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mise à jour du
29 mars 2009
J Pharmacol Exp Ther
2009;329(1):210-217
Pro-erectile Effects of Dopamine D2-like Agonists
are Mediated by the D3 Receptor in Rats and Mice
Collins G, Truccone A, Haji-Abdi F, Newman AH et al.

Chat-logomini

Abstract: Dopamine D2-like agonists induce penile erection (PE) and yawning in a variety of species, effects that have recently been suggested to be specifically mediated by the D4 and D3 receptors, respectively. The current studies were aimed at characterizing a series of D2, D3, and D4 agonists with respect to their capacity to induce PE and yawning in the rat, as well as the pro-erectile effects of apomorphine in wild-type and D4 receptor (R) knock-out (KO) mice.
 
All D3 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 D4 agonists. Likewise, D2, D3, and D4 antagonists were assessed for their capacity to alter apomorphine- and pramipexole-induced PE and yawning. The D3 antagonist, PG01037, inhibited the induction of PE and yawning, whereas the D2 antagonist, L-741,626, reversed the inhibition of PE and yawning observed at higher doses. The D4 antagonist, L-745,870, did not alter apomorphine- or pramipexole-induced PE or yawning. A role for the D3 receptor was further supported as apomorphine was equipotent at inducing PE in wild-type and D4R KO mice, effects that were inhibited by the D3 antagonist, PG01037, in both wild-type and D4R KO mice.
 
Together, these studies provide strong support that D2-like agonist-induced PE and yawning are differentially mediated by the D3 (induction) and D2 receptors (inhibition). These studies fail to support a role for the D4 receptor in the regulation of PE or yawning by D2-like agonists.
 
 
Introduction: The involvement of dopamine in the regulation of penile erection (PE) has been a longstudied phenomenon (Hyyppa et al., 1970). Systemic administration of the non-selective dopamine agonist, apomorphine, is known to induce PE and yawning in a variety of species including rats (Benassi-Benelli et al., 1979), mice (Rampin et al., 2003), monkeys (Gisolfi et al., 1980), and man (Lal et al., 1987), suggesting that the receptor regulation of these effects may be similar across species. Several D3-preferring agonists, including 7-OH-DPAT, pramipexole, and quinpirole have been shown to induce PE over low doses with inhibition of PE occurring at higher doses (Melis et al., 1987; Ferrari et al., 1993; Ferrari and Giuliani, 1995), as has previously been demonstrated for yawning (e.g., Collins et al., 2005; Collins et al., 2007).
 
D2-like agonist-induced PE and yawning are thought to be centrally mediated as they are inhibited by relatively nonselective, centrally active, D2-like antagonists such as haloperidol, sulpiride, and clozapine, but not the peripheral D2-like antagonist domperidone (Benassi-Benelli et al., 1979; Gower et al., 1984; Doherty and Wisler, 1994; Hsieh et al., 2004). Moreover, a significant body of literature supports a common role for the paraventricular nucleus (PVN) in the induction of PE and yawning by both physiologic and pharmacologic means (e.g., Argiolas and Melis, 1998; Melis and Argiolas, 1999; Melis and Argiolas, 2003; Argiolas and Melis, 2005), however, the specific receptor(s) mediating the pro-erectile effects of D2-like agonists are yet to be elucidated. Recently, a specific role for the D4 receptor in the induction of PE by D2-like agonists has been suggested. Dose-dependent increases in the percent incidence of PE were reported following systemic administration of D4-selective agonists (Hsieh et al., 2004).
 
Similar dose-dependent inductions of PE following systemic (Brioni et al., 2004; Enguehard-Gueiffier et al., 2006; Melis et al., 2006) or intra-PVN (Melis et al., 2005; Melis et al., 2006) administration of a variety of D4-selective agonists (e.g., ABT-724, CP226269, PD-168,077 and PIP3EA), with the D4-selective antagonist, L745,870, reported to block PD-168,077- and PIP3EA-induced PE (Melis et al., 2005; Enguehard- Gueiffier et al., 2006; Melis et al., 2006). Although these findings support a role for the D4 receptor in the mediation of PE, it should be noted that D4-selective agonists have generally been reported to induce fewer erections compared to less selective D2-like agonists such as apomorphine, and L-745,870 has been shown to be ineffective at altering the induction of PE by apomorphine (Melis et al., 2006), suggesting that other receptor(s) are also involved in the mediation of D2-like agonist-induced PE.
 
