D-2 agonists protect rodents against pilocarpine-induced convulsions by stimulating D-2 receptors in the striatum, but not in the substantia nigra

Abstract

This study employed the pilocarpine model of epilepsy to determine the relative systemic anticonvulsant potencies of five different D-2 agonists in the mouse, and to investigate the site of anticonvulsant action of LY 171555 in the rat's brain following intracerebral microinjection. Control mice pretreated with saline developed motor seizures when challenged with pilocarpine (400 mg/kg, 11/13 convulsed). D-2 agonists protected mice against pilocarpine-induced seizures in the rank order of potency PHNO greater than pergolide greater than greater than lisuride = LY 171555 much greater than RU 24213, with ED50 values ranging from 0.17 mg/kg for PHNO to greater than 4.5 mg/kg for RU 24213. The response to LY 171555 was abolished by the D-2 blocker metoclopramide (1.25 mg/kg), but not by the D-1 antagonist SCH 23390 (0.25 mg/kg). All D-2 agonists induced head-down sniffing and forward locomotion, consistent with central D-2 activation. LY 171555 (ED50 0.19 mg/kg), but not RU 24213 (ED50 greater than 4.5 mg/kg), was similarly efficacious in the rat. When injected into both hemispheres of the conscious rat via indwelling cannulae, intrastriatal saline failed to afford protection against the convulsant action of pilocarpine (600 mg/kg, 13/15 convulsed), whereas LY 171555 did (1 microgram, 1/12 convulsed). Intrastriatal RU 24213 (1 microgram per side) was without effect (7/10 convulsed). Similarly, no protection resulted when saline (15/16 convulsed) or LY 171555 (1 microgram, 17/23 convulsed) were delivered into both nigras. It is concluded that in this model of limbic seizures in the mouse and rat, D-2 agonists exert a powerful anticonvulsant effect which is mediated by D-2 receptors in the striatum, but not by D-2 receptors in the substantia nigra.