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 #
5R01AA017447-05
Application #
8494459
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
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$330,280
Indirect Cost
$113,372
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Galesi, Fernanda L; Ayanwuyi, Lydia O; Mijares, Miriam Garcia et al. (2016) Role of Hypothalamic-Pituitary-Adrenal axis and corticotropin-releasing factor stress system on cue-induced relapse to alcohol seeking. Eur J Pharmacol 788:84-9
Curran, H Valerie; Freeman, Tom P; Mokrysz, Claire et al. (2016) Keep off the grass? Cannabis, cognition and addiction. Nat Rev Neurosci 17:293-306
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
Herman, Melissa A; Varodayan, Florence P; Oleata, Christopher S et al. (2016) Glutamatergic transmission in the central nucleus of the amygdala is selectively altered in Marchigian Sardinian alcohol-preferring rats: Alcohol and CRF effects. Neuropharmacology 102:21-31
Cannella, Nazzareno; Kallupi, Marsida; Li, Hong Wu et al. (2016) Neuropeptide S differently modulates alcohol-related behaviors in alcohol-preferring and non-preferring rats. Psychopharmacology (Berl) 233:2915-24
Logrip, Marian L; Oleata, Christopher; Roberto, Marisa (2016) Sex differences in responses of the basolateral-central amygdala circuit to alcohol, corticosterone and their interaction. Neuropharmacology 114:123-134
Varodayan, Florence P; Bajo, Michal; Soni, Neeraj et al. (2016) Chronic alcohol exposure disrupts CB1 regulation of GABAergic transmission in the rat basolateral amygdala. Addict Biol :
Ubaldi, Massimo; Cannella, Nazzareno; Ciccocioppo, Roberto (2016) Emerging targets for addiction neuropharmacology: From mechanisms to therapeutics. Prog Brain Res 224:251-84

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