Discriminative stimulus properties of the putative dopamine D 3 receptor agonist, (+)-PD 128907: role of presynaptic dopamine D 2 autoreceptors

Abstract

The putative D 3 receptor agonist, (+)-PD 128907, is widely used to study the functional relevance of D 3 receptors in vivo. Given that non-selective D 2/3/4 receptor agonists serve as effective discriminative stimuli in rats we have trained animals to discriminate (+)-PD 128907 (30 μg kg −1, s.c.) from saline and examined the pharmacological specificity of the response. Consistent with a D 3 receptor mediated response, the non-selective D 2/3 receptor agonist apomorphine and the D 3 preferring agonists 7-OH-DPAT and (−) quinpirole generalised to the cue whilst the D 2/3 receptor antagonists haloperidol, raclopride, spiperone and (+)-butaclamol antagonised drug lever responding. In contrast, the D 1 selective agonist (±)-SKF 81297 and D 1/5 selective antagonist, R-(+)-SCH 23390 had no effect. Results also suggest that presynaptic dopamine receptors are involved. Thus the dopamine depleting agent α-methyl- p-tyrosine potentiated the effects of a submaximal dose of (+)-PD 128907 whereas amphetamine failed to generalise per se and blocked (+)-PD 128907 lever selection. However, studies using subtype selective antagonists argue against a role for the D 3 receptor. Thus the 10-fold selective D 2 receptor antagonist L-741,626 blocked the (+)-PD 128907 discriminative stimulus whereas L-745,829 and GR 103,691, antagonists >40 and >100-fold selective for D 3 receptors, failed to modify the response. These results suggest that presynaptic D 2 receptors mediate the discriminative stimulus properties of (+)-PD 128907 and highlight the lack of selectivity of (+)-PD 128907 for D 3 receptors in vivo.