Ethanol Self-administration Targets GluA2-containing AMPA Receptor Expression and Synaptic Activity in the Nucleus Accumbens in a Manner That Drives the Positive Reinforcing Properties of the Drug

Overview

Journal Psychopharmacology (Berl)

Specialty Pharmacology

Date 2024 Dec 23

PMID 39714485

Authors

Sara Faccidomo

Briana L Saunders

Ashley M May

Vallari R Eastman

Michelle Kim

Seth M Taylor

Jessica L Hoffman

Zoe A McElligott

Clyde W Hodge

Affiliations

Soon will be listed here.

Abstract

Rationale: The positive reinforcing effects of alcohol (ethanol) drive repetitive use and contribute to alcohol use disorder (AUD). Ethanol alters the expression of glutamate AMPA receptor (AMPAR) subunits in reward-related brain regions, but the extent to which this effect regulates ethanol's reinforcing properties is unclear.

Objective: This study investigates whether ethanol self-administration changes AMPAR subunit expression and synaptic activity in the nucleus accumbens core (AcbC) to regulate ethanol's reinforcing effects in male C57BL/6 J mice.

Results: Sucrose-sweetened ethanol self-administration (0.81 g/kg/day) increased AMPAR GluA2 protein expression in the AcbC, without effect on GluA1, compared to sucrose-only controls. Infusion of myristoylated Pep2m in the AcbC, which blocks GluA2 binding to N-ethylmaleimide-sensitive fusion protein (NSF) and reduces GluA2-containing AMPAR activity, reduced ethanol-reinforced responding without affecting sucrose-only self-administration or motor activity. Antagonizing GluA2-lacking AMPARs, through AcbC infusion of NASPM, had no effect on ethanol self-administration. AcbC neurons receiving projections from the basolateral amygdala (BLA) showed increased sEPSC area under the curve (a measurement of charge transfer) and slower decay kinetics in ethanol self-administering mice as compared to sucrose. Optogenetic activation of these neurons revealed an ethanol-enhanced AMPA/NMDA ratio and significantly reduced paired-pulse ratio, suggesting elevated GluA2 contributions specifically within the BLA➔AcbC pathway.

Conclusions: Ethanol use upregulates GluA2 protein expression in the AcbC and AMPAR synaptic activity in AcbC neurons receiving BLA projections and enhances synaptic plasticity directly within the BLA➔AcbC circuit. GluA2-containing AMPAR activity in the AcbC regulates the positive reinforcing effects of ethanol through an NSF-dependent mechanism, highlighting a potential therapeutic target in AUD.

References

Acosta G, Freidman D, Grant K, Hemby S . Alternative splicing of AMPA subunits in prefrontal cortical fields of cynomolgus monkeys following chronic ethanol self-administration. Front Psychiatry. 2012; 2:72. PMC: 3249828. DOI: 10.3389/fpsyt.2011.00072. View

Agoglia A, Holstein S, Reid G, Hodge C . CaMKIIα-GluA1 Activity Underlies Vulnerability to Adolescent Binge Alcohol Drinking. Alcohol Clin Exp Res. 2015; 39(9):1680-90. PMC: 4558330. DOI: 10.1111/acer.12819. View

Agoglia A, Holstein S, Eastman V, Hodge C . Cannabinoid CB1 receptor inhibition blunts adolescent-typical increased binge alcohol and sucrose consumption in male C57BL/6J mice. Pharmacol Biochem Behav. 2016; 143:11-7. PMC: 4905821. DOI: 10.1016/j.pbb.2016.01.009. View

Anton R, Kranzler H, Meyer R . Neurobehavioral aspects of the pharmacotherapy of alcohol dependence. Clin Neurosci. 1995; 3(3):145-54. View

Araki Y, Lin D, Huganir R . Plasma membrane insertion of the AMPA receptor GluA2 subunit is regulated by NSF binding and Q/R editing of the ion pore. Proc Natl Acad Sci U S A. 2010; 107(24):11080-5. PMC: 2890737. DOI: 10.1073/pnas.1006584107. View

