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.
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.
|Robinson, Stacey L; Alexander, Nancy J; Bluett, Rebecca J et al. (2016) Acute and chronic ethanol exposure differentially regulate CB1 receptor function at glutamatergic synapses in the rat basolateral amygdala. Neuropharmacology 108:474-84|
|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|
|Rose, Jamie H; Karkhanis, Anushree N; Chen, Rong et al. (2016) Supersensitive Kappa Opioid Receptors Promotes Ethanol Withdrawal-Related Behaviors and Reduce Dopamine Signaling in the Nucleus Accumbens. Int J Neuropsychopharmacol 19:|
|Peterson, Veronica L; McCool, Brian A; Hamilton, Derek A (2015) Effects of ethanol exposure and withdrawal on dendritic morphology and spine density in the nucleus accumbens core and shell. Brain Res 1594:125-35|
|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|
|Morales, Melissa; McGinnis, Molly M; McCool, Brian A (2015) Chronic ethanol exposure increases voluntary home cage intake in adult male, but not female, Long-Evans rats. Pharmacol Biochem Behav 139:67-76|
|Karkhanis, Anushree N; Alexander, Nancy J; McCool, Brian A et al. (2015) Chronic social isolation during adolescence augments catecholamine response to acute ethanol in the basolateral amygdala. Synapse 69:385-95|
|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|
|Karkhanis, Anushree N; Locke, Jason L; McCool, Brian A et al. (2014) Social isolation rearing increases nucleus accumbens dopamine and norepinephrine responses to acute ethanol in adulthood. Alcohol Clin Exp Res 38:2770-9|
|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|
Showing the most recent 10 out of 29 publications