Testosterone and its metabolites affect afterdischarge thresholds and the development of amygdala kindled seizures

In buys with epilepsy, pubertal increases in seizure frequency may be assoc iated with rising androgen levels. The present study tested the hypothesis that testosterone (T) and/or its metabolites might affect amygdala seizure thresholds and the development of secondary generalization from amygdala fo ci (kindling). Afterdischarge thresholds and kindling rate were measured in gonadectomized (GDX) male rats, with or without T replacement therapy. Dru gs that block either androgen or estradiol (E-2) receptor-mediated response s were also tested. Methods: Kindling electrodes were implanted in the baso lateral amygdala of adult male Wistar rats. In Experiment 1, subjects were GDX and implanted with a silastic capsule containing either. cholesterol (c ontrol); T; 5% E-2 in cholesterol; or 5 alpha-dihydrotestosterone (DHT). In Experiment 2, intact subjects were treated with daily injections of vehicl e (control); daily injections of flutamide (an androgen receptor antagonist ); or Silastic implants containing 1,4,9-androstatriene 3,17-dione (ATD; an aromatase inhibitor). Results: In Experiment 1, initial afterdischarge (AD ) thresholds were significantly lowered by E-2 treatment, as compared to ch olesterol controls, and remained low throughout the kindling paradigm. In T replaced males, AD threshold significantly decreased over the kindling per iod, a response that was not observed in DHT treated rats. Rates of kindlin g were significantly faster as a result of T, E-2 and DHT treatment, as com pared to cholesterol controls. E-2 treated males kindled the fastest of all 3 groups. In Experiment 2, initial AD thresholds were significantly lowere d by flutamide treatment, as compared to cholesterol controls, and remained low throughout the kindling paradigm. AD threshold significantly decreased over the kindling period in intact males, a response that was blocked by A TD treatment. Both flutamide and ATD significantly slowed the rate of kindl ing, as compared to intact controls. ATD had the most dramatic inhibitory e ffect on kindling rate. Conclusions: In males, T and its two metabolites, E -2 and DHT, all appear to enhance the development of amygdala-kindled seizu res. E-2 has the most potent epileptogenic effect. Antagonism of E-2 mediat ed effects in the brain may have potential therapeutic value for males with epilepsy. (C) 1999 Elsevier Science B.V. All rights reserved.