Abstracts

RATIONALE: As part of a program to elucidate genetic factors which contribute to interindividual differences in response to anticonvulsant drugs, we have surveyed inbred strains of mice with regard to the ability of VPA to increase MEST. METHODS: Male mice (8-12 wks) from 9 strains (C57BL/6, DBA/2, 129/Sv, 129/SvIM, A/J, AKR, BALB/c, C3H/He and CBA) were tested for MEST using a single daily electroshock regimen. Mice (n = 10-12)were tested at 24 hr intervals with a 1 mA increase in current per trial until a maximal seizure (tonic hindlimb extension) was observed. Injections of VPA (200 mg/kg, i.p.) or saline (1.0% body weight) were given 30 min before each MEST trial. RESULTS: Results showed significant effects of strain and treatment. DBA/2 mice exhibited the lowest control MEST (24?2 mA, mean?SD) and C57BL/6 mice the highest (75?6). Other strains exhibited intermediate values: AKR (33?2), 129/SvIM: (40?4), 129/Sv: (41?3), BALB (41?4), A/J (47?5), C3H (56?4), CBA (57?4). Pretreatment with VPA exerted strain-specific effects on MEST with values ranging from a low of 130 (?8) (mean?SD) percent of control in 129/SvIM mice to a high of 204 (?17) percent of control in 129/Sv mice. Other strains showed intermediate responses: BALB/c (160?8), C3H (165?17), CBA (172?15), AKR (182?19), D2 (190?21). Effects of VPA on MEST in C57BL/6 and A/J mice have not yet been studied. CONCLUSIONS: Results document a continuous variation in MEST and VPA-induced increase in MEST among inbred mouse strains and identify at least one strain pair (129/Sv and 129/SvIM) that is concordant for MEST and discordant for response to VPA. Such data contribute to a foundation upon which future studies can be developed to map and ultimately identify genes that influence response to VPA and other anticonvulsant drugs. Supported by Univ. Penn & VA funds.