Interestingly, a variety of D3-preferring agonists (e.g., (+)-3-PPP, 7-OH-DPAT, pramipexole, quinelorane, and quinpirole) have also been reported to increase PE (Melis et al., 1987; Ferrari et al., 1993; Doherty and Wisler, 1994; Ferrari and Giuliani, 1995) suggesting that D3 receptors may be involved in the induction of PE by D2-like agonists. The current studies were aimed at characterizing the roles of the D2, D3, and D4 receptors in the regulation of D2-like agonist-induced PE. Thus, in vitro binding affinities for a series of D2-like agonists and antagonists with varying degrees of selectivity for the D2, D3, and D4 receptors were first determined to compare receptor selectivity. Agonists were then assessed for their capacity to induce PE and yawning, and antagonists were assessed for their capacity to alter the induction of PE and yawning by apomorphine or pramipexole in rats. Similarly, the pro-erectile effects of apomorphine were evaluated in D4R WT and KO mice alone, and in combination with the D3 antagonist, PG01037. Convergent evidence from the characterization of the pro-erectile effects of D2-like agonists, as well as the agonist-antagonist interactions in rats and D4R WT and KO mice, supports the notion that the induction of PE and yawning by D2-like agonists used herein are similarly mediated by the D3 receptor, whereas the inhibition of PE and yawning observed at higher doses results from a concomitant activation of the D2 receptor.
 
Discussion: These studies were aimed at characterizing the receptors involved in the regulation of the pro-erectile effects of D2-like agonists in rats and mice. Convergent evidence from the pharmacologic evaluation of the effects of a series of D2-like agonists with varying degrees of selectivity for the D2, D3, and D4 receptors alone, and in combination with D2-, D3-, and D4-selective antagonists suggest that the induction of PE is mediated by an activation of the D3 receptor, whereas the inhibition of PE observed at higher doses results from the concomitant activation of the D2 receptor, as has previously been described for D2-like agonist induced yawning (Collins et al., 2005; Collins et al., 2007).
 
These studies failed to support a role for the D4 receptor in the mediation of D2-like agonist-induced PE as D4-selective agonists failed to induce PE, and D4-selective antagonists failed to inhibit PE in rats, whereas apomorphine was equally effective at inducing PE in WT and D4R KO mice. In agreement with previous reports, apomorphine, pramipexole, and quinpirole induced PE and yawning with inverted U-shaped dose-response curves, and 75 to 87.5% of rats displaying at least one PE at the peak dose, however, these studies are the first to report a similar pro-erectile effect for the D3-preferring agonist, PD-128,907. The results of these studies suggest that the capacity of these agonists to induce PE is related to their activity at the D3, but not D4 receptor as increases in yawning and PE were observed over a similar range of low doses even though large differences exist between their in vitro selectivities for the D3 compared to D4 receptor (e.g., apomorphine D4/D3 0.05 and PD-128,907 D4/D3 1280; Table 1). In agreement with this notion, but contrary to previous findings (Brioni et al., 2004; Melis et al., 2005; Enguehard-Gueiffier et al., 2006), all of the highly selective D4 agonists failed to induce PE. It should be noted however, that the maximal PE responses for apomorphine, quinpirole, and pramipexole were lower than some previous reports (e.g., Melis et al., 2006), suggesting procedural differences may have affected the PE response.
 
Nevertheless, the percent incidence of PE for apomorphine and the D3-preferring agonists were similar to previous reports (e.g., Hsieh et al., 2004), suggesting that any procedural differences only affected the maximal number of PEs observed, not the absolute capacity of the agonists to induce PE. The effects of D2-, D3-, and D4-selective antagonists on apomorphine- and pramipexole-induced PE and yawning further support specific roles for the D3 and D2 receptors in the mediation of D2-like agonist-induced PE. When given at behaviorally active doses (Collins et al., 2005; Enguehard-Gueiffier et al., 2006; Collins et al., 2007), the D3-selective antagonist, PG01037, and D2-selective antagonist, L-741,626, differentially affected apomorphine- and pramipexole-induced PE and yawning, whereas the D4-selective antagonist, L-745,870, did not alter the induction or inhibition of PE or yawning. Similar to the effects of the D3 and D2 antagonists on yawning, PG01037 produced a selective rightward and/or downward shift of the ascending limb, whereas L- 741,626 produced a selective rightward shift of the descending limb of the PE doseresponse curves for apomorphine and pramipexole with respect to both the absolute number, and percent incidence of PE.
 
