Effects of dopamine D 3 receptor agonists on pilocarpine-induced limbic seizures in the rat

Abstract

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 (10mg/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 D2 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 1D 2D 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 2D 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.