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The Mammalian Circadian Clock Exhibits Chronic Ethanol Tolerance and Withdrawal‐Induced Glutamate Hypersensitivity, Accompanied by Changes in Glutamate and TrkB Receptor Proteins
Author(s) -
Lindsay Jonathan H.,
Prosser Rebecca A.
Publication year - 2018
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13554
Subject(s) - glutamate receptor , nmda receptor , glutamatergic , circadian rhythm , endocrinology , circadian clock , chemistry , medicine , pharmacology , receptor , biology , biochemistry
Background Alcohol tolerance and withdrawal‐induced effects are criteria for alcohol use disorders listed by the DSM ‐V. Although tolerance and withdrawal have been studied over many decades, there is still uncertainty regarding mechanistic distinctions that characterize these different forms of ethanol (Et OH )‐induced plasticity. Previously, we demonstrated that the suprachiasmatic nucleus ( SCN ) circadian clock develops both acute and rapid tolerance to Et OH inhibition of glutamate‐induced circadian phase shifts. Here, we demonstrate that chronic Et OH tolerance and withdrawal‐induced glutamate hypersensitivity occur in vitro and that rapid tolerance, chronic tolerance, and glutamate hypersensitivity have distinct cellular changes. Methods We use single‐unit extracellular electrophysiological recordings to determine whether chronic tolerance to Et OH inhibition of glutamatergic phase shifts and withdrawal‐induced glutamate hypersensitivity develop in the SCN . We use Western blotting to compare phosphorylation state and total expression of N‐methyl‐D‐aspartate (NMDA) receptor subunits and associated proteins in the SCN after mice were exposed to varying Et OH consumption paradigms. Results Chronic tolerance developed after a minimum of 8 days of 4 h/d Et OH access, as indicated by a decreased sensitivity to Et OH inhibition of glutamate‐induced phase shifts. We also observed an increased sensitivity to glutamate‐induced phase shifts in SCN tissue following withdrawal. We demonstrated an increase in the ratio of NR 2B: NR 2A NMDA receptor subunit expression after 21 days, but not after 10 days of Et OH drinking. This increase persisted during Et OH withdrawal, along with an increase in NR 2B Y1472 phosphorylation, mature brain‐derived neurotrophic factor, and phosphorylated TrkB. Conclusions These results demonstrate that multiple tolerance forms and withdrawal‐induced glutamate hypersensitivity occur in the SCN and that these different forms of Et OH ‐induced plasticity are accompanied by distinct changes in cellular physiology. Importantly, this study further demonstrates the power of using the SCN as a model system to investigate Et OH ‐induced plasticity.