Role of dopamine D4 receptors in copulatory behavior: Studies with selective D4 agonists and antagonists in male rats

• Dopamine D2-like agonists facilitate and antagonists impair, respectively, male sexual behavior.
• Similar effects are also found with two selective D4 agonists and one D4 receptor antagonist.
• However, D4 agonists/antagonists behave differently from non selective D2 agonists/antagonists.
• These findings suggest a specific role of D4 receptors in the facilitation of male sexual performance.
• This makes D4 receptors a useful target for the therapy of erectile dysfunction.

Dopamine influences the anticipatory and consummatory phases of sexual behavior, by acting on receptors of the D2 family (D2, D3 and D4) and in particular of the D2 subtype, although evidence for a role of D4 receptors in erectile function and copulatory behavior is also available. In order to clarify such a role of D4 receptors, the effect of selective D4 receptor agonists and antagonists on copulatory behavior of sexually potent male rats in classic copulation tests with a receptive female, was compared with that of apomorphine and haloperidol, a classic dopamine receptor agonist and antagonist, respectively. PD-168,077 (0.05–0.2 mg/kg) and ABT-724 (0.01–0.04 mg/kg), two selective D4 receptor agonists, given subcutaneously, improved dose-dependently copulatory behavior as shown by the decrease of mount frequency and post ejaculatory interval induced by PD-168,077, and of mount frequency, ejaculation latency, post ejaculatory and inter intromission intervals induced by ABT-724, and by the increase of ejaculation frequency and copulatory efficacy induced by both drugs. Conversely, L-745,870 (1–5 mg/kg), a selective D4 receptor antagonist, given intraperitoneally, impaired dose-dependently copulatory behavior, as shown by the increase in intromission and ejaculation latencies, mount frequency, post ejaculatory interval and the decrease in ejaculation frequency and copulatory efficacy induced by this drug. L-745,870 (5 mg/kg) administered before PD-168,077 (0.2 mg/kg) or ABT-724 (0.04 mg/kg), also abolished completely the facilitatory effects of both PD-168,077 and ABT-724 on sexual behavior. These results confirm the involvement of D4 receptors in specific aspects of male rat copulatory behavior that overlap only partially with those influenced by apomorphine and haloperidol.