Quantitative Trait Loci Affecting Methamphetamine Responses in BXD Recombinant Inbred Mouse Strains

Abstract

Individual differences in most behavioral and pharmacological responses to abused drugs are dependent on both genetic and environmental factors. The genetic influences on the complex phenotypes related to drug abuse have been difficult to study using classical genetic analyses. Quantitative trait locus (QTL) mapping is a method that has been used successfully to examine genetic contributions to some of these traits by correlating allelic variation in polymorphic genetic markers of known chromosomal location with variation in drug-response phenotypes. We evaluated several behavioral responses to multiple doses of methamphetamine (METH) in C57BL/6J (B6), DBA/2J (D2), and 25 of their recombinant inbred (BXD RI) strains. Stereotyped chewing, horizontal home cage activity, and changes in body temperature after 0, 4, 8, or 16 mg/kg METH, as well as stereotyped climbing behavior after 16 mg/kg METH, were examined. Associations (p < 0.01) between METH sensitivity and allelic status at multiple microsatellite genetic markers were subsequently determined for each response. QTLs were provisionally identified for each phenotype, some unique to a particular behavior and others that appeared to influence multiple phenotypes. Candidate genes suggested by these analyses included several that mapped near genes relevant for the neurotransmitters acetylcholine and glutamate. The locations of QTLs provisionally identified by this analysis were compared with QTLs hypothesized in other studies to influence methamphetamine- and cocaine-related phenotypes. In several instances, QTLs appeared to overlap, which is consistent with idea that common neural substrates underlie some responses to psychostimulants.

Behavioral genetic contributions to the study of addiction-related amphetamine effects

“…1 (Alexander et al, 1996) 2 (Belknap and Crabbe, 1992) 3 (Gora-Maslak et al, 1991) 4 (Grisel et al, 1997) 5 (Palmer et al, 2005) 6 (Torkamanzehi et al, 2006) Neurosci Biobehav Rev. Author manuscript; available in PMC 2008 April 30.…”

“…Twentyfive recombinant inbred strains derived from C57BL/6J and DBA/2J inbred strain progenitors (BXD RI) were included. The strongest association was for degree of locomotor stimulation and degree of hyperthermia induced by methamphetamine (Grisel et al, 1997). It is possible that certain genes (and neurochemical mechanisms) influence both responses to methamphetamine, but also possible that high levels of locomotor behavior lead to increased body temperature.…”

“…In rodents, stereotypic behaviors may include head swaying or bobbing, repetitive forelimb movements, repetitive chewing, and self-mutilation (Atkins et al, 2001;Grisel et al, 1997;Muller et al, 1982). In humans, methamphetamineinduced stereotypic behavior is sometimes referred to as "punding".…”

“…We are not aware of any attempts to directly identify the influential gene responsible for what appeared to be a major single gene effect. However, in a more recent study (Grisel et al, 1997), BXD RI mice were used for mapping the hyperthermic response to 3 doses of methamphetamine (4, 8 and 16 mg/kg). A region of interest was identified on chromosome 1; however, a major gene effect was not strongly indicated in this 27-strain study, as it was in the previous 10-strain study.…”

“…Other amphetamine-related traits that have been subjected to gene mapping efforts using RI strains include methamphetamine-induced stereotyped climbing, repetitive chewing, and acute locomotor activation (Grisel et al, 1997;Torkamanzehi et al, 2006). In all cases, provisional QTL have been identified, but additional work is needed for confirmation, finer mapping and gene identification.…”