Seizures in Male Rats

Drug

PN 15 Rats

Adult Rats

SNRanterior OR SNRposterior

SNRa

SNR, posterior

Muscimol Bicuculline ZAPA Zolpidem 7-vinyl GABA

Proconvulsant Proconvulsant Biphasic effects Anticonvulsant Anticonvulsant

Anticonvulsant Proconvulsant Anticonvulsant Anticonvulsant Anticonvulsant

Proconvulsant No effect Proconvulsant No effect Proconvulsant

Muscimol: GABAa receptor agonist on both low- and high-affinity receptors. Bicuculline: GABAa receptor antagonist on low-affinity receptors. ZAPA: GABAa receptor agonist on low-affinity receptors. Zolpidem: agonist of benzodiazepine I binding site of GABAa receptor. 7-vinyl GABA: irreversible inhibitor of the GABA degradation enzyme, GABA-transaminase. Based on data in (165, 166, 169, 170).

The question is, When does the differentiation of the two SNR seizure-modifying regions occur? At PN25, the SNR starts to differentiate; infusions of muscimol in the SNRanterior have no effects on flurothyl seizures, while infusions in the SNRposterior have proconvulsant effects. This maturation of the "anticonvulsant" SNR region strikingly coincides with sexual maturation (11). In male rats, there is a sudden drop in plasma testosterone levels (PN20-25) (176-178) just prior to the age when the SNRanteior assumes its "anticonvulsant" characteristics. To test the hypothesis that testosterone may play a role in formation of the "anticonvulsant" SNRanterior, male rats were castrated on the day of birth. The rats were exposed to flurothyl at ages PN15 and PN25 following bilateral infusions of muscimol in the SNRanterior or SNRposterior. In the SNRanterior in PN15 neonatally castrated male rats, muscimol infusions had no effects on seizures; in PN25, muscimol infusions had anticonvulsant effects compared to saline-infused neonatally castrated controls. Thus, in neonatally castrated male rats the emergence of the "anti-convulsant" SNRanterior shifted to an earlier time point than that observed in intact or sham-operated male rats, suggesting that the depletion of postnatal testosterone may accelerate the appearance of the "anticonvulsant" SNRanterior (170).

In female rats, a proconvulsant muscimol-sensitive SNR region does not develop. In PN15 female rats, there is only one functional region in the SNR. Infusions of muscimol into this region do not change seizure threshold. In adult female rats, the SNRanterior mediates anticonvul-sant effects of muscimol similarly to the SNRanterior in adult male rats. In contrast to adult male rats, infusions of muscimol in the SNRposterior in female rats have no effects on seizure threshold. As just mentioned, maturation of the SNR regions is under control of perinatal testosterone or its metabolites. Thus, in females, postnatal administration of testosterone leads to the male SNR phenotype (170,179). The male-female differences in seizure control seem to be associated with sex-specific differences in the GABAergic system within the SNR as well as in connectivity patterns (173). Further, it appears that the developmental control of seizures in the SNR is affected by sexually dimorphic maturation of KCC2 in this structure (79).

The data demonstrate that the age-specific susceptibility to seizures may be partly due to developmental maturation of structures controlling seizures. This maturation may be under the influence of gonadal hormones and may exert sexually dimorphic features.

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