function under baseline conditions and subsequent to withdrawal from chronic nicotine administration in rats.


METHODS
A discrete-trial intracranial self-stimulation paradigm procedure was used that provides one with current intensity thresholds, a measure of reward in rats under baseline conditions and subsequent to withdrawal from chronic nicotine (3.16 mg/kg per day for 7 days via osmotic minipump). Somatic signs were recorded based on a checklist of nicotine abstinence signs in animals withdrawn from nicotine.


RESULTS
Bupropion (10-60 mg/kg) dose-dependently lowered reward thresholds in non-withdrawing subjects indicating an increase in reward. Interestingly, a sub-effective dose of bupropion (5 mg/kg) blocked completely the threshold lowering effects of acute nicotine (0.25 mg/kg). Animals withdrawn from chronic nicotine exhibited increases in somatic signs of withdrawal and elevated brain reward thresholds, which is indicative of "diminished interest or pleasure" (i.e. anhedonia) in the rewarding stimuli. Bupropion (10-40 mg/kg) reversed both the reward deficit and the somatic signs, with the highest dose (40 mg/kg) inducing a protracted reversal of the threshold elevation.


CONCLUSIONS
Bupropion acts on multiple levels to alter brain reward circuits influenced by nicotine, in addition to reducing the expression of somatic signs of withdrawal. First, bupropion, unlike other antidepressants, increases brain reward function under baseline conditions in non-withdrawing subjects. Second, at low doses bupropion blocks the rewarding effects of nicotine. Third, bupropion reverses the negative affective aspects of nicotine withdrawal. Such actions are likely to act in concert to mediate the unique anti-smoking properties of bupropion.
Cryan
John F
JF
Department of Neuropharmacology, CVN-7, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Bruijnzeel
Adrie W
AW
Skjei
Karen L
KL
Markou
Athina
A
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D016642:Bupropion / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004558:Electric Stimulation; D008297:Male; D009538:Nicotine / Q000008:administration & dosage / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000502:physiology; D012201:Reward; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000523:psychology*
D018687:Antidepressive Agents, Second-Generation; D011978:Receptors, Nicotinic; D016642:Bupropion; D009538:Nicotine