Proerectile effects of dopamine D 2-like agonists are mediated by the D 3 receptor in rats and mice

Abstract

Dopamine D 2-like agonists induce penile erection (PE) and yawning in a variety of species, effects that have been suggested recently to be specifically mediated by the D 4 and D 3 receptors, respectively. The current studies were aimed at characterizing a series of D 2,D 3, and D 4 agonists with respect to their capacity to induce PE and yawning in the rat and the proerectile effects of apomorphine [(R)-(-)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10, 11-diol hydrochloride] in wild-type and D 4 receptor (R) knockout (KO) mice. All D 3 agonists induced dose-dependent increases in PE and yawning over a similar range of doses, whereas significant increases in PE or yawning were not observed with any of the D 4 agonists. Likewise, D 2, D 3, and D 4 antagonists were assessed for their capacity to alter apomorphine- and pramipexole (N′-propyl-4,5,6,7- tet-rahydrobenzothiazole-2,6-diamine dihydrochloride)-induced PE and yawning. The D 3 antagonist, PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazin-1- yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride], inhibited the induction of PE and yawning, whereas the D 2 antagonist, L-741,626 [3-[4-(4-chlo-rophenyl)-4-hydroxypiperidin-L-yl]methyl-1 H-indole], reversed the inhibition of PE and yawning observed at higher doses. The D 4 antagonist, L-745,870 [3-(4-[4-chlorophenyl]piperazin-1-yl)-methyl-1 H-pyrrolo[2,3-b]pyridine trihydrochloride], did not alter apomorphine- or pramipexole-induced PE or yawning. A role for the D 3 receptor was further supported because apomor-phine was equipotent at inducing PE in wild-type and D 4RKO mice, effects that were inhibited by the D 3 antagonist, PG01037, in both wild-type and D4R KO mice. Together, these studies provide strong support that D2-like agonist-induced PE and yawning aredifferentially mediated by the D 3 (induction) and D 2 (inhibition) receptors. These studies fail to support a role for the D 4 receptor in the regulation of PE or yawning by D 2-like agonists.