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.
|Spierling, Samantha R; Kreisler, Alison D; Williams, Casey A et al. (2018) Intermittent, extended access to preferred food leads to escalated food reinforcement and cyclic whole-body metabolism in rats: Sex differences and individual vulnerability. Physiol Behav 192:3-16|
|Blasio, Angelo; Wang, Jingyi; Wang, Dan et al. (2018) Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice. Biol Psychiatry 84:193-201|
|Kirson, Dean; Oleata, Christopher Shaun; Parsons, Loren Howell et al. (2018) CB1 and ethanol effects on glutamatergic transmission in the central amygdala of male and female msP and Wistar rats. Addict Biol 23:676-688|
|Matzeu, Alessandra; Kallupi, Marsida; George, Olivier et al. (2018) Dynorphin Counteracts Orexin in the Paraventricular Nucleus of the Thalamus: Cellular and Behavioral Evidence. Neuropsychopharmacology 43:1010-1020|
|de Guglielmo, Giordano; Conlisk, Dana E; Barkley-Levenson, Amanda M et al. (2018) Inhibition of Glyoxalase 1 reduces alcohol self-administration in dependent and nondependent rats. Pharmacol Biochem Behav 167:36-41|
|Matzeu, Alessandra; Terenius, Lars; Martin-Fardon, Remi (2018) Exploring Sex Differences in the Attenuation of Ethanol Drinking by Naltrexone in Dependent Rats During Early and Protracted Abstinence. Alcohol Clin Exp Res 42:2466-2478|
|Kononoff, Jenni; Melas, Philippe A; Kallupi, Marsida et al. (2018) Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood. Sci Rep 8:13893|
|Verheij, Michel M M; Contet, Candice; Karel, Peter et al. (2018) Median and Dorsal Raphe Serotonergic Neurons Control Moderate Versus Compulsive Cocaine Intake. Biol Psychiatry 83:1024-1035|
|Schmeichel, Brooke E; Matzeu, Alessandra; Koebel, Pascale et al. (2018) Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats. Neuropsychopharmacology 43:2373-2382|
|Kononoff, Jenni; Kallupi, Marsida; Kimbrough, Adam et al. (2018) Systemic and Intra-Habenular Activation of the Orphan G Protein-Coupled Receptor GPR139 Decreases Compulsive-Like Alcohol Drinking and Hyperalgesia in Alcohol-Dependent Rats. eNeuro 5:|
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