Dopamine Control of Seizure Propagation: Intranigral Dopamine D1 Agonist SKF-38393 Enhances Susceptibility to Seizures

The involvement of dopamine (DA) in human and experimental epilepsy has been discounted as DAergic drugs have little effect on convulsions. This work presents evidence that bilateral microinjection of the DAD1 agonist SKF-38393 into the substantia nigra enhances the susceptibility of rats to seizures, with an ED50 of 20 pmol (range 13-31 pmol), converting subconvulsant doses of the cholinergic agonist pilocarpine (200 mg/kg; i.p.) into convulsant ones. The proconvulsant action of SKF-38393 was reversed by blocking D1-mediated transmission in the substantia nigra with the D1 antagonist SCH-23390. The D2 agonist LY-171555 did not modulate the threshold for limbic seizures when injected into the substantia nigra. In the striatum, the D2 agonist LY-171555 protected rats against limbic seizures induced by systemic administration of pilocarpine (380 mg/kg; i.p.), with an ED50 of 2 pmol (range 1.4-2.8 pmol). The anticonvulsant action of LY-171555 in the striatum was reversed by haloperidol. The D1 agonist SKF-38393 did not affect pilocarpine seizures following administration into the striatum. Systemic administration of DAergic drugs showed that the D1 agonist SKF-38393 decreased the threshold for pilocarpine seizures, with an ED50 of 0.81 mg/kg (range 0.45-1.47 mg/kg), whereas the D2 agonist LY-171555 had no effect on susceptibility of rats to pilocarpine. The proconvulsant action of SKF-38393 was blocked by the D1 antagonist SCH-23390. These results suggest that DA differentially modulates seizure threshold in the forebrain acting via D1 mechanisms in the substantia nigra and D2 mechanisms in the striatum.