In vivo receptor binding, neurochemical and functional studies with the dopamine D-1 receptor antagonist SCH23390.
A series of in vivo experiments were undertaken, relating functional (motor activity, body temperature), dopamine (DA) receptor binding and neurochemical (catecholamine synthesis and utilization, DA release) aspects of the pharmacology of SCH23390 in the rat. The compound inhibited the locomotor hyperactivity, but not the hypothermia, induced by the potent DA stimulant DP-5,6-ADTN. Interstingly, SCH23390 simultaneously failed to displace DP-5,6-ADTN from its binding sites in the rat striatum--used as a direct in vivo biochemical index of DA (D-2) receptor interaction. The spontaneous locomotion in non-pretreated rats was likewise inhibited by SCH23390. The locomotor-suppressive action, but not the DP-5,6-ADTN-displacing capacity of the D-2 blocker haloperidol was significantly enhanced by SCH23390, suggesting that motility can be suppressed by either enhanced D-1 or D-2 (postsynaptic) receptor blockade, but also that the D-1 and D-2 sites involved may be physically distinct. SCH23390 only slightly altered in vivo neurochemical of DA synthesis, release and nerve-impulse flow, indicating that, while similar in suppressing dopaminergic behaviour, the D-1 antagonist is less effective than traditional neuroleptics as an activator of DA neuronal feedback mechanisms. The weak increases of DA synthesis and release nonetheless obtained were equal in magnitude (30-40%) in the limbic vs. striatal brain areas; also in this respect, SCH23390 thus differs from classical neuroleptics, which generally display more marked effects in the striatum than in limbic tissue. No major changes in the in vivo indices of NA synthesis and utilization (or in 5-HT synthesis) were found after SCH23390 administration, by and large supporting the DA receptor specificity of the compound. In summary, the studies demonstrated that SCH23390 can offset and accentuate, respectively, behavioural consequences of D-2 receptor stimulation and blockade. Importantly, at the same time no direct interaction at the level of D-2 DA receptor sites in the striatum was detected. Only slight, D-2 antagonist-like, changes in neurochemical indices of dopaminergic activity were observed after D-1 receptor blockade by means of SCH23390. With regard to DA agonist hypothermia, SCH23390 was without effect per se, but (at a high dose) attenuated the action of the D-2 antagonist haloperidol. The observations may indicate that the complex interactions between central D-1 and D-2 receptor-controlled mechanisms that influence behaviour, neurochemistry, and possibly autonomic nervous expression, are not identical.
Hjorth
S
S
Department of Pharmacology, University of Göteborg, Sweden.
Carlsson
A
A
D000818:Animals; D001552:Benzazepines / Q000378:metabolism / Q000494:pharmacology*; D001833:Body Temperature Regulation / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D001552:Benzazepines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013764:Tetrahydronaphthalenes; C015842:2-(N,N-dipropyl)amino-5,6-dihydroxytetralin; D006220:Haloperidol; D004298:Dopamine