title: CYP2D1 polymorphism in methamphetamine-treated rats: genetic differences in neonatal mortality and effects on spatial learning and acoustic startle.
abstract: d-Methamphetamine (MA) is one of more than two dozen drugs included in the cytochrome P450-mediated "debrisoquine oxidation polymorphism" panel. The human gene (CYP2D6) is responsible for the "poor metabolizer" (PM) and "extensive metabolizer" (EM) phenotypes for drugs such as MA; a similar polymorphism (the CYP2D1 gene) exists in rats. Female Black or Dark Agouti rats exhibit the PM phenotype, whereas Sprague-Dawley (SD) rats show the EM trait. We sought to test the possibility that these strains of rats might exhibit altered MA-induced developmental neurotoxicity. Neonatal exposure to MA on days 11-20 has previously been shown to induce spatial learning deficits in Sprague-Dawley rats when tested as adults. Therefore, in the present experiment, on postpartum days 11 through 20, ACI (Black Agouti) and SD progeny were administered 30 mg/kg MA twice daily. MA treatment caused larger increases in mortality in ACI than in SD rats, suggesting that decreased MA metabolism leads to enhanced toxicity and lethality. Female offspring were assessed behaviorally as adults. No differences were observed in acoustic startle or straight swimming channel performance. In the Morris maze, both MA-treated rat strains showed longer latencies to find the hidden platform during acquisition, reinstatement, and shift trials, and spent less time in the target quadrant on probe trials; no strain differences in learning were found. Although these data do not support our hypothesis that MA-induced developmental neurotoxicity might be enhanced in the ACI rat, this interpretation is tempered by the high mortality rate (65%) of MA-treated ACI neonates, suggesting a possible "survivor effect" in this strain.
authors.affiliation: Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, OH 45229-3039, USA. charles.vorhees@chmcc.org
authors.forename: C V
authors.initials: CV
authors.lastname: Vorhees
authors.forename: T M
authors.initials: TM
authors.lastname: Reed
authors.forename: M A
authors.initials: MA
authors.lastname: Schilling
authors.forename: J E
authors.initials: JE
authors.lastname: Fisher
authors.forename: M S
authors.initials: MS
authors.lastname: Moran
authors.forename: G D
authors.initials: GD
authors.lastname: Cappon
authors.forename: D W
authors.initials: DW
authors.lastname: Nebert
mesh_terms: D000161:Acoustic Stimulation; D000429:Alcohol Oxidoreductases; D000818:Animals; D000831:Animals, Newborn; D000833:Animals, Suckling; D001189:Aryl Hydrocarbon Hydroxylases; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D004353:Drug Evaluation, Preclinical; D005260:Female; D018782:Maze Learning / Q000187:drug effects*; D008694:Methamphetamine / Q000378:metabolism / Q000633:toxicity*; D010641:Phenotype; D011110:Polymorphism, Genetic; D051381:Rats; D011912:Rats, Inbred ACI; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects*; D015996:Survival Rate
chemical_list: D008694:Methamphetamine; D003577:Cytochrome P-450 Enzyme System; D000429:Alcohol Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; C504568:Cyp2d1 protein, rat; D000072467:Cytochrome P450 Family 2