The goal of the current application is to understand the relationship between chronic alcohol exposure, withdrawal from this exposure, and the neurobiological mechanisms regulating anxiety-like behavior. The proposed experiments will utilize a rat model of chronic ethanol exposure and will integrate electrophysiological, cellular and molecular biological, and behavioral experimental approaches to examine the role of a specific brain region, the lateral/basolateral amygdala (BLA), in these processes. This brain area has been extensively implicated as an important regulatory component of the neural circuitry controlling anxiety-like behavior in rodents. Furthermore, findings from the previous funding period have shown extensive neurophysiological adaptations in both the glutamatergic and GABAergic neurotransmitter systems in the BLA. The objectives of the current proposal are therefore to 1) understand the neurobiological and cellular mechanisms governing these alterations and 2) define the role of BLA neurotransmitter systems in regulating anxiety-like behavior associated with chronic ethanol exposure and subsequent withdrawal. Our proposed experiments will specifically test the central hypothesis that anxiety during withdrawal from chronic ethanol exposure is caused by functional alterations within the major amygdala neurotransmitter systems.
Specific Aim 1 will test this hypothesis by characterizing neurophysiological and molecular alterations in glutamate neurotransmission following a chronic intermittent ethanol inhalation exposure in rats. Experimental approaches include in vitro slice patch-clamp electrophysiology to examine the function of BLA glutamatergic afferents and biochemical analysis of glutamate receptor expression and localization.
Specific Aim 2 will examine chronic ethanol- and withdrawal-related alterations in rat BLA GABAergic neurotransmission and receptor expression. In vitro slice whole-cell electrophysiology will be used in this aim as well. In addition, cell and molecular biological approaches will be employed to analyze molecular adaptations in the BLA GABAergic system.
Specific Aim 3 will address our central hypothesis by directly examining the BLA glutamatergic and GABAergic systems in the context of enhanced expression of anxiety-like behavior following chronic ethanol exposure. The proposed experiments will specifically examine the evolving relationship between exposure and withdrawal time course and neurophysiological function. Additionally, traditional behavioral pharmacological approaches will be used to better understand how changes in this neurobiological function contribute to the expression of withdrawal-related anxiety. Ultimately, the proposed experiments will better define the specific neurobiological contributions of the amygdala to anxiety-like behavior expressed following chronic alcohol exposure and withdrawal. These studies could therefore provide insight into the cellular mechanisms governing anxiety-associated 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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-A (02))
Program Officer
Liu, Qi-Ying
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Wake Forest University Health Sciences
Schools of Medicine
United States
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McCool, Brian A; Christian, Daniel T; Fetzer, Jonathan A et al. (2014) Lateral/basolateral amygdala serotonin type-2 receptors modulate operant self-administration of a sweetened ethanol solution via inhibition of principal neuron activity. Front Integr Neurosci 8:5
McCool, Brian A; Chappell, Ann M (2014) Persistent enhancement of ethanol drinking following a monosodium glutamate-substitution procedure in C57BL6/J and DBA/2J mice. Alcohol 48:55-61
Christian, Daniel T; Alexander, Nancy J; Diaz, Marvin R et al. (2013) Thalamic glutamatergic afferents into the rat basolateral amygdala exhibit increased presynaptic glutamate function following withdrawal from chronic intermittent ethanol. Neuropharmacology 65:134-42
McCool, Brian A; Chappell, Ann M (2012) Using monosodium glutamate to initiate ethanol self-administration in inbred mouse strains. Addict Biol 17:121-31
Diaz, Marvin R; Chappell, Ann M; Christian, Daniel T et al. (2011) Dopamine D3-like receptors modulate anxiety-like behavior and regulate GABAergic transmission in the rat lateral/basolateral amygdala. Neuropsychopharmacology 36:1090-103
Diaz, Marvin R; Christian, Daniel T; Anderson, Nancy J et al. (2011) Chronic ethanol and withdrawal differentially modulate lateral/basolateral amygdala paracapsular and local GABAergic synapses. J Pharmacol Exp Ther 337:162-70
McCool, Brian A (2011) Ethanol modulation of synaptic plasticity. Neuropharmacology 61:1097-108
McCool, Brian A; Chappell, Ann M (2009) Early social isolation in male Long-Evans rats alters both appetitive and consummatory behaviors expressed during operant ethanol self-administration. Alcohol Clin Exp Res 33:273-82
Silberman, Yuval; Bajo, Michal; Chappell, Ann M et al. (2009) Neurobiological mechanisms contributing to alcohol-stress-anxiety interactions. Alcohol 43:509-19
Budygin, Evgeny A; Oleson, Erik B; Mathews, Tiffany A et al. (2007) Effects of chronic alcohol exposure on dopamine uptake in rat nucleus accumbens and caudate putamen. Psychopharmacology (Berl) 193:495-501

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