The escalation in ethanol consumption following chronic intermittent ethanol exposure is blunted in mice expressing etha
- PDF / 883,476 Bytes
- 9 Pages / 595.276 x 790.866 pts Page_size
- 72 Downloads / 149 Views
ORIGINAL INVESTIGATION
The escalation in ethanol consumption following chronic intermittent ethanol exposure is blunted in mice expressing ethanol-resistant GluN1 or GluN2A NMDA receptor subunits Paula A. Zamudio 1 & Dominic A. Gioia 1 & Marcelo Lopez 1 & Gregg E. Homanics 2 & John J. Woodward 1 Received: 14 August 2020 / Accepted: 7 October 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract N-Methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels essential for glutamatergic transmission and plasticity. NMDARs are inhibited by acute ethanol and undergo brain region-specific adaptations after chronic alcohol exposure. In previous studies, we reported that knock-in mice expressing ethanol-insensitive GluN1 or GluN2A NMDAR subunits display altered behavioral responses to acute ethanol and genotype-dependent changes in drinking using protocols that do not produce dependence. A key unanswered question is whether the intrinsic ethanol sensitivity of NMDARs also plays a role in determining behavioral adaptations that accompany the development of dependence. To test this, we exposed mice to repeated cycles of chronic intermittent ethanol (CIE) vapor known to produce a robust escalation in ethanol consumption and preference. As expected, wild-type mice showed a significant increase from baseline in ethanol consumption and preference after each of the four weekly CIE cycles. In contrast, ethanol consumption in male GluN2A(A825W) mice was unchanged following cycles 1, 2, and 4 of CIE with a modest increase appearing after cycle 3. Wild-type and GluN2A(A825W) female mice did not show a clear or consistent escalation in ethanol consumption or preference following CIE treatment. In male GluN1(F639A) mice, the increase in ethanol consumption observed with their wild-type littermates was delayed until later cycles of exposure. These results suggest that the acute ethanol sensitivity of NMDARs especially those containing the GluN2A subunit may be a critical factor in the escalation of ethanol intake in alcohol dependence. Keywords Alcohol dependence . Glutamate . Knock-in mutation . Ethanol sensitivity . Two-bottle choice
Introduction As key players in glutamatergic synaptic neuronal transmission and plasticity, ethanol-sensitive N-methyl-D-aspartate receptors (NMDARs) are hypothesized to play a significant role in the pathophysiology of alcohol use disorders. For example, NMDARs have been shown to mediate the rewarding effects of ethanol and influence the severity of withdrawal symptoms, craving, and relapse in ethanol dependent subjects (Barker * John J. Woodward [email protected] Gregg E. Homanics [email protected] 1
Department of Neuroscience, Medical University of South Carolina, MSC 861, 30 Courtenay Drive, Charleston, SC 29425-5712, USA
2
Department of Anesthesiology, University of Pittsburgh, 6060 Biomedical Science Tower-3, Pittsburgh, PA 15261, USA
et al. 2017; Becker and Lopez 2016; Biala and Kotlinska 1999; Boyce-Rustay and Holmes 2006a; Daut et al. 2015; Jury et al.
Data Loading...
