Differential modulatory actions of GABAA agonists on susceptibility to GABAA antagonists-induced seizures in morphine dependent rats: Possible mechanisms in seizure propensity

Abstract

In order to clarify the mechanisms involved in the susceptibility to GABAA antagonists-induced seizures in morphine dependent rats, we investigated how GABAA agonists modulate this vulnerability. Seizures were induced to animals by infusion of GABAA antagonists: pentylenetetrazole (PTZ), picrotoxin (PIC) and bicuculline (BIC). GABAA agonists, muscimol (MUS) and 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridin-3-ol (THIP), were administered intravenous (i.v.) before antagonists. Morphine-dependence significantly decreased the PTZ threshold dose (19.16±1.89 versus 25.74±1.25mg/kg) while, it had no effect on PIC induced seizures. BIC doses for both threshold and tonic–clonic seizures induction were significantly lower in morphine dependent rats (0.10±0.01 and 0.12±0.02 versus 0.25±0.02 and 0.39±0.07mg/kg respectively). In morphine-dependence, although pre-treatment with MUS significantly increased the required dose of PTZ for seizures threshold, THIP significantly decreased the required dose of PTZ for tonic–clonic convulsion. Moreover, MUS pretreatment completely recovered the effect of morphine dependency on BIC seizure activity.The results suggest that the capability of GABAA agonists on modulation of propensity to seizures induced by different antagonists in morphine-dependence is dissimilar. Therefore, it seems that long-term morphine alters some properties of GABA system so that the responsive rate of GABAA receptors not only to its antagonists, but also to its agonists will change differently.