Brain norepinephrine and convulsions in the genetically epilepsy-prone rat: sex-dependent responses to Ro 4-1284 treatment

Seizure predisposition in the Genetically Epilepsy-Prone Rat (GEPR) is at least partially dependent on central nervous system noradrenergic deficits. We have previously shown that moderate seizure GEPRs (GEPR-3) experience an increase in seizure severity after receiving Ro 4-1284, a monoamine vesicle inactivating drug. We are now reporting the effect of this drug on severe seizure GEPRs (GEPR-9). Motives for this study were: (a) to determine the effects of further depletion of innately deficient monoaminergic stores on seizure latencies and (b) to investigate whether a previously documented seizure severity difference between the sexes is related to the defective monoaminergic system in these subjects. GEPR-9s with known seizure history were tested for latency to onset of running phase and convulsion 45 minutes after Ro 4-1284 or saline administration. Brain norepinephrine levels were also determined. Ro 4-1284 caused severe depletion of monoamines in all brain areas assayed in both sexes of GEPR-9s and also caused a reduction in the latencies for onset of running and convulsion. The drug-induced norepinephrine depletion across the brain areas surveyed was significantly greater in females than in their male littermates. These observations prompt us to postulate that noradrenergic neurons in female GEPR-9s are functionally different from those in males and that this difference is detected in the differential effectiveness of Ro 4-1284 between the two sexes. Also, the influence of gonadal hormones on seizure predisposition and on the neurochemical actions of Ro 4-1284 may be different in GEPR-9 males and females.