In monkeys, D1 dopamine receptor agonists produce behavioral responses that range from agonist to antagonist-like effects. As some, but not all D1 agonists, elicit self-administration, we investigated whether the behavioral effects are reflected in their binding to the D1 dopamine receptor. D1 agonist affinity and response to a guanine nucleotide, GppNHp (100 fM), were measured in striatum of cynomolgus monkey brain (Macaca fascicularis). The affinities of most of the drugs for the D1 receptor were reduced by the guanine nucleotide GppNHp, but the magnitude of the response differed among the drugs. For dihydrexidine the loss in affinity (12-fold) was comparable to that of dopamine. For other drugs, affinity losses ranged from 1.1 - 3.5 fold. D1 agonists which sustained more than 2.5-fold losses in affinity with GppNHp, displayed agonist-like effects and maintained self-administration. Drugs which were less responsive to GppNHp, produced antagonist-like effects and were not self-administered. The extent to which D1 agonists respond to guanine nucleotides in vitro appears to predict whether a D1 dopamine receptor drug will produce agonist-like effects and maintain self-administration in vivo.
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