Activation of dopamine D ₄ receptors by ABT-724 induces penile erection in rats

Abstract

Apomorphine, a nonselective dopamine receptor agonist, facilitates penile erection and is effective in patients suffering from erectile dysfunction. The specific dopamine receptor subtype(s) responsible for its erectogenic effect is not known. Here we report that the dopamine D4 receptor plays a role in the regulation of penile function. ABT-724 is a selective dopamine D 4 receptor agonist that activates human dopamine D 4 receptors with an EC50 of 12.4 nM and 61% efficacy, with no effect on dopamine D 1, D2, D3, or D5 receptors. ABT-724 dose-dependently facilitates penile erection when given s.c. to conscious rats, an effect that is blocked by haloperidol and clozapine but not by domperidone. A proerectile effect is observed after intracerebroventricular but not intrathecal administration, suggesting a supraspinal site of action. s.c. injections of ABT-724 increase intracavernosal pressure in awake freely moving rats. In the presence of sildenafil, a potentiation of the proerectile effect of ABT-724 is observed in conscious rats. The ability of ABT-724 to facilitate penile erection together with the favorable side-effect profile indicates that ABT-724 could be useful for the treatment of erectile dysfunction. P enile erection is the result of a complex series of integrated neuronal and vascular events that leads to accumulation of blood in the penis to achieve rigidity. The coordination of several neural events is required to release endogenous mediators (i.e., nitric oxide) at the level of the penile smooth muscle to induce relaxation, whereas a disruption of this series of events can lead to erectile dysfunction (ED) (1, 2). Traditionally, drugs used for the treatment of ED have had a peripheral site of action, including phosphodiesterase (PDE)-5 inhibitors like sildenafil, but the recent demonstration that apomorphine can facilitate penile erection in ED patients has introduced a new approach to treatment, because apomorphine acts on central dopaminergic systems (3,4). Dopamine is the main catecholamine in the CNS and is involved in a variety of physiological functions, including sexual behavior, cognition, motor coordination, cardiovascular control, reward, hormonal regulation; abnormalities in dopaminergic neurotransmission have been implicated in Parkinson's disease, schizophrenia, attention-deficit disorder, depression, and drug abuse, among other disorders (5, 6). The regional distribution of the receptor subtypes, the recent generation of knock-out animals, and the availability of a large number of dopaminergic agents have aided researchers in clarifying the biological role of the dopamine receptors. Dopamine receptors in mammalian tissues have been classified as D 1 -like (D 1 and D 5 ) and D 2 -like (D 2 , D 3 , and D 4 ) based on their binding properties and their ability to activate or inhibit forskolin-induced adenylate cyclase activity, a classification supported by the cloning of the different subtypes during the last decade (7,8).Within the D 2 -like family, the D 2 receptor is highly expressed...

Yawning and hypothermia in rats: effects of dopamine D3 and D2 agonists and antagonists

“…McCall et al (2005) reported a 200% increase in striatal acetylcholine release in rats at doses of sumanirole roughly equivalent to those which induced yawning. The two D4-preferring agonists, given at behaviorally active doses (Brioni et al 2004;Enguehard-Gueiffier et al 2006), did not produce either yawning or hypothermia suggesting that at these doses, they are devoid of significant D2 and D3 receptor agonist activity.…”

“…As shown in Figure 1, sumanirole induced significant increases in yawning, although these increases were relatively small and observed only at the highest dose, whereas significant decreases in core body temperature were observed at lower doses; sumanirole will subsequently be referred to as a D2-preferring agonist. The D4-preferring agonists, 077 (Figure 2), failed to induce significant levels of yawning or hypothermia over a wide range of behaviorally active doses (Brioni et al 2004;Enguehard-Gueiffier et al 2006) suggesting that, at these doses, they are devoid of agonist activity at the D3 and D2 receptors. D3 values, as well as the in vivo selectivity ratios for each of the agonists.…”

The scientific and clinical basis for the treatment of Parkinson disease (2009)

“…782 Interestingly, normal aging in all mammalian species is associated with reduced levels of dopamine and increasing sexual dysfunction, whereas dopamine agonists enhance sexual function in both rodents and humans. 783,784 The management of male sexual dysfunction in patients with PD involves identifying and correcting any underlying treatable causes, and introducing pharmacologic therapy aimed at improving erectile function. Previously untreated or undertreated patients with PD may find that antiparkinsonian treatment helps sexual function, possibly by alleviating bradykinesia or by restoring dopaminergic tone.…”

Effects of acute and chronic apomorphine on sex behavior and copulation-induced neural activation in the male rat

“…Adding to the complexity, apomorphine, as a non-selective dopaminergic receptor agonist, affects several types of dopaminergic receptors among them D 1 , D 2 and D 4 (Brioni and Moreland, 2006;Brioni et al, 2004;Melis et al, 2005Melis et al, , 2006Schechter and Greer, 1987), whereas chronic treatment with apomorphine may change the balance between dopamine D 1 and D 2 receptors, favoring the D 1 type (Acerbo et al, 2005).…”

“…However, the role of dopamine D 1 vs D 2 receptors is complex (Hull et al, 1992) and hard to define, because of conflicting findings (Paredes and Agmo, 2004). The possible involvement of dopamine D 4 receptors in the pro-erectile effects of apomorphine Brioni et al, 2004;Hsieh et al, 2004) may shed new light on the existing confusing situation.…”