Effects of the alpha4beta2 partial agonist varenicline on brain activity and working memory in abstinent smokers.
BACKGROUND
Cognitive alterations are a core symptom of nicotine withdrawal, contributing to smoking relapse. In rodents and humans, cognitive deficits can be reversed by treatment with the alpha4beta2 nicotinic receptor partial agonist varenicline. This neuroimaging study examined the neural mechanisms that underlie these effects.


METHODS
Twenty-two smokers completed 13 days of varenicline and placebo treatment in a double-blind crossover study with two functional magnetic resonance imaging sessions: after 3 days of abstinence while on varenicline and after 3 days of abstinence while on placebo (counterbalanced randomized order, 2-week washout). Blood oxygenation level-dependent (BOLD) data were acquired during performance of a visual N-back working memory task.


RESULTS
In a region of interest analysis, significant effects of treatment on mean percent signal change (varenicline > placebo) were observed in the dorsal anterior cingulate/medial frontal cortex, left dorsolateral prefrontal cortex, and right dorsolateral prefrontal cortex. In a cross-region model, there was a significant interaction of treatment by memory load, indicating significant increases in BOLD signal for varenicline versus placebo at the 2-back and 3-back levels but not the 1-back level. Varenicline improved performance (correct response time) in highly dependent smokers with no effect among less dependent smokers. In highly dependent smokers, faster correct response time was associated with increased BOLD signal.


CONCLUSIONS
This study provides novel evidence that the alpha4beta2 partial agonist varenicline increases working memory-related brain activity after 3 days of nicotine abstinence, particularly at high levels of task difficulty, with associated improvements in cognitive performance among highly dependent smokers.
Loughead
James
J
Brain Behavior Laboratory, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Ray
Riju
R
Wileyto
E Paul
EP
Ruparel
Kosha
K
Sanborn
Paul
P
Siegel
Steven
S
Gur
Ruben C
RC
Lerman
Caryn
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D001552:Benzazepines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D003071:Cognition / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects*; D008875:Middle Aged; D009483:Neuropsychological Tests; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010100:Oxygen / Q000097:blood; D011597:Psychomotor Performance / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D012907:Smoking / Q000503:physiopathology / Q000523:psychology*; D016540:Smoking Cessation / Q000523:psychology*; D000068580:Varenicline; D055815:Young Adult
D001552:Benzazepines; D018722:Nicotinic Agonists; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D010100:Oxygen; D000068580:Varenicline