Abstracts

The substantia nigra pars reticulata (SNR) controls seizures via its GABAergic system in a sex specific manner. In postnatal day (PN) 15 rats, muscimol (a GABAA receptor agonist) in the SNR has a proconvulsant effect in males ([ldquo]male phenotype[rdquo]) but no effect in females or in males castrated at PN0 ([ldquo]female phenotype[rdquo]). We have previously shown that the presence of testosterone may be responsible for this sex-specific effect. Daily administration (PN0[ndash]14) of testosterone (TP) induces the [ldquo]male phenotype[rdquo] in females or neonatally castrated males. Both androgen and estrogen receptors are present in the SNR at PN0. In this study we determined whether the natural early perinatal surge of testosterone and which of its neuroactive metabolites (dihydrotestosterone; DHT or estrogen; DES) are responsible for determining of the [ldquo]male phenotype[rdquo] (masculinization). We used following groups of rats: males castrated at PN3 (natural testosterone early perinatal surge); males castrated at PN0 and females treated with TP (0.1mg) or DHT (0.1mg) or DES (2[micro]g) at PN0-2. At PN13, rats were implanted bilaterally into the SNR. Muscimol (100 ng/0.25[micro]l) was infused at PN15; after 30 minutes rats were exposed to flurothyl, a volatile convulsant, and the latency to first clonic and tonic-clonic seizure was recorded. Cannula placements were confirmed histologically. Presence of testosterone or its metabolites during the early neonatal period results in masculinization of the nigral seizure controlling GABAergic network. Thus, in females or in neonatally castrated males treated with testosterone or DHT or DES, muscimol infusions had a procovnulsant effect. Early perinatal testosterone surge is responsible for the development of [ldquo]male phenotype[rdquo] of the SNR muscimol response. Activation of both estrogen and androgen receptors is important for the masculinization of the nigral seizure controlling GABAergic network. (Supported by NIH Grants NS 20253, NS 36238, CURE grant and the Heffer Family Medical Foundation.)