Modeling genetically controlled DBH activity in mice

Emory University, Atlanta GA

Investigators

Abstract

[unreadable] DESCRIPTION (provided by applicant): Dopamine beta-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons, adrenergic neurons, and adrenal chromaffin cells. Therefore, DBH controls both NE synthesis and the DA/NE ratio in noradrenergic cells. DBH enzymatic activity in humans varies between individuals. A common polymorphism (a C to T change at position -1021) has been identified in the human Dbh gene that accounts for most of the genetic variability and about half of the total variability observed in DBH enzymatic activity. DBH has recently become of interest in the field of drug addiction for two reasons. First, the rewarding and aversive effects of cocaine appear to be influenced by Dbh genotype in humans. Second, the DBH inhibitor disulfiram has shown promise as a pharmacotherapy for cocaine dependence. Because of technical and ethical issues in human research, very little is known about the neurochemical consequences of the Dbh C-1021T polymorphism. Therefore, it is of interest to create a rodent model of the C-1021T polymorphism and assess both neurochemical and behavioral differences between the C and the T alleles of Dbh. We propose to create transgenic mice bearing a bacterial artificial chromosome (BAG) that contains either the C allele or the T allele of the human Dbh gene. Completion of this aim will provide us with the tools necessary to ascertain how the C-1021T polymorphism controls DBH enzymatic activity, its effect on catecholamine neurochemistry, and the behavioral consequences of these changes, especially as they relate to drug addiction. [unreadable] [unreadable]