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.
|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 :|
|Varodayan, Florence P; Sidhu, Harpreet; Kreifeldt, Max et al. (2018) Morphological and functional evidence of increased excitatory signaling in the prelimbic cortex during ethanol withdrawal. Neuropharmacology 133:470-480|
|Serrano, Antonia; Pavon, Francisco J; Buczynski, Matthew W et al. (2018) Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake. Neuropsychopharmacology 43:1840-1850|
|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|
|Roberto, Marisa; Spierling, Samantha R; Kirson, Dean et al. (2017) Corticotropin-Releasing Factor (CRF) and Addictive Behaviors. Int Rev Neurobiol 136:5-51|
|Borghese, Cecilia M; Herman, Melissa; Snell, Lawrence D et al. (2017) Novel Molecule Exhibiting Selective Affinity for GABAA Receptor Subtypes. Sci Rep 7:6230|
|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|
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