Abstracts

It is known that testosterone influences seizures and epilepsy, but it is not clear whether there are differential effects on seizure threshold, epileptogenesis, or the chronic condition. Using the pilocarpine model of epilepsy, we tested the hypothesis that testosterone influences the initial precipitating event (status epilepticus), consequences of status (damage, sprouting), and the state of spontaneous recurrent seizures (the chronic period). Orchidectomy was used to reduce serum testosterone, and sham surgery was used as a control condition., Orchidectomized or sham adult male Sprague-Dawley rats were administered atropine methylbromide (1mg/kg, s.c.) and pilocarpine (380mg/kg, i.p.) 2 wks after surgery, and diazepam (5mg/kg., i.p.) was injected 1 hr after the onset of status. Spontaneous seizures were assessed by behavioral observation. To evaluate hyperexcitability [italic]in vitro[/italic], extracellular recordings were made in hippocampal slices to detect spontaneous population bursts in area CA3, which occur in intact male rats in the chronic period. After recordings, slices were immersion-fixed, resectioned, and used for immunocytochemistry to detect neuronal loss and mossy fiber sprouting using antibodies to the neuronal marker NeuN, and neuropeptide Y, respectively., There was no difference in the incidence of status in orchidectomized (59%; n=19/32) vs. sham controls (66%, n=10/15; p=0.63). The incidence of CA3 bursts in orchidectomized rats was significantly lower (32%, n=8/25, n=4 rats), when tested 12-14 weeks after status, relative to sham and intact rats (pooled; 86%, n=36/42, n=7 rats; p=0.0001). This was unlikely to have been due to differential neuronal damage or sprouting, because they appeared to be similar throughout the septotemporal axis in the two groups. If orchidectomy was conducted after the chronic period was established, it did not stop spontaneous seizures, or have any effect on the incidence of CA3 bursts in slices from these rats (orch., 92%; sham, 100%; p=1.0)., Orchidectomy 2 wks prior to status had no apparent effect on the incidence of status, but it did appear to reduce the incidence of CA3 bursts in slices from rats that were examined during the chronic period in the pilocarpine model. However, orchidectomy after the onset of the chronic period did not influence CA3 bursts. The results suggest that orchidectomy, and most likely testosterone, has a major effect on the development, but not the maintenance, of area CA3 network bursts in the pilocarpine model. This effect would be consistent with recent studies illustrating the influence of testosterone on synaptic remodeling in CA3, and the evidence that synaptic reorganization plays a role in epileptogenesis., (Supported by NINDS 37652, Helen Hayes Hospital Foundation, New York State Dept. of Health.)