Genetic differences in spatial learning between Dark Agouti and Sprague-Dawley strains: Possible correlation with the CYP2D2 polymorphism in rats treated neonatally with methamphetamine

Following neonatal exposure to d-methamphetamine, adult rats have previousl y been shown to exhibit augmented acoustic startle and spatial learning def icits. R-Methamphetamine is structurally similar to several phenylethylamin es that are metabolized by CYP2D6. In humans, allelic differences in the CY P2D6 confer the extensive or poor metabolizer phenotype for the more than t hree dozen drugs that are members of the CYP2D6-mediated 'debrisoquine/spar teine panel.' An analogous genotype exists with the CYP2D2 gene in rats; Fe male Dark Agouti rats show the poor metabolizer phenotype, whereas Sprague- Dawley rats show the extensive metabolizer phenotype; male Dark Agouti rats are intermediate. We sought to test the possibility that these strains mig ht exhibit altered d-methamphetamine-induced developmental neurotoxicity. D ark Agouti and Sprague-Dawley litters (11-20 days of age) were given d-meth amphetamine or vehicle alone subcutaneously twice daily (15 mg/kg). Offspri ng were assessed as adults (beginning at 50 days of age) on acoustic startl e, straight-channel swimming; and spatial learning and memory in a Morris h idden platform maze. Increases in d-methamphetamine-induced acoustic startl e were found in both male and female Dark Agouti rats, but not Sprague-Dawl ey rats. In the Morris maze, d-methamphetamine-induced spatial navigation d eficits were found in both strains among males, suggesting some mechanism o ther than the CYP2D2 polymorphism. In contrast, among females only the d-me thamphetamine-treated Dark Agouti rats showed deficits in spatial navigatio n. The maze deficits in Dark Agouti females, and enhanced acoustic startle in Dark Agouti females and males, support the hypothesis that the CYP2D2 po or metabolizer phenotype confers increased vulnerability to d-methamphetami ne-induced developmental neurotoxicity, indicating that the parent drug rat her than a CYP2D2-mediated metabolite is responsible for this behavioural d efect-which occurs in adults who had been exposed to d-methamphetamine duri ng the neonatal period. Pharmacogenetics 9:171-181 (C) 1999 Lippincott Will iams & Wilkins.