The primary objective of this project is to understand the neuronal, cellular and synaptic mechanisms underlying alcohol intoxication and dependence, using intracellular and patch-clamp recording in brain slices and in vivo microdialysis. A central hypothesis is that adaptive changes in synapses cause alcohol dependence. We also hypothesize that neuroadaptations in the GABAergic system play a major role in alcohol reinforcing actions. Our past research has centered on neurons of the central nucleus of the amygdala (CeA), because behavioral studies suggest that the amygdala, and its connections to the NAcc and bed nucleus of the stria terminalis, termed the 'extended amygdala,'play a major role in the acute reinforcing effects of ethanol and in the anxiogenic response to ethanol withdrawal. Our planned studies are based on the following rationale: 1) Acute ethanol markedly enhances GABAergic neurotransmission in CeA through the activation of CRF1 receptors. We present the first direct evidence that this ethanol-induced increase in GABAergic response is in part due to increased GABA release. 2) Our preliminary data also indicate that chronic ethanol treatment (GET) greatly enhances baseline GABAergic tone in the CeA. 3) Despite this large increase in basal GABA release, there is a lack of tolerance to acute ethanol-induced GABA release in CeA of GET rats. 4) Our preliminary evidence of neuroadaptive changes in the CRF system and in GABAB receptors in modulating synaptic efficacy following GET. Therefore in this application we propose to study the cellular and molecular basis of ethanol interactions with GABAergic transmission using a multidisciplinary approach.
Specific Aims 1 and 2 will test, in vitro and in vivo, the possible involvement of presynaptic CRF receptors, membrane Ca++ channel and their transduction mechanisms coupled to the regulation of GABA release machinery in the effect of acute (Aim 1) and chronic (Aim2) ethanol in CeA neurons. Understanding the specific presynaptic mechanisms underlying ethanol enhancement of GABA IPSPs induced by both acute and chronic ethanol represents a new challenge for alcohol research and a possible target for the development of therapeutic compounds for the treatment of alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA015566-06
Application #
8211155
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Liu, Qi-Ying
Project Start
2005-12-05
Project End
2014-07-31
Budget Start
2011-02-01
Budget End
2011-11-30
Support Year
6
Fiscal Year
2011
Total Cost
$275,779
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Varodayan, Florence P; Correia, Diego; Kirson, Dean et al. (2017) CRF modulates glutamate transmission in the central amygdala of naïve and ethanol-dependent rats. Neuropharmacology 125:418-428
Logrip, Marian L; Oleata, Christopher; Roberto, Marisa (2017) Sex differences in responses of the basolateral-central amygdala circuit to alcohol, corticosterone and their interaction. Neuropharmacology 114:123-134
Natividad, Luis A; Buczynski, Matthew W; Herman, Melissa A et al. (2017) Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype. Biol Psychiatry 82:500-510
Varodayan, Florence P; Bajo, Michal; Soni, Neeraj et al. (2017) Chronic alcohol exposure disrupts CB1 regulation of GABAergic transmission in the rat basolateral amygdala. Addict Biol 22:766-778
Roberto, Marisa; Varodayan, Florence P (2017) Synaptic targets: Chronic alcohol actions. Neuropharmacology 122:85-99
Blasio, Angelo; Wang, Jingyi; Wang, Dan et al. (2017) Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice. Biol Psychiatry :
Varodayan, Florence P; de Guglielmo, Giordano; Logrip, Marian L et al. (2017) Alcohol Dependence Disrupts Amygdalar L-Type Voltage-Gated Calcium Channel Mechanisms. J Neurosci 37:4593-4603
Natividad, Luis A; Steinman, Michael Q; Laredo, Sarah A et al. (2017) Phosphorylation of calcium/calmodulin-dependent protein kinase II in the rat dorsal medial prefrontal cortex is associated with alcohol-induced cognitive inflexibility. Addict Biol :
Borghese, Cecilia M; Herman, Melissa; Snell, Lawrence D et al. (2017) Novel Molecule Exhibiting Selective Affinity for GABAA Receptor Subtypes. Sci Rep 7:6230
Kirson, Dean; Oleata, Christopher Shaun; Parsons, Loren Howell et al. (2017) CB1 and ethanol effects on glutamatergic transmission in the central amygdala of male and female msP and Wistar rats. Addict Biol :

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