Heavy alcohol drinking and repeated withdrawals are associated with increased relapse and allostatic adaptations in the hypothalamic-pituitary-adrenal (HPA) axis. Excessive alcohol intake is also associated with perturbations in cortico-limbic-HPA function that may contribute to alcohol dependence and high rates of relapse. Our preliminary evidence suggests that a critical modulator of high rates of voluntary drinking in alcohol-dependent mice is the small-conductance calcium-activated potassium (SK) channels. SK channels in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) regulate NMDA receptor-dependent calcium influx, intrinsic excitability, and basal firing rates. Results from our preliminary studies demonstrate that SK channel expression is significantly reduced in mPFC and NAc in C57BL/6J mice following chronic intermittent ethanol (CIE) exposure or prolonged stress. Moreover, microinjection studies show that blocking SK channel activity in NAc enhances voluntary consumption in control, but not alcohol-dependent mice. These data suggest that the down-regulation of SK channels observed following CIE is critically involved in the escalation of drinking in CIE exposed mice. Thus, the overarching hypothesis of this proposal is that CIE increases the excitation at glutamatergic synapses through a combination of increased NMDA receptors and a decrease in SK channel activity in key brain regions that control drinking. These studies will test the hypotheses that: 1) chronic ethanol exposure and stress alter glutamatergic synapses, 2) divergent drinking patterns in genetically modified mice are linked to alterations in SK channel expression, and 3) SK channels in mPFC and NAc regulate escalation of drinking in CIE exposed mice. We expect that data collected from these studies will advance our understanding of synaptic plasticity in key brain regions involved in alcohol seeking behaviors and will validate the hypothesis that SK channels are an important new therapeutic target for the treatment of alcohol dependence.

Public Health Relevance

The results from these studies will provide insight into changes in key brain regions involved in alcohol abuse and dependence. In addition, these studies may identify a novel therapeutic target for the treatment of alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AA020930-01
Application #
8231618
Study Section
Special Emphasis Panel (ZAA1-DD (51))
Program Officer
Cui, Changhai
Project Start
2012-02-10
Project End
2017-01-31
Budget Start
2012-02-10
Budget End
2013-01-31
Support Year
1
Fiscal Year
2012
Total Cost
$183,680
Indirect Cost
$59,151
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
McGuier, Natalie S; Padula, Audrey E; Lopez, Marcelo F et al. (2015) Withdrawal from chronic intermittent alcohol exposure increases dendritic spine density in the lateral orbitofrontal cortex of mice. Alcohol 49:21-7
Uys, Joachim D; Mulholland, Patrick J; Townsend, Danyelle M (2014) Glutathione and redox signaling in substance abuse. Biomed Pharmacother 68:799-807