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.
Similar content being viewed by others
References
American Psychiatric Association (2013) Desk reference to the diagnostic criteria from DSM-5. American Psychiatric Publishing, Washington, DC
Anderson RI, Spear LP (2011) Autoshaping in adolescence enhances sign-tracking behavior in adulthood: impact on ethanol consumption. Pharmacol Biochem Behav 98:250–260
Barker JM, Bryant KG, Osborne JI, Chandler LJ (2017) Age and sex interact to mediate the effects of intermittent, high-dose ethanol exposure on behavioral flexibility. Front Pharmacol 8:450
Becker HC, Lopez MF (2016) An animal model of alcohol dependence to screen medications for treating alcoholism. Int Rev Neurobiol 126:157–177
Bertholomey ML, Nagarajan V, Torregrossa MM (2016) Sex differences in reinstatement of alcohol seeking in response to cues and yohimbine in rats with and without a history of adolescent corticosterone exposure. Psychopharmacology 233:2277–2287
Biala G, Kotlinska J (1999) Blockade of the acquisition of ethanol-induced conditioned place preference by N-methyl-D-aspartate receptor antagonists. Alcohol Alcohol 34:175–182
Boyce-Rustay JM, Holmes A (2006a) Ethanol-related behaviors in mice lacking the NMDA receptor NR2A subunit. Psychopharmacology 187:455–466
Boyce-Rustay JM, Holmes A (2006b) Genetic inactivation of the NMDA receptor NR2A subunit has anxiolytic- and antidepressant-like effects in mice. Neuropsychopharmacology 31:2405–2414
Cailhol S, Mormede P (2001) Sex and strain differences in ethanol drinking: effects of gonadectomy. Alcohol Clin Exp Res 25:594–599
Carpenter-Hyland EP, Chandler LJ (2007) Adaptive plasticity of NMDA receptors and dendritic spines: implications for enhanced vulnerability of the adolescent brain to alcohol addiction. Pharmacol Biochem Behav 86:200–208
Carpenter-Hyland EP, Woodward JJ, Chandler LJ (2004) Chronic ethanol induces synaptic but not extrasynaptic targeting of NMDA receptors. J Neurosci 24:7859–7868
Carr LG, Habegger K, Spence J, Ritchotte A, Liu L, Lumeng L, Li TK, Foroud T (2003) Analyses of quantitative trait loci contributing to alcohol preference in HAD1/LAD1 and HAD2/LAD2 rats. Alcohol Clin Exp Res 27:1710–1717
Colville AM, Iancu OD, Oberbeck DL, Darakjian P, Zheng CL, Walter NA, Harrington CA, Searles RP, McWeeney S, Hitzemann RJ (2017) Effects of selection for ethanol preference on gene expression in the nucleus accumbens of HS-CC mice. Genes Brain Behav 16:462–471
Daut RA, Busch EF, Ihne J, Fisher D, Mishina M, Grant SG, Camp M, Holmes A (2015) Tolerance to ethanol intoxication after chronic ethanol: role of GluN2A and PSD-95. Addict Biol 20:259–262
den Hartog CR, Beckley JT, Smothers TC, Lench DH, Holseberg ZL, Fedarovich H, Gilstrap MJ, Homanics GE, Woodward JJ (2013) Alterations in ethanol-induced behaviors and consumption in knock-in mice expressing ethanol-resistant NMDA receptors. PLoS One 8:e80541
den Hartog CR, Gilstrap M, Eaton B, Lench DH, Mulholland PJ, Homanics GE, Woodward JJ (2017) Effects of repeated ethanol exposures on NMDA receptor expression and locomotor sensitization in mice expressing ethanol resistant NMDA receptors. Front Neurosci 11:84
Domart MC, Benyamina A, Lemoine A, Bourgain C, Blecha L, Debuire B, Reynaud M, Saffroy R (2012) Association between a polymorphism in the promoter of a glutamate receptor subunit gene (GRIN2A) and alcoholism. Addict Biol 17:783–785
