NEUROACTIVE STEROIDS EXACERBATE GAMMA-HYDROXYBUTYRIC ACID-INDUCED ABSENCE SEIZURES IN RATS

Certain naturally-occurring steroid metabolites and their synthetic an alogs (neuroactive steroids) allosterically enhance GABA(A) receptor f unction and possess potent anticonvulsant properties. In the present s tudy, the effect of two synthetic neuroactive steroids, alphaxalone (5 alpha-pregnane 3 alpha-ol-11, 20-dione) and tetrahydrodeoxycorticoste rone was studied in a rat model of generalized absence seizures induce d by gamma-hydroxybutyric acid. Both steroids dose-dependently exacerb ated gamma-hydroxybutyric acid-induced absence seizures upon systemic administration and after focal administration into thalamic ventrobasa l nucleus. However, alphaxalone and tetrahydrodeoxycorticosterone fail ed to potentiate gamma-hydroxybutyric acid-induced absence seizures wh en injected into thalamic reticular nucleus. In all the doses of stero ids tested in thalamic reticular nucleus, the duration of gamma-hydrox ybutyric acid-seizures was neither prolonged nor shortened. This nonre sponsiveness of thalamic reticular nucleus to neuroactive steroids in modulating absence seizures may have arisen due to the molecular heter ogeneity of GABA(A) receptor subunits within the thalamus. (C) 1998 El sevier Science B.V. All rights reserved.