title: Effects of dopamine D3 receptor agonists on pilocarpine-induced limbic seizures in the rat.
abstract: The discrete localization of D3 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 D3 receptors were capable of attenuating limbic motor seizures induced by pilocarpine, dopamine agonists with preferential or non-selective D3 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 D1 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 D3 > D2 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 D3 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 D3 agonist 7-OH-DPAT (20 pmol to 7 nmol) afforded no protection against pilocarpine-induced seizures. Apomorphine, a mixed D1/D2/D3 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 D2/D3 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 D2 rather than D3 receptors.
authors.affiliation: Department of Pharmacology, School of Pharmacy, London, U.K.
authors.forename: A M
authors.initials: AM
authors.lastname: Alam
authors.forename: M S
authors.initials: MS
authors.lastname: Starr
mesh_terms: D000818:Animals; D001058:Apomorphine; D015259:Dopamine Agents / Q000494:pharmacology; D004873:Ergolines / Q000494:pharmacology; D007267:Injections; D008032:Limbic System; D008297:Male; D009714:Nucleus Accumbens / Q000502:physiology; D009830:Olfactory Bulb / Q000502:physiology; D010627:Phenethylamines / Q000494:pharmacology; D010862:Pilocarpine; D019257:Quinpirole; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000502:physiology*; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D012640:Seizures / Q000139:chemically induced*
chemical_list: D015259:Dopamine Agents; C493595:Drd3 protein, rat; D004873:Ergolines; D010627:Phenethylamines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D010862:Pilocarpine; D019257:Quinpirole; C016868:N-n-propyl-N-phenylethyl-4(3-hydroxyphenyl)ethylamine hydrochloride; D001058:Apomorphine