Discriminative stimulus properties of the dopamine D 3 receptor agonists, PD128,907 and 7-OH-DPAT: a comparative characterization with novel ligands at D 3 versus D 2 receptors

Abstract

Rats were trained to recognize a discriminative stimulus (DS) elicited by the preferential dopamine D 3 receptor agonists, PD128,907 (0.16 mg/kg, i.p.) and 7-OH-DPAT (0.16 mg/kg, i.p.). PD128,907 and 7-OH-DPAT showed “full” (≥80%) and mutual generalization. Chemically-diverse, preferential D 3 versus D 2 agonists, quinelorane, CGS15855A, pramipexole, ropinirole and piribedil, generalized to PD128,907 (and 7-OH-DPAT) in this order of potency, which correlated more strongly with affinity/activity at cloned human (h)D 3 ( r=0.68/0.81, n=7) than hD 2 (0.27/0.64, n=7) receptors. Further, generalization potency strongly correlated with potency for suppression of response rates (0.86), induction of hypothermia (0.92), reduction of striatal dopamine turnover (0.92) and diminution of immobility in a forced-swim procedure (0.97). Nafadotride, UH232 and AJ76, which show a mild preference for D 3 versus D 2 sites, blocked the PD128,907 DS, and the modestly-selective D 3 antagonist, U99194A, was partially effective. Both nafadotride and U99194A blocked the 7-OH-DPAT DS. However, antagonist potency ( n=4) versus PD128,907 correlated better with affinity at D 2 (0.89) versus D 3 (0.27) sites. Further, whereas the preferential D 2 versus D 3 antagonist, L741,626, antagonized the PD128,907 DS, the selective D 3 antagonists, S11566, S14297 (its eutomer) and GR218,231 were ineffective against PD128907 and 7-OH-DPAT DS. S11566 and GR218,231 likewise did not generalize to PD128,907. In conclusion, under the present conditions, D 2 receptors are principally implicated in the DS properties of PD128,907 and 7-OH-DPAT.