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.