title: Roxindole: psychopharmacological profile of a dopamine D2 autoreceptor agonist.
abstract: The putative, selective dopamine (DA) dopamine-2 autoreceptor agonist roxindole, which also exhibits serotonin-1A-agonistic and 5-hydroxytryptamine reuptake-inhibiting properties, was examined for its behavioral effects in rats and mice. Roxindole inhibited apomorphine-induced climbing in mice and stereotyped behavior in rats with ED50 values of 1.4 mg/kg s.c. and 0.65 mg/kg s.c., respectively, and inhibited conditioned avoidance response in rats (ED50 = 1.5 mg/kg s.c.). Thus roxindole showed a profile resembling those of the classical antipsychotic haloperidol and the atypical neuroleptic clozapine but differing from that of the DA autoreceptor agonist talipexole, which did not prevent apomorphine-induced behaviors. Unlike haloperidol, roxindole did not induce catalepsy in rats and mice. Investigations directed to the DA autoreceptor properties revealed that spontaneous motility of rats with normosensitive postsynaptic DA receptors was monophasically decreased by roxindole and talipexole, with a threshold dose of 0.0625 mg/kg s.c. for both compounds. In reserpinized rats with presumably hypersensitive postsynaptic DA receptors, roxindole only partially reversed reserpine-induced hypomotility (threshold dose: 0.25 mg/kg); talipexole re-established the activity level to that of normal rats. In contrast to apomorphine, roxindole did not induce and talipexole only marginally induced stereotyped behavior in normal rats. After administration of the DA dopamine-1 agonist SKF 38393, talipexole induced stereotyped behavior in rats, which indicated its activity at postsynaptic dopamine-2 receptors. In contrast, roxindole did not induce stereotyped behavior in rats when co-administered with SKF 38393. These results indicate that, compared with talipexole, roxindole possesses a greater selectivity for DA autoreceptors.
authors.affiliation: Merck KGaA, Dept. CNS-Research, Darmstadt, Germany.
authors.forename: G D
authors.initials: GD
authors.lastname: Bartoszyk
authors.forename: J
authors.initials: J
authors.lastname: Harting
authors.forename: K O
authors.initials: KO
authors.lastname: Minck
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D000078183:Oxindoles; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects*
chemical_list: D001381:Azepines; D018491:Dopamine Agonists; D007211:Indoles; D000078183:Oxindoles; D011725:Pyridines; D017448:Receptors, Dopamine D2; C059613:roxindole; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C024763:talipexole; D001058:Apomorphine