Discriminative stimulus properties of the putative dopamine D3 receptor agonist, (+)-PD 128907:: role of presynaptic dopamine D2 autoreceptors

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 mu g 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 alpha-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. (C) 1998 Elsevier Science Ltd. All rights reserved.