Abstract
Rationale: Varenicline, the most effective single agent for smoking cessation, is a partial agonist at α4β2 nicotinic acetylcholine receptors. Increasing evidence implicates glutamate in the pathophysiology of addiction and one of the benefits of treatment for smoking cessation is the ability to regain cognitive control.Objective: To evaluate the effects of 12-week varenicline administration on glutamate levels in the dorsal anterior cingulate cortex (dACC) and functional changes within the cognitive control network.Methods: We used single-voxel proton magnetic resonance spectroscopy (1H-MRS) in the dACC and functional MRI (fMRI) during performance of a Stroop color-naming task before and after smoking cessation with varenicline in 11 healthy smokers (open label design). Using the dACC as a seed region, we evaluated functional connectivity changes using a psychophysiological interaction (PPI) analysis.Results: We observed a significant decrease in dACC glutamate + glutamine (Glx)/Cr levels as well as significant blood oxygen level-dependent signal (BOLD) decreases in the rostral ACC/medial orbitofrontal cortex and precuneus/posterior cingulate cortex. These BOLD changes are suggestive of alterations in default mode network (DMN) function and are further supported by the results of the PPI analysis that revealed changes in connectivity between the dACC and regions of the DMN. Baseline measures of nicotine dependence and craving positively correlated with baseline Glx/Cr levels.Conclusions: These results suggest possible mechanisms of action for varenicline such as reduction in Glx levels in dACC and shifts in BOLD connectivity between large scale brain networks. They also suggest a role for ACC Glx in the modulation of behavior. Due to the preliminary nature of this study (lack of control group and small sample size), future studies are needed to replicate these findings.
Highlights
Varenicline is an α4β2 nicotinic acetylcholine receptor partial agonist (Rollema et al, 2007) that is more efficacious than nicotine replacement therapies or bupropion for smoking cessation (Gonzales et al, 2006) but still only results in smoking cessation rates of 25–30% 6 months after treatment (Tonstad et al, 2006)
We observed a significant decrease in dorsal ACC (dACC) glutamate + glutamine (Glx)/Cr levels as well as significant blood oxygen level-dependent signal (BOLD) decreases in the rostral anterior cingulate cortex (ACC)/medial orbitofrontal cortex and precuneus/posterior cingulate cortex
These BOLD changes are suggestive of alterations in default mode network (DMN) function and are further supported by the results of the psychophysiological interaction (PPI) analysis that revealed changes in connectivity between the dACC and regions of the DMN
Summary
Varenicline is an α4β2 nicotinic acetylcholine receptor (nAChR) partial agonist (Rollema et al, 2007) that is more efficacious than nicotine replacement therapies or bupropion for smoking cessation (Gonzales et al, 2006) but still only results in smoking cessation rates of 25–30% 6 months after treatment (Tonstad et al, 2006). It is critical to understand the mechanism of action of varenicline so that more effective smoking cessation drugs can be developed. Preclinical research in animal models of nicotine-dependence indicates that reducing glutamatergic transmission through pharmacological manipulations decreases the rewarding effect of nicotine (Paterson et al, 2003; Paterson and Markou, 2005). Pre-clinical animal research indicates varenicline may act on glutamate levels by increasing glutamic acid decarboxylase expression in prefrontal cortex (Maloku et al, 2011). Prior MRS studies suggest a role for ACC glutamate levels in the modulation of addiction behaviors. A recent MRS study in alcohol-dependent subjects (Umhau et al, 2010) found a reduction of glutamate levels in the anterior cingulate cortex (ACC) following a 4-week treatment www.frontiersin.org
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