Evidence suggests that glutamate receptor trafficking induces long-term changes in the nucleus accumbens (NAc) which may constitute an important neuroadaptation contributing to the development of ethanol dependence. We have observed that low frequency conditioning stimulation (LFS) of excitatory afferents to shell NAc medium spiny neurons (msns) normally induces NMDA-receptor dependent synaptic depression in slices from ethanol na?ve mice. However, a single 4 day bout of passive chronic intermittent ethanol (CIE) in vivo exposure induces a polarity shift in plasticity to LFS conditioning and induces synaptic potentiation (LTP) rather than LTD (metaplasticity). In addition, the shell and core subregions of the NAc likely encode different aspects of drug responding with the shell responding more to novelty and the core encoding more established learned behaviors. These findings promote our overarching hypothesis that D1-dopamine receptor-expressing medium spiny neurons of the shell and core of the nucleus accumbens differentially encode passive and operant ethanol experience through selective neuroadaptations in glutamatergic synaptic transmission and plasticity We propose in aim 1 to measure glutamatergic transmission and metaplasticity in shell/core NAc medium spiny neurons from transgenic mice expressing eGFP under the control of the dopamine D1- receptor promoter (drd1-eGFP mice) (1) after passive exposure to chronic intermittent ethanol vapor or (2) trained for volitional, operant ethanol self-administration. All experiments in aim 1 will use whole-cell voltage clamp recordings from identified drd1-eGFP shell/core msns. Alterations in glutamatergic transmission will be assessed by pharmacological isolation of NMDA and AMPA-subcomponents and AMPA:NMDA ratios. Metaplasticity will be assessed by determining the expression of LTD or LTP in response to conditioning stimulation in shell/core drd1-eGFP msns from the different ethanol experience groups.
In aim 2, we will determine whether interference with GluR2 internalization alters operant self-administration behavior in mice. Injection of a peptide fragment which disrupts GluR2- mediated AMPA channel internalization will be made into the NAc to determine whether interruption of AMPAR trafficking can modulate or occlude operant responding for ethanol in the same mouse model used in aim 1. Injections will also be made into other mesocorticolimbic structures (VTA, PFC) to determine whether the behavioral effects of occlusion of LTD are limited to the NAc.
These aims will advance our understanding of neuroadaptive alterations in an important mesocorticolimbic structure which may underlie the development of ethanol dependence.

Public Health Relevance

This project uses two mouse animal models to investigate the changes in brain function that may contribute to or underlie the development of alcoholism. Some experiments involve testing the ability of a novel protein to prevent drinking in mice trained to drink significant quantities of alcohol. If our hypotheses are correct, the ability of this protein to inhibit drinking will be the first demonstration that modification these particular brain mechanisms can affect drinking in animals and may enable the development of new drugs for alcoholism.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Liu, Qi-Ying
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University of Texas Austin
Schools of Pharmacy
United States
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Woodward Hopf, F; Mangieri, Regina A (2018) Do Alcohol-Related AMPA-Type Glutamate Receptor Adaptations Promote Intake? Handb Exp Pharmacol :
Renteria, Rafael; Buske, Tavanna R; Morrisett, Richard A (2018) Long-term subregion-specific encoding of enhanced ethanol intake by D1DR medium spiny neurons of the nucleus accumbens. Addict Biol 23:689-698
Renteria, Rafael; Maier, Esther Y; Buske, Tavanna R et al. (2017) Selective alterations of NMDAR function and plasticity in D1 and D2 medium spiny neurons in the nucleus accumbens shell following chronic intermittent ethanol exposure. Neuropharmacology 112:164-171
Mangieri, Regina A; Maier, Esther Y; Buske, Tavanna R et al. (2017) Anaplastic Lymphoma Kinase Is a Regulator of Alcohol Consumption and Excitatory Synaptic Plasticity in the Nucleus Accumbens Shell. Front Pharmacol 8:533
Renteria, R; Jeanes, Z M; Mangieri, R A et al. (2016) Using In Vitro Electrophysiology to Screen Medications: Accumbal Plasticity as an Engram of Alcohol Dependence. Int Rev Neurobiol 126:441-65
Maiya, Rajani; Mangieri, Regina A; Morrisett, Richard A et al. (2015) A Selective Role for Lmo4 in Cue-Reward Learning. J Neurosci 35:9638-47
Jeanes, Z M; Buske, T R; Morrisett, R A (2014) Cell type-specific synaptic encoding of ethanol exposure in the nucleus accumbens shell. Neuroscience 277:184-95
Salinas, Armando G; Nguyen, Chinh T Q; Ahmadi-Tehrani, Dara et al. (2014) Reduced ethanol consumption and preference in cocaine- and amphetamine-regulated transcript (CART) knockout mice. Addict Biol 19:175-84
Renteria, Rafael; Jeanes, Zachary M; Morrisett, Richard A (2014) Ethanol attenuation of long-term depression in the nucleus accumbens can be overcome by activation of TRPV1 receptors. Alcohol Clin Exp Res 38:2763-9
Theile, J W; Morikawa, H; Gonzales, R A et al. (2011) GABAergic transmission modulates ethanol excitation of ventral tegmental area dopamine neurons. Neuroscience 172:94-103

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