There is a high degree of co-morbidity between anxiety disorders and alcohol abuse, with the results of most studies suggesting that anxiety disorders predate alcohol abuse. Corticotropin-releasing factor (CRF) is a neuropeptide that is released during stress and the peptide effects both anxiety-like endophenotypes and alcohol endophenotypes. We have found that the Wistar-Kyoto (WKY) and Brown Norway (BN) rat strains have a polymorphism that has not previously been described, in the conserved region upstream of the CRF1 receptor gene (CRHR1) on chromosome 10.
Three Specific Aims will be addressed in this exploratory project.
Specific Aim 1. To determine: 1) Whether rat strain-dependent differences in baseline or stress-induced levels of anxiety-like behaviors predict baseline and/or stress-induced changes in alcohol consumption; 2) Whether rat strain-dependent baseline levels of alcohol consumption predict stress-induced increases in consumption. We will also examine the effect of the polymorphism on CRF mRNA levels in a number of brain regions. Finally, we will perform additional sequencing of the coding region of the CRF1 receptor in these rat strain, and screen outbred rat strains to identify how common the WKY variant might be.
Specific Aim 2. To develop a BN line with a WKY chromosome 10, and a WKY line with a BN chromosome 10. To further sequence the coding region of the CRF1 receptor in WKY and BN rats. To examine the abundance of CRF1 mRNA in several regions of WKY and BN brain. To examine the commonality of the WKY chromosome 10 variant in outbred rats.
Specific Aim 3. To examine whether there are rat strain-dependent difference in sensitivity to the behavioral effects of alcohol. Thus, we seek to examine the relationships among baseline anxiety- and alcohol- like endophenotypes, as well as the relationships between baseline and stress-induced changes in the endophenotypes in these two strains of rat. Using the backcrossed rats we develop, we will begin to explore the functional significance of the polymorphism in the conserved region upstream of the CRF1 receptor gene (CRHR1) on chromosome 10. ? ? Public Health Relevance: There is a high degree of comorbidity between anxiety and alcohol use disorders, and the stress-related neuropeptide, corticotropin-releasing factor appears to be involved in both. The purpose of these studies is to examine the relationship between stress and different CRF genotypes on anxiety and alcohol use endophenotypes. ? ? ?
|Sutherland, Jane E; Conti, Lisa H (2011) Restraint stress-induced reduction in prepulse inhibition in Brown Norway rats: role of the CRF2 receptor. Neuropharmacology 60:561-71
|Sutherland, Jane E; Burian, Linda C; Covault, Jonathan et al. (2010) The effect of restraint stress on prepulse inhibition and on corticotropin-releasing factor (CRF) and CRF receptor gene expression in Wistar-Kyoto and Brown Norway rats. Pharmacol Biochem Behav 97:227-38