Abstract
Evidence suggests a predictive link between elevated basal activity within reward-related networks (e.g., cortico-basal ganglia-thalamic networks) and vulnerability for alcoholism. Both calcium channel function and cyclic adenosine monophosphate (cAMP)/protein kinase A-mediated signaling are critical modulators of reward neurocircuitry and reward-related behaviors. Calcium/calmodulin-stimulated adenylyl cyclases (AC) 1 and 8 are sensitive to activity-dependent increases in intracellular calcium and catalyze cAMP production. Therefore, we hypothesized AC1 and 8 regulate brain activity in reward regions of the cortico-basal ganglia-thalamic circuit and that this regulatory influence predicts voluntary ethanol drinking responses. This hypothesis was evaluated by manganese-enhanced magnetic resonance imaging and chronic, intermittent ethanol access procedures. Ethanol-naïve mice with genetic deletion of both AC1 and 8 (DKO mice) exhibited bilateral reductions in baseline activity within cortico-basal ganglia-thalamic regions associated with reward processing compared to wild-type controls (WT, C57BL/6 mice). Significant activity changes were not evident in regions either outside of the cortico-basal ganglia-thalamic network or within the network that are not associated with reward processing. Parallel studies demonstrated that reward network hypoactivity in DKO mice predicted a significant attenuation in consumption and preference levels to escalating ethanol concentrations (12, 20 and 30%) compared to WT mice, an effect that was maintained over extended access (14 sessions) to 20% ethanol. Summarizing, these data support a contribution of AC1 and 8 in cortico-basal ganglia-thalamic activity and the predictive value of this regulatory influence on ethanol drinking behavior, which merits the future evaluation of calcium-stimulated ACs in the neural processes that engender vulnerability to maladaptive alcohol drinking.
Highlights
In recent years, studies identifying the neurocircuitry mediating alcohol action have strongly implicated the major nuclei and connectivity of the cortical-basal ganglia (BG)-thalamicElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.network in alcohol pathophysiology
To establish if the genotypic reduction in ethanol drinking responses was maintained over extended access, consumption (Fig. 3a, b, c) and preference ratios (Fig. 3d, e) were assessed in a separate cohort of WT and DKO mice given intermittent access to 20% ethanol for 14 sessions (n = 8/ genotype)
Intermittent access to this ethanol concentration was shown to induce a gradual escalation in intake that reaches a stable baseline in rodents without the need for an initiation method (Hwa et al 2011; Melendez 2011)
Summary
Concerted activity across this anatomically vast network was shown to have a specific role in mediating reward-guided action and its aberrant regulation in an alcohol-addictive state (Balleine et al 2015; Noori et al 2012; Yager et al 2015). The transition from recreational to compulsive drug seeking, associated with addiction, likely involves dysregulation of integrative cortico-BG-thalamic circuits, leading to loss of control over goal-directed actions, dysfunction of habit learning processes. While human imaging studies have extensively characterized functional alterations associated with alcohol abuse, there is a growing interest in defining if these alterations are the sole result of chronic alcohol use or represent innate factors which predict biological propensity for alcohol. Altered resting brain function was observed in focal cortico-limbic and thalamic areas in ethanol-naïve animals with genetic predisposition to alcohol, highlighting the predictive value of heritable neurofunctional alterations in alcohol susceptibility (Gozzi et al 2013)
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