Substantia nigra regulates action of antiepileptic drugs

Abstract

The cholinergic agonist pilocarpine triggers sustained limbic seizures in rodents. Pilocarpine seizures were blocked by systemic administration of benzodiazepines, barbiturates, valproate and trimethadione, while diphenylhydantoin did not affect, and ethosuximide increased the susceptibility of rats to such seizures. This pattern of action of antiepileptic drugs is characteristic for pilocarpine seizures and different from other rodent models of epilepsy. Although the anatomical substrates in the forebrain involved in the expression of anticonvulsant activity are unknown, the basal ganglia are believed to be essential for the motor expression of pilocarpine seizures. Bilateral microinjections into the substantia nigra, a major output station of the basal ganglia, of midazolam (ED50 38.5 nmol; range 29-52 nmol), phenobarbital (ED50 16 nmol; range 7-39 nmol) and trimethadione (ED50 30 nmol; range 16-56 nmol) protected rats against pilocarpine seizures (380 mg/kg i.p.) Diphenylhydantoin (up to 100 nmol) remained inactive, while ethosuximide (ED50 38 nmol; range 22-65.5 nmol) reduced the threshold for pilocarpine seizures, converting subconvulsant doses of pilocarpine (200 mg/kg i.p.) into convulsant ones. The profiles of action of antiepileptic drugs on pilocarpine seizures were similar following intranigral and systemic administration. These observations suggest that the substantia nigra may mediate some actions of antiepileptic drugs.