This project proposes to continue cellular studies of the role of neurotransmitters and their receptors in alcohol intoxication and addiction, with the rationale that the synapse is the most sensitive site of ethanol action, and particularly those synapses mediated by glutamate, GABA, and neuropeptide release. Our past studies led us to hypothesize a role for 'metabotropic' receptors and postsynaptic NMDA and GABAA receptors in ethanol intoxication and dependence. A second rationale is based on behavioral findings suggesting that the extended amygdala is a key system in the addictive properties of several drugs, including alcohol, and that several transmitters, neuropeptides, and endocannabinoids may be involved there. The amygdala has been implicated in motivated behaviors and anxiety states. Stressors and anxiety-provoking stimuli may trigger relapse in human alcoholics, and ethanol withdrawal is associated with increases both in anxiety-like behavior and in ethanol self-administration in rodents. Therefore, we hypothesize that the same neuropharmacological systems within the extended amygdala's circuitry mediate increases in anxiety state and in ethanol self-administration that occur during withdrawal from chronic ethanol, and we propose the following 3 sets of cellular studies to test this hypothesis: 1) Examination of the effects and interactions of acute and chronic ethanol administration, early withdrawal and protracted abstinence on CRF effects in central amygdala (CeA) neurons. 2) Examination of the effects of acute and chronic ethanol administration, early withdrawal and abstinence on neuropeptide Y (NPY) effects in CeA neurons. 3) Testing the effects of acute and chronic ethanol, early withdrawal and abstinence on endocannabinoid effects in CeA and nucleus accumbens (NAcc). In all 3 of these aims, subjects will be sham (control) male rats or those receiving chronic ethanol either via ethanol vapor inhalation and/or via self-administration, and their CeA or NAcc sliced and studied 1-12 hours or 1-2 weeks after withdrawal. We will record from amygdala and NAcc brain slices with intracellular (current- and voltageclamp) and """"""""patch-slice"""""""" whole-cell clamp methods. The infrared DIC-videomicroscopic method will be used to identify morphologically distinct cells types for comparison of electrophysiological and pharmacological properties. We will record evoked, pharmacologically-isolated monosynaptic currents or potentials, and spontaneous and miniature synaptic events, to better test the specificity and site of action of ethanol and ligands. We believe these studies will provide important new information on possible sequelae of ethanol intoxication at the cellular level, and, by virtue of analyses of ethanol and peptide/cannabinoid interactions in control, chronic and protracted abstinence models, will also provide clues as to the cellular and ion channel correlates of ethanol dependence.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Comprehensive Center (P60)
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Scripps Research Institute
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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
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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:
Kreisler, A D; Mattock, M; Zorrilla, E P (2018) The duration of intermittent access to preferred sucrose-rich food affects binge-like intake, fat accumulation, and fasting glucose in male rats. Appetite 130:59-69
Varodayan, F P; Khom, S; Patel, R R et al. (2018) Role of TLR4 in the Modulation of Central Amygdala GABA Transmission by CRF Following Restraint Stress. Alcohol Alcohol 53:642-649
McClatchy, Daniel B; Yu, Nam-Kyung; Martínez-Bartolomé, Salvador et al. (2018) Structural Analysis of Hippocampal Kinase Signal Transduction. ACS Chem Neurosci :
Berger, Anthony L; Henricks, Angela M; Lugo, Janelle M et al. (2018) The Lateral Habenula Directs Coping Styles Under Conditions of Stress via Recruitment of the Endocannabinoid System. Biol Psychiatry 84:611-623
Mason, Barbara J; Quello, Susan; Shadan, Farhad (2018) Gabapentin for the treatment of alcohol use disorder. Expert Opin Investig Drugs 27:113-124

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