Recent research has highlighted the role of the central nucleus of the amygdala (CeA) and the recruitment of the corticotropin-releasing factor (CRF) system in the development of ethanol dependence. Particularly, CRF type 1 receptor (CRF1) antagonists block the anxiogenic effects and the increase in ethanol self-administration produced by stressors and ethanol withdrawal. Notably, chronic CRF1 antagonism abolishes dependence-induced escalation of ethanol drinking in rats exposed to chronic intermittent ethanol. We demonstrated that acute ethanol and CRF increase GABAergic transmission in mouse and rat CeA via CRF1 activation, and the effects of CRF and CRF1 antagonists on GABAergic transmission are enhanced in CeA neurons from ethanol-dependent rats. However, the CeA is comprised of heterogeneous cell types and technical limitations have precluded the identification and further characterization of neurons from which recordings were obtained. Thus, despite the vast knowledge accumulated on the CRF1-mediated effects of acute and chronic ethanol in this brain region, the underlying local neuronal microcircuitry needs to be delineated. Thus, in this research proposal we will use an innovative transgenic mouse model expressing green fluorescent protein (GFP) in neurons expressing CRF1 (CRF1:GFP mice) to compare the electrophysiological, neurochemical, morphological and hodological properties of CeA CRF1-expressing neurons to those of unlabeled neurons. Using electrophysiology in combination with histochemical and neurotracing methods, we will obtain novel information on functionality and connectivity of these neurons, thereby providing mechanistic insights into the role of the CRF system in the development of alcohol dependence. Drs. Contet and Mandyam, key personnel involved in the present study, possess all the necessary expertise needed to accomplish such a multidisciplinary project. A better understanding of the molecular mechanisms underlying ethanol effects and the neuroadaptations shaping the CRF neurocircuitry involved in ethanol-dependence represent a challenge to alcohol researchers and will be useful toward uncovering new therapeutic agents to alleviate alcoholism.

Public Health Relevance

Despite the importance of extrahypothalamic corticotropin releasing factor (CRF) in the development of ethanol dependence, the neuronal circuitry involved in CRF1-mediated effects of ethanol in the extended amygdala has not yet been delineated. Using an innovative transgenic mouse model expressing green fluorescent protein in neurons expressing CRF1 receptors, the present application will compare the electrophysiological, neurochemical, morphological and hodological properties of CRF1-expressing and non-expressing neurons in the central nucleus of the amygdala. Determining the critical neuroadaptive changes in the functionality of CRF circuitry induced by ethanol dependence may be invaluable in the development of pharmacotherapeutics 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 #
1R01AA021491-01A1
Application #
8501922
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Liu, Qi-Ying
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$379,000
Indirect Cost
$179,000
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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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
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
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 :
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
Schmeichel, Brooke E; Herman, Melissa A; Roberto, Marisa et al. (2017) Hypocretin Neurotransmission Within the Central Amygdala Mediates Escalated Cocaine Self-administration and Stress-Induced Reinstatement in Rats. Biol Psychiatry 81:606-615
Herman, Melissa A; Contet, Candice; Roberto, Marisa (2016) A Functional Switch in Tonic GABA Currents Alters the Output of Central Amygdala Corticotropin Releasing Factor Receptor-1 Neurons Following Chronic Ethanol Exposure. J Neurosci 36:10729-10741
Varodayan, Florence P; Soni, Neeraj; Bajo, Michal et al. (2016) Chronic ethanol exposure decreases CB1 receptor function at GABAergic synapses in the rat central amygdala. Addict Biol 21:788-801
Herman, Melissa Ann; Roberto, Marisa (2016) Cell-type-specific tonic GABA signaling in the rat central amygdala is selectively altered by acute and chronic ethanol. Addict Biol 21:72-86

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