CNS Stimulation and PGE 2 Release. III. Pentamethylenetetrazole-Induced Seizures

Abstract

Measurement of prostaglandin E₂ (PGE₂) in the ventriculocisternal perfusate of the halothane anesthetized, artificially ventilated cat has revealed low but measurable levels of the prostanoid (64 ± 5 pg/min). Administration of pentamethylenetetrazole (PTZ) resulted in a rapid appearance of paroxysmal bursting, the magnitude and duration of which was dose dependent. During the 30-min interval after seizure initiation, PGE₂ secretion rates into the ventriculocisternal perfusate rose by five- to sevenfold. Though the initial rate of PGE₂ secretion correlated closely with the initial magnitude of bursting, there were significant differences, viz. the time courses. Thus, after a low dose of PTZ (200 mg/kg) the increase and return to normal of PGE₂ secretion was time locked with the onset and offset of seizures. In contrast, after high doses of PTZ (250 mg/kg i. v.), seizure activity returned to near baseline by 90 min, while the levels of PGE2 secretion remained elevated for periods in excess of 150 min. Pretreatment with clonazepam (CLP: 3 mg/kg i. v. infusion) blocked seizures otherwise induced by PTZ (250 mg/kg) and the increase in PGE₂ secretion. CLP administration 60 min after the initiation of seizures, blocked further seizure activity but did not alter the elevated secretion of PGE₂. We thus believe these data jointly support the hypothesis that under intense paroxysmal bursting there is a change in neuronal state such that large stores of free fatty acids are available either because they have accumulated during the seizure because of a continued Ca²⁺ influx or the presence of large and continuing concentrations of Ca²⁺ accumulating in the cytosol secondary to energy failure.