Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA.
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA.
Brain Imaging Behav. 2019 Apr;13(2):396-407. doi: 10.1007/s11682-018-9856-6.
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.
有证据表明，与酗酒易感性相关的奖励相关网络（例如皮质基底神经节丘脑网络）中的基础活动升高之间存在预测性关联。钙通道功能和环腺苷单磷酸（cAMP）/蛋白激酶 A 介导的信号转导是奖励神经回路和奖励相关行为的关键调节剂。钙/钙调蛋白刺激的腺苷酸环化酶（AC）1 和 8 对细胞内钙依赖性增加敏感，并催化 cAMP 的产生。因此，我们假设 AC1 和 8 调节皮质基底神经节丘脑回路中奖励区域的大脑活动，并且这种调节作用预测自愿性乙醇饮用反应。通过锰增强磁共振成像和慢性间歇性乙醇摄入程序评估了这一假设。与野生型对照（WT，C57BL/6 小鼠）相比，缺乏两种 AC1 和 8 的基因敲除（DKO 小鼠）的乙醇-naive 小鼠在与奖励处理相关的皮质基底神经节丘脑区域中表现出基线活动的双侧减少。在不与奖励处理相关的皮质基底神经节丘脑网络外部或网络内的区域中，没有明显的活动变化。平行研究表明，DKO 小鼠奖励网络活动不足预测其对递增乙醇浓度（12、20 和 30%）的消耗和偏好水平显著降低，与 WT 小鼠相比，这种作用在延长（14 个疗程）接触 20%乙醇时得以维持。综上所述，这些数据支持 AC1 和 8 在皮质基底神经节丘脑活动中的作用以及这种调节作用对乙醇饮用行为的预测价值，这值得未来评估钙刺激的 AC 在产生适应不良饮酒易感性的神经过程中的作用。
