AUTHORS: Teresa Franklin, Ph.D.*a, Ze Wang Ph.Da, Jesse Suh, Psy.D.a, d, Rebecca Hazan, B.A.a, Jeffrey Cruz, B.A.a, Yin Li, M.A.a, Marina Goldman, M.D.a, John A. Detre, M.D.bc, Charles P. O'Brien M.D., Ph.D.a,d, Anna Rose Childress, Ph.D.a,d

aDepartment of Psychiatry, University of Pennsylvania, Philadelphia, PA USA
bDepartment of Radiology, University of Pennsylvania, Philadelphia, PA USA
cDepartment of Neurology, University of Pennsylvania, Philadelphia, PA USA
dVA VISN4 MIRECC, Philadelphia, PA US


Context: Varenicline, an effective smoking cessation medication, functions as an α4β2 nicotinic acetylcholine receptor partial agonist. It indirectly affects the dopaminergic reward system to reduce 1) withdrawal symptoms during abstinence and 2) the reinforcement received from nicotine while smoking. We hypothesized that varenicline would have a third mechanism to blunt responses to smoking cues in the reward-related ventral striatum/medial orbitofrontal cortex and would be associated with a reduction in smoking cue-elicited craving.

Design: Arterial spin labeled perfusion functional magnetic resonance imaging (fMRI), a biomarker of regional brain activity, was used to test our hypothesis. Perfusion fMRI is quantitative and stable across time facilitating the measurement of medication-induced neural modifications both in response to a challenge (smoking cue exposure) and also in the brain in the resting condition (without provocation). Smokers were imaged during rest and in response to smoking cues before and after a three-week randomized placebo-controlled medication regimen. Subjects were nonabstinent to explicitly examine varenicline effects on cue reactivity independent of withdrawal.

Results: Pre-randomization smoking cues versus nonsmoking cues activated the ventral striatum/medial orbitofrontal cortex (T=3.77) and elicited subjective reports of craving (p=0.006). Craving reports correlated with increased activity in the posterior cingulate (T=4.11). Varenicline diminished smoking cue-elicited ventral striatum/medial orbitofrontal cortex responses (T values from -3.75 to -5.63) and reduced self-reported smoking cue-elicited craving while placebo-treated subjects exhibited responses similar to those observed prior to randomization. Varenicline-induced activation of lateral orbitofrontal cortex in the brain at rest (T=5.63) predicted blunting of smoking cue responses in the medial orbitofrontal cortex (r=-0.74).

Conclusions: Varenicline's reciprocal actions in reward activated medial orbitofrontal cortex and reward evaluating lateral orbitofrontal cortex underlie a diminished SC response, revealing a distinctive new action that likely contributes to its clinical efficacy.