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 #
5U01AA020930-02
Application #
8424260
Study Section
Special Emphasis Panel (ZAA1-DD (51))
Program Officer
Cui, Changhai
Project Start
2012-02-10
Project End
2017-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$170,823
Indirect Cost
$55,011
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Uys, Joachim D; McGuier, Natalie S; Gass, Justin T et al. (2016) Chronic intermittent ethanol exposure and withdrawal leads to adaptations in nucleus accumbens core postsynaptic density proteome and dendritic spines. Addict Biol 21:560-74
Nimitvilai, Sudarat; Lopez, Marcelo F; Mulholland, Patrick J et al. (2016) Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol. Neuropsychopharmacology 41:1112-27
Mulholland, Patrick J; Chandler, L Judson; Kalivas, Peter W (2016) Signals from the Fourth Dimension Regulate Drug Relapse. Trends Neurosci 39:472-85
Zhu, Yun; Su, Shan; Qin, Lili et al. (2016) Rational improvement of gp41-targeting HIV-1 fusion inhibitors: an innovatively designed Ile-Asp-Leu tail with alternative conformations. Sci Rep 6:31983
Spencer, Kathryn B; Mulholland, Patrick J; Chandler, L Judson (2016) FMRP Mediates Chronic Ethanol-Induced Changes in NMDA, Kv4.2, and KChIP3 Expression in the Hippocampus. Alcohol Clin Exp Res 40:1251-61
Rinker, Jennifer A; Fulmer, Diana B; Trantham-Davidson, Heather et al. (2016) Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking. Alcohol :
McGuier, Natalie S; Griffin 3rd, William C; Gass, Justin T et al. (2016) Kv7 channels in the nucleus accumbens are altered by chronic drinking and are targets for reducing alcohol consumption. Addict Biol 21:1097-1112
Sun, Zhiwu; Zhu, Yun; Wang, Qian et al. (2016) An immunogen containing four tandem 10E8 epitope repeats with exposed key residues induces antibodies that neutralize HIV-1 and activates an ADCC reporter gene. Emerg Microbes Infect 5:e65
McGuier, Natalie S; Padula, Audrey E; Mulholland, Patrick J et al. (2015) Homer2 deletion alters dendritic spine morphology but not alcohol-associated adaptations in GluN2B-containing N-methyl-D-aspartate receptors in the nucleus accumbens. Front Pharmacol 6:28
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

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