INTERACTIONS BETWEEN D1 AND D2 DOPAMINE-RECEPTOR FAMILY AGONISTS AND ANTAGONISTS - THE EFFECTS OF CHRONIC EXPOSURE ON BEHAVIOR AND RECEPTOR-BINDING IN RATS AND THEIR CLINICAL IMPLICATIONS

Functional interactions between dopamine receptor subtypes may affect behavioral and biochemical responses which serve as models for neurops ychiatric illnesses and the clinical effects of drug therapy. We evalu ated the effects of chronic exposure to the selective D1 receptor anta gonist SCH 23390, and the selective D2 receptor antagonist metoclopram ide, on spontaneous and drug-induced behavior and receptor density in rats, and then determined how these effects would be modified by concu rrent administration of antagonists or agonists [SKF 38393, LY 171555 (quinpirole)] selective for the complementary receptor subtype. Admini stered alone, both the D1 and D2 antagonists had acute cataleptic effe cts to which animals became tolerant following chronic treatment, but the selective antagonists had opposing effects on spontaneous locomoto r activity, Both antagonists produced equivalent, supersensitive behav ioral responses to apomorphine, and resulted in an increase in D2 rece ptor density. Coadministration of the D1 and D2 antagonists had a syne rgistic effect on catalepsy, attenuated the effects on spontaneous loc omotor activity observed with either drug alone, and had an additive e ffect on both apomorphine-induced stereotypic behavior and D2 receptor proliferation. On the other hand, when either selective antagonist wa s combined with the agonist selective for the complementary receptor s ubtype, both D2 receptor proliferation and behavioral supersensitivity were completely blocked. Combined antagonist-agonist treatments had o pposing effects on the development of tolerance to antagonist-induced catalepsy. D2 but not D1 - receptor densities were correlated with ani mals' behavioral responses to apomorphine. There results support and e xtend the notion that complex functional interactions between D1 and D 2 receptor families occur within the central nervous system, and sugge st that novel effects might be derived from combined administration of receptor selective agonists and antagonists.