Abstracts

Seizures affect males more often than females. The substantia nigra pars reticulata (SNR) belongs to an endogenous seizure-controlling network. Previous studies suggest that the SNR has age- and sex-specific features in terms of seizure control via activation of the GABAA receptor system. The sexual differentiation of the SNR is apparent during early development. At postnatal day 15 (P15), bilateral SNR infusions of the GABAA receptor agonist muscimol have a proconvulsant effect in males and no effect on flurothyl clonic seizure threshold in females. Exposure to testosterone during early postnatal development determines the male SNR response to muscimol. Here we investigated whether the testosterone effects on development of the male SNR response to muscimol are mediated via activation of androgen receptors during early postnatal development., In order to block the androgen receptors, male rat pups were injected daily with the androgen receptor antagonist flutamide (10 mg/kg i.p.) at P0-P2. Previously we have found that testosterone exposure during this time period leads to the male, proconvulsant effects of SNR muscimol infusions. At P13, we implanted cannulae in the SNR bilaterally using stereotaxic surgery. At P15, muscimol (100 ng/0.25 [mu]l per side) or saline (0.25[mu]l per side) was infused bilaterally 30 minutes prior to flurothyl seizure testing. The clonic seizure threshold was determined as the amount of flurothyl necessary to induce the seizure. Subsequently cannulae placements were confirmed histologically. Only rats with bilateral SNR canulae placements were used for statistical evaluation., Muscimol infusions in the SNR of P15 male rats treated with flutamide at P0-P2 had no effect on flurothyl seizure threshold compared to saline-infused controls. This is in contrast to previously published data in na[iuml]ve male rats, in which SNR muscimol infusions have a proconvulsant effect on flurothyl clonic seizures., The results of the present study suggest that activation of androgen receptors during the early postnatal period participates in the development of proconvulsant SNR responses to muscimol. Understanding the mechanisms involved in sex-dependent sensitivity to seizures may lead to development of sex-specific treatment strategies., (Supported by NIH Grant NS 20253 and the Heffer Family Medical Foundation.)