Ary A, Cozzoli D, Finn D, Crabbe J, Dehoff M, Worley P . Ethanol up-regulates nucleus accumbens neuronal activity dependent pentraxin (Narp): implications for alcohol-induced behavioral plasticity. Alcohol. 2012; 46(4):377-87. PMC: 3358440. DOI: 10.1016/j.alcohol.2011.10.003. View

Backstrom P, Hyytia P . Ionotropic glutamate receptor antagonists modulate cue-induced reinstatement of ethanol-seeking behavior. Alcohol Clin Exp Res. 2004; 28(4):558-65. DOI: 10.1097/01.alc.0000122101.13164.21. View

Bauer M, McVey M, Germano D, Zhang Y, Boehm 2nd S . Intra-dorsolateral striatal AMPA receptor antagonism reduces binge-like alcohol drinking in male and female C57BL/6J mice. Behav Brain Res. 2021; 418:113631. PMC: 8671209. DOI: 10.1016/j.bbr.2021.113631. View

Becker J, Koob G . Sex Differences in Animal Models: Focus on Addiction. Pharmacol Rev. 2016; 68(2):242-63. PMC: 4813426. DOI: 10.1124/pr.115.011163. View

10.

Bellone C, Luscher C . Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression. Nat Neurosci. 2006; 9(5):636-41. DOI: 10.1038/nn1682. View

11.

Besheer J, Cox A, Hodge C . Coregulation of ethanol discrimination by the nucleus accumbens and amygdala. Alcohol Clin Exp Res. 2003; 27(3):450-6. DOI: 10.1097/01.ALC.0000057036.64169.C1. View

12.

Besheer J, Grondin J, Salling M, Spanos M, Stevenson R, Hodge C . Interoceptive effects of alcohol require mGlu5 receptor activity in the nucleus accumbens. J Neurosci. 2009; 29(30):9582-91. PMC: 2845172. DOI: 10.1523/JNEUROSCI.2366-09.2009. View

13.

Besheer J, Grondin J, Cannady R, Sharko A, Faccidomo S, Hodge C . Metabotropic glutamate receptor 5 activity in the nucleus accumbens is required for the maintenance of ethanol self-administration in a rat genetic model of high alcohol intake. Biol Psychiatry. 2009; 67(9):812-22. PMC: 2854174. DOI: 10.1016/j.biopsych.2009.09.016. View

14.

Bredt D, Nicoll R . AMPA receptor trafficking at excitatory synapses. Neuron. 2003; 40(2):361-79. DOI: 10.1016/s0896-6273(03)00640-8. View

15.

Cannady R, Fisher K, Durant B, Besheer J, Hodge C . Enhanced AMPA receptor activity increases operant alcohol self-administration and cue-induced reinstatement. Addict Biol. 2012; 18(1):54-65. PMC: 3535558. DOI: 10.1111/adb.12000. View

16.

Cannady R, Fisher K, Graham C, Crayle J, Besheer J, Hodge C . Potentiation of amygdala AMPA receptor activity selectively promotes escalated alcohol self-administration in a CaMKII-dependent manner. Addict Biol. 2016; 22(3):652-664. PMC: 4935658. DOI: 10.1111/adb.12357. View

17.

Chater T, Goda Y . The role of AMPA receptors in postsynaptic mechanisms of synaptic plasticity. Front Cell Neurosci. 2014; 8:401. PMC: 4245900. DOI: 10.3389/fncel.2014.00401. View

18.

Conboy L, Sandi C . Stress at learning facilitates memory formation by regulating AMPA receptor trafficking through a glucocorticoid action. Neuropsychopharmacology. 2009; 35(3):674-85. PMC: 3055605. DOI: 10.1038/npp.2009.172. View

19.

Conrad K, Tseng K, Uejima J, Reimers J, Heng L, Shaham Y . Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature. 2008; 454(7200):118-21. PMC: 2574981. DOI: 10.1038/nature06995. View

20.

Coombs I, Bats C, Sexton C, Studniarczyk D, Cull-Candy S, Farrant M . Enhanced functional detection of synaptic calcium-permeable AMPA receptors using intracellular NASPM. Elife. 2023; 12. PMC: 10168695. DOI: 10.7554/eLife.66765. View