Short-term nicotine deprivation alters dorsal anterior cingulate glutamate concentration and concomitant cingulate-cortical functional connectivity

Abstract

Most cigarette smokers who wish to quit too often relapse within the first few days of abstinence, primarily due to the aversive aspects of the nicotine withdrawal syndrome (NWS), which remains poorly understood. Considerable research has suggested that the dorsal anterior cingulate cortex (dACC) plays a key role in nicotine dependence, with its functional connections between other brain regions altered as a function of trait addiction and state withdrawal. The flow of information between dACC and fronto-striatal regions is secured through different pathways, the vast majority of which are glutamatergic. As such, we investigated dACC activity using resting state functional connectivity (rsFC) with functional magnetic resonance imaging (fMRI) and glutamate (Glu) concentration with magnetic resonance spectroscopy (MRS). We also investigated the changes in adenosine levels in plasma during withdrawal as a surrogate for brain adenosine, which plays a role in fine-tuning synaptic glutamate transmission. Using a double-blind, placebo-controlled, randomized crossover design, nontreatment seeking smoking participants (N = 30) completed two imaging sessions, one while nicotine sated and another after 36 h nicotine abstinence. We observed reduced dACC Glu (P = 0.029) along with a significant reduction in plasma adenosine (P = 0.03) and adenosine monophosphate (AMP; P < 0.0001) concentrations during nicotine withdrawal in comparison with nicotine sated state. This withdrawal state manipulation also led to an increase in rsFC strength (P < 0.05) between dACC and several frontal cortical regions, including left superior frontal gyrus (LSFG), and right middle frontal gyrus (RMFG). Moreover, the state-trait changes in dACC Glu and rsFC strength between the dACC and both SFG and MFG were positively correlated (P = 0.012, and P = 0.007, respectively). Finally, the change in circuit strength between dACC and LSFG was negatively correlated with the change in withdrawal symptom manifestations as measured by the Wisconsin Smoking Withdrawal Scale (P = 0.04) and Tobacco Craving Questionnaire (P = 0.014). These multimodal imaging-behavioral findings reveal the complex cascade of changes induced by acute nicotine deprivation and call for further investigation into the potential utility of adenosine- and glutamate-signaling as novel therapeutic targets to treat the NWS.

Fig. 1. Relationship between changes in plasma nicotine and clinical manifestations of withdrawal.

Correlation analysis between the change (Δ) in plasma nicotine concentrations (Withdrawal-satiety) and a ΔPANAS positive subscale; r = 0.393, P = 0.03), and b with ΔSATI-S, r = −0.506 m P = 0.019).

Fig. 2. dACC rsFC and Glu changes between nicotine satiety and withdrawal.

a Merged dACC MRS voxel in the sagittal, axial and coronal planes. Color spectrum from green to red denotes the degree of overlap. b The ≥80% voxel overlap used as seed for whole brain resting state functional connectivity analysis. c Voxel-wise resting state one-sample T-test analysis when contrasting withdrawal and satiety conditions. Significant cluster (P_corrected < 0.05) at the left superior frontal gyrus (LSFG) shown in the three planes. d rsFC z-values in both satiety and withdrawal conditions and e shows the correlation between Δ-dACC Glu and Δ-rsFC (dACC-LSFG) F(1,20) = 7.497, P = 0.012 by linear regression. f Voxel-wise resting state one-sample T-test analysis when contrasting withdrawal and satiety conditions. Significant cluster (P_corrected < 0.05) at the right middle frontal gyrus (RMFG) in the three planes. g rsFC z-values in both satiety and withdrawal and h the correlation between Δ-dACC Glu and Δ-rsFC (dACC-RMFG) F(1,20) = 8.864, P = 0.007 by linear regression.

Fig. 3. The relationship between changes in resting state functional connectivity strength and clinical manifestations of nicotine withdrawal.

The change (withdrawal-satiety) in rsFC between dACC and LSFG correlates with a change in WSWS total score F(1,20) = 4.824, P = 0.04 and b with the change in total TCS: F(1,20) = 7.231, P = 0.014 by linear regression.