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.
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.
|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|
|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|
|RÃªgo, Heleine M C; Alves, ThaÃs 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|
|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|
|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|
|Niu, Li-na; Watson, Devon; Thames, Kyle et al. (2015) Effects of a discoloration-resistant calcium aluminosilicate cement on the viability and proliferation of undifferentiated human dental pulp stem cells. Sci Rep 5:17177|
Showing the most recent 10 out of 14 publications