Withdrawal stress following chronic ethanol exposure results in heightened anxiety-like behaviors that contribute to relapse in abstinent alcoholics. However, very little is known about the neurobiological mechanisms controlling these outcomes. Animal models can make significant contributions towards understanding these issues. For example, we have shown that the rat glutamatergic and GABAergic synaptic function in the lateral/basolateral amygdala (BLA) are dramatically regulated by chronic ethanol exposure and withdrawal. Similarly, the rat BLA CRF/urocortin system appears to enhance excitatory BLA responses. Chronic ethanol-related alterations in glutamate, GABA, and CRF/urocortin all potentially contribute to withdrawal-anxiety. But, the precise contributions of any individual alteration are confounded by their fundamental contributions in ethanol-naive animals. The C57BL/6J (B6) and DBA/2J (D2) mouse offer an alternative approach. These inbred lines differ dramatically with respect to a number of different ethanol related behaviors, including their behavioral sensitivity to chronic ethanol exposure and withdrawal. This is extended to withdrawal-anxiety by preliminary evidence provided in the current application that shows greater D2 sensitivity. Furthermore, our published and preliminary findings suggest that BLA GABAergic and potentially glutamatergic synaptic function in these two mouse lines are markedly distinct. This strongly suggests that chronic ethanol exposures producing substantial withdrawal-anxiety in one strain but not the other can be used to highlight individual neurophysiological changes with the greatest behavioral impact. The proposed experiments will therefore test the central hypothesis that the greater withdrawal-related increases in anxiety in D2 mice will be reflected by more significant increases in BLA excitatory neurotransmitter systems, like glutamate and CRF/urocortin. Our primarily electrophysiological analysis of these systems as well as GABAergic function will be integrated with both behavioral measures of anxiety during withdrawal-stress in B6, D2, and genetically modified mice. The proposed experiments are significant because they offer a unique opportunity to define specific BLA neurobiological targets for future therapies.

Public Health Relevance

The proposed research will help establish the neural systems important for abnormal behaviors caused by chronic ethanol exposure. The application uses rodent models, specifically inbred mouse strains, behavioral measures of anxiety, and a number of characterizations in brain tissue to accomplish this overall goal.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
4U01AA020942-05
Application #
8998907
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Liu, Qi-Ying
Project Start
2012-02-10
Project End
2017-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Huang, Qi; Barnes, Jonathan B; Schoeffel, G John et al. (2017) Effect of Canal Anastomosis on Periapical Fluid Pressure Build-up during Needle Irrigation in Single Roots with Double Canals using a Polycarbonate Model. Sci Rep 7:1582
Gioia, Dominic A; McCool, Brian (2017) Strain-Dependent Effects of Acute Alcohol on Synaptic Vesicle Recycling and Post-Tetanic Potentiation in Medial Glutamate Inputs to the Mouse Basolateral Amygdala. Alcohol Clin Exp Res 41:735-746
Niu, Li-Na; Jee, Sang Eun; Jiao, Kai et al. (2017) Collagen intrafibrillar mineralization as a result of the balance between osmotic equilibrium and electroneutrality. Nat Mater 16:370-378
Tian, F; Zhou, L; Zhang, Z et al. (2016) Paucity of Nanolayering in Resin-Dentin Interfaces of MDP-based Adhesives. J Dent Res 95:380-7
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
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:
Rêgo, Heleine M C; Alves, Thaís S; Bresciani, Eduardo et al. (2016) Can long-term dentine bonding created in real life be forecasted by parameters established in the laboratory? Sci Rep 6:37799
Liu, Si-ying; Tonggu, Lige; Niu, Li-na et al. (2016) Antimicrobial activity of a quaternary ammonium methacryloxy silicate-containing acrylic resin: a randomised clinical trial. Sci Rep 6:21882
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

Showing the most recent 10 out of 18 publications