Quantitative trait loci affecting risk for pentobarbital withdrawal map near alcohol withdrawal loci on mouse chromosomes 1, 4, and 11

Abstract

Barbiturate dependence is associated with the development of physiological dependence (withdrawal), tolerance, or a maladaptive pattern of drug use. Analysis of strain and individual differences with animal models for physiological dependence liability are useful means to identify potential genetic determinants of liability in humans. Behavioral and quantitative trait locus (QTL) mapping analyses were conducted with mice that are resistant versus sensitive to pentobarbital withdrawal. With a multistage genetic mapping strategy, a pentobarbital withdrawal QTL (Pbw1) was mapped to the distal region of mouse Chromosome (Chr) 1 and may be identical to an alcohol withdrawal QTL mapped to this chromosomal region. Two suggestive QTLs for pentobarbital withdrawal, both in proximity to QTLs definitely mapped for alcohol withdrawal, were also tentatively identified. These were on Chr 11 in proximity to a gene cluster including several members of the GABAA receptor gene family, and on Chr 4 near a locus associated with beta-carboline-induced seizure severity. These data represent the first detection and mapping of loci influencing risk for physiological dependence on barbiturates, and suggest the involvement of common genes in physiological dependence on pentobarbital and alcohol.