title: Effects of the alpha4beta2 partial agonist varenicline on brain activity and working memory in abstinent smokers.
abstract: 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.
authors.affiliation: Brain Behavior Laboratory, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: James
authors.initials: J
authors.lastname: Loughead
authors.forename: Riju
authors.initials: R
authors.lastname: Ray
authors.forename: E Paul
authors.initials: EP
authors.lastname: Wileyto
authors.forename: Kosha
authors.initials: K
authors.lastname: Ruparel
authors.forename: Paul
authors.initials: P
authors.lastname: Sanborn
authors.forename: Steven
authors.initials: S
authors.lastname: Siegel
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Gur
authors.forename: Caryn
authors.initials: C
authors.lastname: Lerman
mesh_terms: 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
chemical_list: D001552:Benzazepines; D018722:Nicotinic Agonists; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D010100:Oxygen; D000068580:Varenicline