The overall goal of the current application is to understand the neurobiological mechanisms that help confer pathological behaviors like enhanced negative affect following ethanol physical dependence. We will accomplish this goal by utilizing a rat model of chronic ethanol exposure and by integrating optogenetic, synaptic neurophysiology, and behavioral experimental approaches to examine adaptations glutamatergic and GABAergic neurotransmission in a specific brain region, the lateral/basolateral amygdala (BLA). This brain area has been extensively implicated as an important regulatory component of the neural circuitry controlling both anxiety-like behavior during withdrawal from chronic ethanol exposure as well as reward-seeking in drug- naive and -exposed animals. Findings from the previous funding period have demonstrated that the extensive glutamatergic and GABAergic synaptic adaptations occur within specific pre- and postsynaptic compartments and potentially within specific afferent systems. The objectives of the current proposal are therefore to understand the neurobiological and cellular mechanisms governing the specificity of these alterations. Our proposed experiments will test the central hypothesis that specific alterations in synaptic function at distinct BLA afferents following chronc ethanol lead to the development and expression of withdrawal-related anxiety.
Specific Aim 1 will test this hypothesis by defining the regional origin for pre- and post-synaptic alterations expressed following chronic ethanol exposure and withdrawal. We will utilize optogenetic approaches to control synaptic transmission arising from specific afferents along with in vitro slice patch-clamp electrophysiology. These studies are significant because they will first implicate specific brain regions involved in BLA alterations during ethanol physical dependence. Second, these afferents carry unique forms of information;so any region-specific involvement will identify for the first time how information processing may be disrupted by chronic ethanol exposure.
Specific Aim 2 will examine the functional and behavioral relationships between BLA neurophysiology and the plasticity-like state resulting from chronic intermittent ethanol/withdrawal. In this case, we will address our central hypothesis by directly examining BLA glutamatergic and GABAergic synaptic alterations using in vitro slice recordings interpreted in the context of enhanced expression of anxiety-like behavior following chronic ethanol exposure. The proposed experiments will specifically examine the evolving relationship using exposure and withdrawal time courses. These studies are significant because they will identify the precise cellular and synaptic mechanisms leading to ethanol conditioning in the BLA. Ultimately, the application will better define specific neurobiological contributions by the amygdala to enhanced anxiety-like behavior following chronic alcohol exposure and withdrawal. These studies will provide insight into potential cellular mechanisms governing abuse and relapse in human alcoholics.

Public Health Relevance

The focus of this research project is to understand the impact of chronic ethanol exposure and withdrawal on neurophysiological processes that regulate emotions like anxiety. Once the project is completed, we will better understand how chronic ethanol exposure and withdrawal alter the brain, and the research could provide specifi neurophysiological targets for therapeutics development.

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)
Program Officer
Liu, Qi-Ying
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Wake Forest University Health Sciences
Schools of Medicine
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Morales, Melissa; McGinnis, Molly M; Robinson, Stacey L et al. (2018) Chronic Intermittent Ethanol Exposure Modulation of Glutamatergic Neurotransmission in Rat Lateral/Basolateral Amygdala is Duration-, Input-, and Sex-Dependent. Neuroscience 371:277-287
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Gioia, Dominic A; Alexander, Nancy J; McCool, Brian A (2016) Differential Expression of Munc13-2 Produces Unique Synaptic Phenotypes in the Basolateral Amygdala of C57BL/6J and DBA/2J Mice. J Neurosci 36:10964-10977
McCool, Brian A; Chappell, Ann M (2015) Chronic intermittent ethanol inhalation increases ethanol self-administration in both C57BL/6J and DBA/2J mice. Alcohol 49:111-20
Robinson, Stacey L; McCool, Brian A (2015) Microstructural analysis of rat ethanol and water drinking patterns using a modified operant self-administration model. Physiol Behav 149:119-30

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