OPPOSITE EFFECTS OF STIMULATION OF D1 AND D2 DOPAMINE-RECEPTORS ON THE EXPRESSION OF MOTOR SEIZURES IN MOUSE AND RAT

The ability of drugs, selective for dopamine D1 and D2 receptors, to influence the production of motor seizures was studied in mice and rats. Mice, which had been injected with reserpine (5 mg/kg) to deplete stores of monoamines in brain, could be made to convulse 24 hr later by injecting the D1 agonists, SKF 38393 (15-30 mg/kg) and CY 208-243 (0.3-3 mg/kg). The D2 agonists, lisuride (0.5-5 mg/kg) and RU 24213 (0.5-15 mg/kg) and the mixed D1 D2 agonist, apomorphine (0.05-0.5 mg/kg), had no effect on the seizure thresholds by themselves. However, the proconvulsant action of SKF 38393, 15 mg/kg, was prevented by the simultaneous injection of lisuride (5 mg/kg), RU 24213 (5 mg/kg) or apomorphine (0.5 mg/kg) and also by the selective D1 blocking drug, SCH 23390 (0.1 mg/kg). Rats were made to convulse by injecting the cholinergic agonist, pilocarpine (200-600 mg/kg) coupled with methyl scopolamine (1 mg/kg), to prevent peripheral autonomie effects. The smallest dose of pilocarpine (200 mg/kg) was subconvulsant, whereas the larger ones (400 and 600 mg/kg) dose-dependently induced tonic convulsions. The drug SKF 38393 (30 mg/kg) was found to be proconvulsant and caused seizures to develop in 100% of animals, at all dose levels of pilocarpine. This effect was blocked by SCH 23390 (0.25 mg/kg) which, by itself, reduced the severity and increased the latency of pilocarpine-induced convulsions, but not their frequency. The D2 agonist LY 171555 (0.5 mg/kg) was also anticonvulsant in this model and was antagonised by the D2 blocking drug metoclopramide (1.25 mg/kg), which was ineffective alone. These results provide evidence that D1 and D2 receptors, respectively, mediate proconvulsant and anticonvulsant effects of dopaminergic agonists in the reserpine-treated mouse and the pilocarpine-treated rat models of epilepsy. © 1990.