Component 5 staff
Research Component 5:
Genetics of the CRF System, Alcohol Dependence and Inhibition

PI: Andrey Ryabinin
Co-Is:
Deborah Finn, Robert Hitzemann, Suzanne Mitchell, Tamara Phillips

Differences in impulse control and sensitivity to alcohol withdrawal symptoms can influence individual predisposition to alcoholism. Recent studies by PARC investigators have found a very strong positive correlation between measures of behavioral disinhibition/impulsivity with measures of alcohol withdrawal severity in genetic mouse models. This Component begins to test potential molecular mechanisms underlying these relationships using a candidate gene approach.

The candidate gene system tested in this component is the corticotropin releasing factor (CRF) system. The CRF system consists of 4 peptide molecules: CRF, urocortin (Ucn1), Ucn2 and Ucn3, and three proteins interacting with these peptide molecules: CRF1 receptor, CRF2 receptor and CRF-binding protein. Our studies suggest that several of these CRF system molecules can regulate severity of alcohol withdrawal and impulsivity, and the goal of this component is to examine the specific contribution of these molecules in greater detail.

This will be achieved in four specific aims:

1: We will investigate the magnitude of withdrawal-induced convulsions after acute and chronic ethanol exposure in mutant mice deficient in CRF, Ucn1, CRF1 receptor or CRF2 receptor, compared to their wildtype (WT) littermates.

2: We will investigate measures of impulsivity in the Go/No-go task in mutant mice deficient in CRF, Ucn1, CRF1 receptor or CRF2 receptor KO mice, compared to their wildtype (WT) littermates.

3: We will identify gene networks contributing to the effects of components of CRF system on withdrawal severity and impulsivity by microarray analysis of gene expression in infralimbic cortex, a brain region important for impulse control, in mice deficient in CRF, Ucn1, CRF1 receptor or CRF2 receptor KO mice and their respective WT littermates.

4: We will identify sequence differences in genes encoding CRF, Ucn1, Ucn2, Ucn3, CRF1, CRF2 and CRF—binding protein in mouse strains known to have differences in signs of ethanol-induced withdrawal and measures of impulsivity.

Taken together, the results of these experiments will provide important information on the specific roles of components of the CRF system in ethanol withdrawal and measures of behavioral inhibition, phenotypes associated with alcoholism and excessive alcohol intake .

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by Mark Rutledge-Gorman
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