Agonist and antagonist activity of low efficacy D2 dopamine receptor agonists in rats discriminating d-amphetamine from saline.

The ability of the low efficacy D2 agonists preclamol and SDZ 208-911 to both antagonise, and substitute for, the d-amphetamine discriminative cue was investigated in rats trained to discriminate d-amphetamine (0.5mg/kg) from saline. All doses of preclamol (2.0-16.0mg/kg) and SDZ 208-911 (0.125-1.0mg/kg) only partially antagonised d-amphetamine discrimination. In contrast, the lower efficacy D2 agonist SDZ 208-912 completely blocked the cueing properties of d-amphetamine. Preclamol (4.0 and 16.0mg/kg) and SDZ 208-911 (1.0mg/kg) also partially substituted for d-amphetamine. In an additional study, the former drug enhanced the discriminative effects of a low dose of d-amphetamine (0.125mg/kg), whilst antagonising the effects of the training dose. Preclamol also partially antagonised the ability of the selective D2 agonist quinpirole (0.125mg/kg) to substitute for d-amphetamine. In contrast to the drug discrimination findings, preclamol completely antagonised the locomotor hyperactivity induced by acute d-amphetamine, in animals which had received the same long-term d-amphetamine treatment as the drug discrimination rats. The present findings reveal that preclamol and SDZ 208-911 can exert both agonist and antagonist activity in animals trained to discriminate d-amphetamine from saline. This partial agonist profile is probably due to the low efficacy D2 agonists interacting with a postsynaptic D2 receptor population possessing a higher response capability than those D2 receptors mediating d-amphetamine-induced locomotor hyperactivity.