Fritz M, Klawonn AM, Zahr NM (2019) Neuroimaging in alcohol use disorder: from mouse to man. J Neurosci Res
Griffin WC 3rd, Lopez MF, Becker HC (2009) Intensity and duration of chronic ethanol exposure is critical for subsequent escalation of voluntary ethanol drinking in mice. Alcohol Clin Exp Res 33:1893–1900
Honse Y, Ren H, Lipsky RH, Peoples RW (2004) Sites in the fourth membrane-associated domain regulate alcohol sensitivity of the NMDA receptor. Neuropharmacology 46:647–654
Hwa L, Besheer J, Kash T (2017) Glutamate plasticity woven through the progression to alcohol use disorder: a multi-circuit perspective. F1000Res 6:298
Jury NJ, DiBerto JF, Kash TL, Holmes A (2017) Sex differences in the behavioral sequelae of chronic ethanol exposure. Alcohol 58:53–60
Jury NJ, Radke AK, Pati D, Kocharian A, Mishina M, Kash TL, Holmes A (2018) NMDA receptor GluN2A subunit deletion protects against dependence-like ethanol drinking. Behav Brain Res 353:124–128
Kotlinska J, Biala G, Rafalski P, Bochenski M, Danysz W (2004) Effect of neramexane on ethanol dependence and reinforcement. Eur J Pharmacol 503:95–98
Levran O, Londono D, O’Hara K, Randesi M, Rotrosen J, Casadonte P, Linzy S, Ott J, Adelson M, Kreek MJ (2009) Heroin addiction in African Americans: a hypothesis-driven association study. Genes Brain Behav 8:531–540
Lo CL, Lossie AC, Liang T, Liu Y, Xuei X, Lumeng L, Zhou FC, Muir WM (2016) High resolution genomic scans reveal genetic architecture controlling alcohol preference in bidirectionally selected rat model. PLoS Genet 12:e1006178
Lopez MF, Miles MF, Williams RW, Becker HC (2017) Variable effects of chronic intermittent ethanol exposure on ethanol drinking in a genetically diverse mouse cohort. Alcohol 58:73–82
Miyamoto Y, Yamada K, Noda Y, Mori H, Mishina M, Nabeshima T (2001) Hyperfunction of dopaminergic and serotonergic neuronal systems in mice lacking the NMDA receptor epsilon1 subunit. J Neurosci 21:750–757
Morales M, McGinnis MM, McCool BA (2015) Chronic ethanol exposure increases voluntary home cage intake in adult male, but not female, long-Evans rats. Pharmacol Biochem Behav 139:67–76
Ogata J, Shiraishi M, Namba T, Smothers CT, Woodward JJ, Harris RA (2006) Effects of anesthetics on mutant N-methyl-D-aspartate receptors expressed in Xenopus oocytes. J Pharmacol Exp Ther 318:434–443
Petrenko AB, Yamakura T, Kohno T, Sakimura K, Baba H (2013) Increased brain monoaminergic tone after the NMDA receptor GluN2A subunit gene knockout is responsible for resistance to the hypnotic effect of nitrous oxide. Eur J Pharmacol 698:200–205
Piano MR, Carrigan TM, Schwertz DW (2005) Sex differences in ethanol liquid diet consumption in Sprague-Dawley rats. Alcohol 35:113–118
Priddy BM, Carmack SA, Thomas LC, Vendruscolo JC, Koob GF, Vendruscolo LF (2017) Sex, strain, and estrous cycle influences on alcohol drinking in rats. Pharmacol Biochem Behav 152:61–67
Ren H, Zhao Y, Wu M, Dwyer DS, Peoples RW (2017) Two adjacent phenylalanines in the NMDA receptor GluN2A subunit M3 domain interactively regulate alcohol sensitivity and ion channel gating. Neuropharmacology 114:20–33
Ron D, Wang J (2009) The NMDA receptor and alcohol addiction. In: Van Dongen AM (ed) Biology of the NMDA Receptor (Frontiers in Neuroscience), Boca Raton
