Calcium/calmodulin-stimulated adenylyl cyclases 1 and 8 regulate reward-related brain activity and ethanol consumption.

Autor: Bosse KE; Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA.; Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA., Ghoddoussi F; Department of Anesthesiology, Wayne State University School of Medicine, Detroit, MI, USA., Eapen AT; Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA.; Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA., Charlton JL; Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA.; Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA., Susick LL; Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA.; Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA., Desai K; Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA., Berkowitz BA; Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA.; Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA., Perrine SA; Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA., Conti AC; Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA. alana.conti@wayne.edu.; Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA. alana.conti@wayne.edu.; Department of Neurosurgery, Wayne State University, 4646 John R St., Detroit, MI, 48201, USA. alana.conti@wayne.edu.
Jazyk: angličtina
Zdroj: Brain imaging and behavior [Brain Imaging Behav] 2019 Apr; Vol. 13 (2), pp. 396-407.
DOI: 10.1007/s11682-018-9856-6
Abstrakt: 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.
Databáze: MEDLINE
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