Alcoholism is an etiologically and clinically heterogeneous disorder in which compulsive alcohol seeking and use represent core symptoms. Exposure to alcohol is a necessary precondition. Environment and heritability factors can also play a dramatic role in controlling individual vulnerability to developing alcohol abuse. However, the interaction between environmental stress and heritable factors in the development of alcoholism is still largely unexplored. Understanding the nature of this interaction in regulating individual risk of becoming an alcohol abuser represents a major challenge in this research area and may provide invaluable help for the development of preventive strategies or pharmacotherapeutic remedies. In this application we propose to use the genetically selected Marchigian Sardinian alcohol-preferring (msP) msP rats, which have genetic polymorphism of the Corticotropin-Releasing Factor 1 Receptor (CRF1R) promoter, CRF1R density in the limbic system, and are highly sensitive to stress and stress-induced alcohol seeking, to provide information on the basic mechanisms controlling alcohol abuse progression. This will be achieved by looking at the consequences of exposing subjects with different innate propensities to developing alcohol abuse, to stress and to intoxicating doses of ethanol. The long term objective is to identify new effective pharmacotherapeutic approaches to alcoholism. Experiments are planned to evaluate the effect of acute and chronic treatment with CRF1R antagonists on binge ethanol drinking, relapse and anxiety-like behaviors in nondependent and postdependent msP rats. Using electrophysiology together with in situ hybridization, autoradiography and brain microdialysis technique, we expect to obtain information at neurocircuitry and at functional levels on the significance of the CRF1R system in the innate predisposition or environmentally-induced (alcohol dependence) propensity to abuse ethanol. The key personnel involved in the present study possess all the necessary expertise needed to accomplish such a multidisciplinary program. In particular, Dr. R. Ciccocioppo will supervise behavioral experiments, breeding programs and animal selections. Dr. M. Roberto will be dedicated to electrophysiology experiments and to research program coordination. Dr. L. Parsons will work on neurochemistry experiments. Drs. M. Heilig and G. Schumann will consult and collaborate on molecular biology and genetic studies respectively.

Public Health Relevance

Heritability factors play a dramatic role in controlling individual vulnerability to developing alcohol abuse. However, the interaction between environmental stress, prolonged alcohol exposure and these heritable factors in the etiology of alcohol dependence is not well understood. The present application studies the interaction of these factors in an innovative genetic animal model by determining whether rats selectively bred for excessive-drinking phenotype co-inherit a dysregulation of the brain stress system. The experiments will provide a systematic investigation at molecular, neurochemical and behavioural levels of the proposed rat model that will be critical to understanding the link between genetically determined vulnerability to excessive alcohol drinking, innate hypersensitivity to stress and ethanol-induced neuroadaptation of the brain stress system. Insight into the nature and influence of these interactions may be invaluable in the development of pharmacotherapeutics for alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA017447-02
Application #
7930509
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (03))
Program Officer
Grandison, Lindsey
Project Start
2009-09-10
Project End
2014-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$369,475
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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
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
Egervari, Gabor; Ciccocioppo, Roberto; Jentsch, J David et al. (2018) Shaping vulnerability to addiction - the contribution of behavior, neural circuits and molecular mechanisms. Neurosci Biobehav Rev 85:117-125
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
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
Cippitelli, Andrea; Domi, Esi; Ubaldi, Massimo et al. (2017) Protection against alcohol-induced neuronal and cognitive damage by the PPAR? receptor agonist pioglitazone. Brain Behav Immun 64:320-329
Roberto, Marisa; Varodayan, Florence P (2017) Synaptic targets: Chronic alcohol actions. Neuropharmacology 122:85-99
Varodayan, F P; Logrip, M L; Roberto, M (2017) P/Q-type voltage-gated calcium channels mediate the ethanol and CRF sensitivity of central amygdala GABAergic synapses. Neuropharmacology 125:197-206
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

Showing the most recent 10 out of 46 publications