Ronald KM, Mirshahi T, Woodward JJ (2001) Ethanol inhibition of N-methyl-D-aspartate receptors is reduced by site-directed mutagenesis of a transmembrane domain phenylalanine residue. J Biol Chem 276:44729–44735
Schumann G, Johann M, Frank J, Preuss U, Dahmen N, Laucht M, Rietschel M, Rujescu D, Lourdusamy A, Clarke TK, Krause K, Dyer A, Depner M, Wellek S, Treutlein J, Szegedi A, Giegling I, Cichon S, Blomeyer D, Heinz A, Heath S, Lathrop M, Wodarz N, Soyka M, Spanagel R, Mann K (2008) Systematic analysis of glutamatergic neurotransmission genes in alcohol dependence and adolescent risky drinking behavior. Arch Gen Psychiatry 65:826–838
Schweitzer P, Cates-Gatto C, Varodayan FP, Nadav T, Roberto M, Lasek AW, Roberts AJ (2016) Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice. Neuropharmacology 107:1–8
Smothers CT, Woodward JJ (2006) Effects of amino acid substitutions in transmembrane domains of the NR1 subunit on the ethanol inhibition of recombinant N-methyl-D-aspartate receptors. Alcohol Clin Exp Res 30:523–530
Smothers CT, Woodward JJ (2016) Differential effects of TM4 tryptophan mutations on inhibition of N-methyl-d-aspartate receptors by ethanol and toluene. Alcohol 56:15–19
Szumlinski K, Woodward JJ (2014) Glutamate signaling in alcohol abuse and dependence. In: Noronha ABC, Cui C, Harris RA, Crabbe JC (eds) Neurobiology of alcohol dependence. Academic Press, London, pp 173–206
Xie Q, Buck LA, Bryant KG, Barker JM (2019) Sex differences in ethanol reward seeking under conflict in mice. Alcohol Clin Exp Res 43:1556–1566
Xu M, Smothers CT, Woodward JJ (2015) Cysteine substitution of transmembrane domain amino acids alters the ethanol inhibition of GluN1/GluN2A N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 353:91–101
Zamudio PA, Smothers TC, Homanics GE, Woodward JJ (2020) Knock-in mice expressing an ethanol-resistant GluN2A NMDA receptor subunit show altered responses to ethanol. Alcohol Clin Exp Res 44:479–491
Zamudio-Bulcock PA, Homanics GE, Woodward JJ (2018) Loss of ethanol inhibition of N-methyl-D-aspartate receptor-mediated currents and plasticity of cerebellar synapses in mice expressing the GluN1(F639A) subunit. Alcohol Clin Exp Res 42:698–705
Zhao B, Zhu Y, Wang W, Cui HM, Wang YP, Lai JH (2013) Analysis of variations in the glutamate receptor, N-methyl D-aspartate 2A (GRIN2A) gene reveals their relative importance as genetic susceptibility factors for heroin addiction. PLoS One 8:e70817
Funding
This work was supported by NIH grants K01AA028059 (PAZ), F32AA026774 (DAG), R37AA009986 (JJW), R37AA10422 (GEH), AA020889 (GEH) and P50AA010761 (JJW, ML).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
All experiments were approved by the MUSC Institutional Animal Care and Use Committees and conformed to NIH guidelines for the use of animals in biomedical research.
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Zamudio, P.A., Gioia, D.A., Lopez, M. et al. The escalation in ethanol consumption following chronic intermittent ethanol exposure is blunted in mice expressing ethanol-resistant GluN1 or GluN2A NMDA receptor subunits. Psychopharmacology 238, 271–279 (2021). https://doi.org/10.1007/s00213-020-05680-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-020-05680-z