Abstract
8-[3-(4-Fluorophenoxy) propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (AMI-193) was developed as a 5-HT 2A-selective antagonist with in vivo activity suitable for behavioral studies. However, AMI-193 is a potent dopamine D 2-receptor antagonist with low nanomolar affinity. Accordingly, D 2-actions may contribute to its behavioral pharmacology. In the present study, the effects of AMI-193 on operant behavior were characterized in squirrel monkeys. In subjects trained under a fixed-interval (FI) schedule of stimulus termination, AMI-193 (0.003–0.01 mg/kg) dose-dependently decreased response rate. When administered in combination with cocaine (0.03–3.0 mg/kg) or the selective dopamine uptake inhibitor, GBR 12909 (0.03–3.0 mg/kg), the rate-decreasing effects of AMI-193 were reversed by both dopamine indirect agonists. In drug-discrimination experiments, AMI-193 (0.003 and 0.01 mg/kg) attenuated the discriminative-stimulus effects of cocaine. AMI-193 (0.003 and 0.01 mg/kg) also reduced response rate under a second-order schedule of i.v. self-administration of cocaine (0.1 mg/infusion). The profile of behavioral effects and drug interactions observed in the present study, in conjunction with the relatively high affinity of AMI-193 for dopamine D 2 receptors, suggests that its D 2-antagonist effects play a prominent role in the behavioral pharmacology of AMI-193.
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