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

Barbiturate dependence is associated with the development of physiological dependence (withdrawal), tolerance, or a maladaptive pattern of drug use. A nalysis of strain and individual differences with animal models for physiol ogical dependence liability are useful means to identify potential genetic determinants of liability in humans. Behavioral and quantitative trait locu s (QTL) mapping analyses were conducted with mice that are resistant versus sensitive to pentobarbital withdrawal. With a multistage genetic mapping s trategy, a pentobarbital withdrawal QTL (Pbw1) was mapped to the distal reg ion of mouse Chromosome (Chr) 1 and may be identical to an alcohol withdraw al QTL mapped to this chromosomal region. Two suggestive QTLs for pentobarb ital withdrawal, both in proximity to QTLs definitely mapped for alcohol wi thdrawal, were also tentatively identified. These were on Chr 11 in proximi ty to a gene cluster including several members of the GABA(A) receptor gene family, and on Chr 4 near a locus associated with beta-carboline-induced s eizure severity. These data represent the first detection and mapping of lo ci influencing risk for physiological dependence on barbiturates, and sugge st the involvement of common genes in physiological dependence on pentobarb ital and alcohol.