Effective mapping strategies for quantitative trains must allow for the detection of the more important quantitative trait loci (QTLs) while minimizing false positives. Type I (false-positive) and Type II (false-negative) error rates were estimated from a computer simulation of QTL mapping in the BXD recombinant inbred (RI) set compromising 26 strains of mice, and comparisons made with theoretical predictions. The results are generally applicable to other RI sets when corrections are made for differing strain numbers and marker densities. Regardless of the number or magnitude of simulated QTLs contributing to the trait variance, the p value necessary to provide adequate protection against both Type I (alpha=.0001) and Type II (beta=.2) errors, a QTL would have to account for more than half of the between-strain (genetic) variance if the BXD or similar set was used alone. In contrast, a two-step mapping strategy was also considered, where RI strains are used as a preliminary screen for QTLs to be specifically tested (confirmed) in an F2 (or other) population. In this case, QTLs accounting for approximately 16% of the between-strain variance could be detected with an 80% probability in the BXD set when alpha = 0.2. To balance the competing goals of minimizing Type I and II errors, an economical strategy is to adopt a more stringent alpha initially for the RI screen, since this requires only a limited genome search in the F2 of the RI-implicated regions (approximately 10% of the F2 genome when p < .01 in the RIs). If confirmed QTLs do not account in the aggregate for a sufficient proportion of the genetic variance, then a more relaxed alpha value can be used in the RI screen to increase the statistical power. This flexibility in setting RI alpha values is appropriate only when adequate protection against Type I errors comes from the F2 (or other) confirmation test(s).

To determine genetic differences in voluntary morphine consumption, 15 commonly used inbred strains of mice were given ad libitum two-bottle choice between saccharin alone or saccharin/morphine in one bottle and water in the other bottle. Subsequently, the saccharin was gradually reduced to zero, leaving only morphine. Independent groups of mice of the same strains were exposed to quinine in a parallel manner to control for the bitter alkaloid taste of morphine. Of the 15 strains, the C57BL/6J strain showed the highest consumption of morphine, both with or without saccharin and greatest consumption of morphine relative to quinine; it also showed only a slight decline in fluid consumption when morphine was added to the saccharin bottle. In marked contrast, the SWR/J strain showed the least consumption of morphine by the same criteria, followed closely by the AKR/J, CE/J, DBA/2J and SJL/J strains. The strain differences for all the morphine drinking measures exceeded an order of magnitude. Strain-specific voluntary morphine/saccharin consumption was not significantly correlated with saccharin consumption alone, but was highly correlated with morphine consumption alone. The results show that these behaviors are under an unusually large degree of genetic determination, and some of the largest strain differences remained essentially the same regardless of whether saccharin was present, or whether quinine was used as a control tastant.

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.

Recombinant inbred (RI) mouse strains were developed primarily as a tool to detect and provisionally map major gene loci--those with effects large enough to cause a bimodal distribution in the trait of interest. This implied that progress toward gene mapping was possible only for gene loci accounting for at least half of the genetic variance. More recently, QTL (quantitative trait loci) approaches have been advanced that do not require bimodal distributions and are thus applicable to a much wider range of phenotypes. They offer the prospect of meaningful progress toward detecting and mapping minor as well as major gene loci affecting any trait of interest, provided there is a significant degree of genetic determination among the RI strains. This paper presents a review of RI gene mapping efforts concerning phenotypes related to drug abuse and presents new data for studies now in progress for nitrous oxide and acute ethanol withdrawal intensity. These two studies exemplify several strengths and limitations of the RI QTL approach.