EFFECTS OF DOPAMINE D-3 RECEPTOR AGONISTS ON PILOCARPINE-INDUCED LIMBIC SEIZURES IN THE RAT

The discrete localization of D-3 receptors in the nucleus accumbens and subjacent islands of Calleja bears a close resemblance to the dopamine-sensitive anticonvulsant site in the anteroventral striatum. To determine if these D-3 receptors were capable of attenuating limbic motor seizures induced by pilocarpine, dopamine agonists with preferential or non-selective D-3 affinity were injected stereotaxically into these limbic brain regions of the rat via indwelling cannulae prior to pilocarpine challenge. Reliable clonic seizures were obtained by administering the proconvulsive dopamine D-1 agonist SKF 38393 (10 mg/kg i.p.) followed by a subconvulsant dose of pilocarpine (280-300 mg/kg i.p.). Bilateral intra-accumbens pretreatment with the D-3 > D-2 agonist RU 24213 (0.2 pmol-7 nmol) significantly delayed the onset of seizures, with a minimum effective dose of 2 pmol, without altering their frequency or severity. The more selective D-3 agonist LY 171555 (0.2 pmol-7.8 nmol) was less potent, and only attenuated pilocarpine-induced seizures at a dose (500 pmol that would have stimulated accumbens D-2 receptors as well. Intra-accumbens injections of the highly potent and selective D-3 agonist 7-OH-DPAT (20 pmol to 7 nmol) afforded no protection against pilocarpine-induced seizures. Apomorphine, a mixed D-1/D-2/D-3 agonist, delayed seizure onset at 100-500 pmol, but not at higher doses. RU 24213, LY 171555 and 7-OH-DPAT were all modestly anticonvulsant when microinjected into the islands of Calleja at D-2/D-3 unselective doses. These data support the notion that dopamine systems limit seizure propagation through the limbic forebrain, but suggest this protective effect is mediated by D-2 rather than D-3 receptors.