Cocaine-induced seizure thresholds: Quantitative trait loci detection and mapping in two populations derived from the C59BL/6 and DBA/2 mouse strains

Seizures are a well known consequence of human cocaine abuse, and in rodent models, sensitivity to cocaine seizures has been shown to be strongly infl uenced by genotype. For example, several studies have reported significant differences between the C57BL/6 (B6) and DBA/2 (D2) inbred mouse strains in their sensitivity to cocaine-induced seizures. This prompted our use of th e BXD recombinant inbred (RI) strain set and an F-2 population derived from the B6 and D2 progenitor strains for further genetic analyses and for gene mapping efforts in this study. Cocaine was infused into the lateral tail v ein, and the doses needed to induce a running bouncing clonic seizure and a tonic hindlimb extensor seizure were recorded for each mouse. In the BXD R i set, a genome-wide search was carried out for QTLs (quantitative trait lo ci), which are sites on a chromosome containing genes that influence seizur e susceptibility. An F-2 population (B6D2F2, n = 408) was subsequently used as a second, confirmation step. Based on both RI and F-2 results, three QT Ls emerged as significant (P < .00005): one for clonic seizures on chromoso me 9 (distal), and two for tonic seizures on chromosomes 14 (proximal to mi d) and 15 (distal). Two additional QTLs emerged as suggestive (P < .0015), both associated with clonic seizures on chromosomes 9 (proximal) and 15 (di stal). Both QTLs on chromosome 9 were sex-specific, with much larger effect s on the phenotype seen in females than in males.