Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress

doi:10.1073/pnas.0604419103

Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress

*Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892;
^†Department of Experimental Medicine and Public Health, University of Camerino, 62032 Camerino, Italy; and
^‡Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden

Edited by Tomas Hökfelt, Karolinska Institutet, Stockholm, Sweden, and approved August 18, 2006 (received for review May 29, 2006)

Abstract

Alcoholism is a chronic relapsing disorder with substantial heritability. Uncovering gene–environment interactions underlying this disease process can aid identification of novel treatment targets. Here, we found a lowered threshold for stress-induced reinstatement of alcohol seeking in Marchigian–Sardinian Preferring (msP) rats genetically selected for high alcohol preference. In situ hybridization for a panel of 20 stress-related genes in 16 brain regions was used to screen for differential gene expression that may underlie this behavioral phenotype. An innate up-regulation of the Crhr1 transcript, encoding the corticotropin-releasing hormone receptor 1 (CRH-R1), was found in several limbic brain areas of msP rats genetically selected for high alcohol preference, was associated with genetic polymorphism of the Crhr1 promoter, and was accompanied by increased CRH-R1 density. A selective CRH-R1 antagonist (antalarmin, 10–20 mg/kg) was devoid of effects on operant alcohol self-administration in unselected Wistar rats but significantly suppressed this behavior in the msP line. Stress-induced reinstatement of alcohol seeking was not significantly affected by antalarmin in Wistar rats but was fully blocked in msP animals. These data demonstrate that Crhr1 genotype and expression interact with environmental stress to reinstate alcohol-seeking behavior.

Footnotes

^§To whom correspondence should be addressed at:
10 Center Drive, 10/1-5334, Bethesda, MD 20892-1108.
E-mail: markus.heilig{at}mail.nih.gov
Author contributions: A.C.H. and A.C. contributed equally to this work; M.H. and R.C. contributed equally to this work; A.C.H., A.C., W.H.S., M.H., and R.C. designed research; A.C.H., A.C., A.F., K.B., L.S., and A.T. performed research; M.M. contributed new reagents/analytic tools; A.C.H., A.C., W.H.S., A.F., K.B., L.S., A.T., M.H., and R.C. analyzed data; and A.C.H., A.C., W.H.S., M.H., and R.C. wrote the paper.
The authors declare no conflict of interest.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

msP,

Marchigian–Sardinian Preferring;

CRH-R1,

corticotropin-releasing hormone receptor 1;

CORT,

corticosterone;

SES,

standardized effect size.