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Vol. 293, Issue 3, 1063-1073, June 2000

S33084, a Novel, Potent, Selective, and Competitive Antagonist at Dopamine D3-Receptors: II. Functional and Behavioral Profile Compared with GR218,231 and L741,626

Mark J. Millan, Anne Dekeyne, Jean-Michel Rivet, Thierry Dubuffet, Gilbert Lavielle and Mauricette Brocco

Departments of Psychopharmacology (M.J.M., A.D., J.-M.R., M.B.) and Chemistry F (T.D., G.L.), Institut de Recherches Servier, Centre de Recherches de Croissy, Paris, France

The selective dopamine D3-receptor antagonist S33084 dose dependently attenuated induction of hypothermia by 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT) and PD128,907. S33084 also dose dependently reduced 7-OH-DPAT-induced penile erections (PEs) but had little effect on 7-OH-DPAT-induced yawning and hypophagia, and it did not block contralateral rotation elicited by the preferential D3 agonist quinpirole in unilateral substantia nigra-lesioned rats. In models of potential antipsychotic activity, S33084 had little effect on conditioned avoidance behavior and the locomotor response to amphetamine and cocaine in rats, and weakly inhibited apomorphine-induced climbing in mice. Moreover, S33084 was inactive in models of potential extrapyramidal activity in rats: induction of catalepsy and prolactin secretion and inhibition of methylphenidate-induced gnawing. Another selective D3 antagonist, GR218,231, mimicked S33084 in inhibiting 7-OH-DPAT-induced PEs and hypothermia but neither hypophagia nor yawning behavior. Similarly, it was inactive in models of potential antipsychotic and extrapyramidal activity. In distinction to S33084 and GR218,231, the preferential D2 antagonist L741,626 inhibited all responses elicited by 7-OH-DPAT. Furthermore, it displayed robust activity in models of antipsychotic and, at slightly higher doses, extrapyramidal activity. In summary, S33084 was inactive in models of potential antipsychotic and extrapyramidal activity and failed to modify spontaneous locomotor behavior. Furthermore, it did not affect hypophagia or yawns, but attenuated hypothermia and PEs, elicited by 7-OH-DPAT. This profile was shared by GR218,231, whereas L741,626 was effective in all models. Thus, D2-receptors are principally involved in these paradigms, although D3-receptors may contribute to induction of hypothermia and PEs. S33084 should comprise a useful tool for further exploration of the pathophysiological significance of D3- versus D2-receptors.

0022-3565/00/2933-1063$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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