Alcoholism is a chronic, relapsing disorder, characterized by withdrawal syndromes of negative emotional symptoms that putatively promote relapse via negative reinforcement mechanisms. The present application tests the overarching hypothesis that excitatory glutamatergic signaling in the amygdala is altered during ethanol withdrawal, partly due to actions of corticotropin-releasing factor systems and neuronal pentraxin 2, and thereby promote negative emotional symptoms and relapse risk during abstinence. To test this hypothesis, SPECIFIC AIM 1 will use site-specific administration of recently available, highly available classand subunit selective antagonists of ionotropic glutamate receptors to test their functional involvement in the increased anxiety-like behavior and ethanol self-administration of alcohol withdrawal.
SPECIFIC AIM 2 will use glutamate system-restricted knockdown of CRF1 signaling to test the hypothesis that CRF1-driven increases in glutamatergic signaling originating from the BLA promotes anxiety-like behavior and ethanol self-administration during withdrawal from chronic intermittent ethanol exposure. Finally, SPECIFIC AIM 3 will use dominant negative Narp-mediated knockdown of Narp function and glutamate system-restricted overexpression of the Nptx2 gene to test the hypothesis that chronic intermittent ethanol-induced Narp, via increased trafficking of AMPAR to the post-synaptic density leads to increased anxiety-like behavior and ethanol self-administration behavior. The studies will involve close collaboration with the Roberto/Siggins, Parsons and Mandyam research components, benefit from the consultation of Dr. Catherine Rivier, and rely closely upon the Animal Models (Koob/George) and Viral Vector (Contet) Cores of the proposed TSRI-ARC.
The proposed studies will reveal neuroadaptive changes in excitatory stress neurocircuitry of the brain that result from chronic intermittent exposure or access to ethanol. Understanding the mechanisms associated with ethanol-induced plasticity of amygdala glutamatergic circuitry may yield new prophylactic and therapeutic approaches to alcoholism.
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