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

In boys with epilepsy, pubertal increases in seizure frequency may be associated 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 foci (kindling). Afterdischarge thresholds and kindling rate were measured in gonadectomized (GDX) male rats, with or without T replacement therapy. Drugs that block either androgen or estradiol (E(2)) receptor-mediated responses were also tested.

Kindling electrodes were implanted in the basolateral amygdala of adult male Wistar rats. In Experiment 1, subjects were GDX and implanted with a silastic capsule containing either: cholesterol (control); T; 5% E(2) in cholesterol; or 5alpha-dihydrotestosterone (DHT). In Experiment 2, intact subjects were treated with daily injections of vehicle (control); daily injections of flutamide (an androgen receptor antagonist); or Silastic implants containing 1,4,9-androstatriene 3,17-dione (ATD; an aromatase inhibitor).

In Experiment 1, initial afterdischarge (AD) thresholds were significantly lowered by E(2) treatment, as compared to cholesterol controls, and remained low throughout the kindling paradigm. In T replaced males, AD threshold significantly decreased over the kindling period, a response that was not observed in DHT treated rats. Rates of kindling were significantly faster as a result of T, E(2) and DHT treatment, as compared to cholesterol controls. E(2) treated males kindled the fastest of all 3 groups. In Experiment 2, initial AD thresholds were significantly lowered 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 ATD treatment. Both flutamide and ATD significantly slowed the rate of kindling, as compared to intact controls. ATD had the most dramatic inhibitory effect on kindling rate.

In males, T and its two metabolites, E(2) and DHT, all appear to enhance the development of amygdala-kindled seizures. E(2) has the most potent epileptogenic effect. Antagonism of E(2) mediated effects in the brain may have potential therapeutic value for males with epilepsy.