Together with previous reports describing specific roles for the D3 and D2 receptors in the regulation of D2-like agonist-induced yawning (Collins et al., 2005; Collins et al., 2007), the differential and selective effects of the D3 and D2 antagonists on PE, combined with the fact that both apomorphine and a variety of D3-preferring agonists were equipotent at inducing PE and yawning suggest that the induction of PE and yawning by D2-like agonists is mediated by the D3 receptor, whereas the inhibition of PE and yawning observed at higher doses results from a concomitant activation of the D2 receptor. It should be noted, however, that unlike pramipexole apomorphine also has activity at D1-like receptors which may also influence the PE response, although the precise role of D1 receptors in the modulation of PE is currently unclear (Melis et al., 1987; Zarrindast and Jamshidzadeh, 1992; D'Aquila et al., 2003; Hsieh et al., 2004), and may involve peripheral rather than central D1 receptors (El-Din et al., 2007). A role for the D3 receptor in the induction of PE and yawning is further supported by the dose-response analysis of a series of D2-like antagonists on pramipexole-induced PE and yawning.
 
Dose-dependent inhibition of pramipexole-induced PE was observed following pretreatment with D3-selecitve (PG01037 and SB-277011A), non-selective D2/D3 (raclopride), non-selective D2-like (haloperidol), and D2-selective (L-741,626) antagonists, an effect that was correlated with their capacity to inhibit yawning, but not observed with the D4-selective antagonists (L-745,870 and Ro 61-6270). Furthermore, all of the D2-like antagonists inhibited PE and yawning with similar potencies regardless of the fact that large differences exist with respect to their in vitro selectivity for D3 compared to D4 receptors (e.g., PG01037 D4/D3 1.3 x 1004, raclopride D4/D3 64, and haloperidol D4/D3 0.1; Table 1), whereas antagonists highly selective for D4 compared to D3 receptors (e.g., L-745,870 D4/D3 1.7 x 10-04 and Ro 61-6270 D4/D3 9.1 x 10-05; Table 1) failed to alter pramipexole-induced PE or yawning.
 
Although Ro 61-6270 has not been extensively characterized (Clifford and Waddington, 2000), L-745,870 has been shown to possess favorable pharmacokinetics (0.3 mg/kg; p.o. is thought to be sufficient to occupy ~90% of D4 receptors; Patel et al., 1997), and has been shown to inhibit PD-168,077- and PIP3EA-induced PE at a dose of 1.0 mg/kg (Enguehard- Gueiffier et al., 2006; Melis et al., 2006), suggesting that the doses used in the current studies were sufficient to block D4 receptors. Together with previous reports that L- 745,870 was unable to alter apomorphine-induced PE (Melis et al., 2006), the current studies suggest that the pro-erectile effects of D2-like agonists (e.g., apomorphine and pramipexole) are mediated by activation of the D3, but not D4 receptor. Despite the distinct and differential effects of PG01037 and L-741,626 observed in the current studies, the fact that relatively large doses of the D3-selective antagonists (PG01037 and SB-277011A) were required to inhibit pramipexole-induced yawning and PE, whereas similar effects were observed with relatively low doses of non-selective (raclopride and haloperidol) and selective (L-741,626) D2 antagonists, effects that may suggest that the inhibition of PE is mediated by antagonist activity at receptor(s) other than the D3 receptor.
 
These are not, however, the first studies to suggest a disconnect between the in vitro and in vivo potencies of the D3-antagonists, PG01037 and SB- 277011A. In fact, a number of previous studies have reported similar in vivo potencies when these antagonists have been evaluated in a variety of operant procedures (3.2- 24.0 mg/kg; Andreoli et al., 2003; Xi et al., 2004; Gilbert et al., 2005; Cervo et al., 2007). Moreover, previous studies aimed at characterizing the in vivo selectivity of D2-like agonists and antagonists, suggest that PG01037 and SB-277011A are devoid of significant D2, cholinergic, and serotonergic antagonist activities at doses up to 56.0 mg/kg, whereas L-741,626 displays a much more limited in vivo D2-selectivity with significant D3 antagonist activity observed at doses as low as 3.2 mg/kg (Collins et al., 2005; Collins et al., 2007). Perhaps the strongest evidence in support of a specific role for the D3 receptor in the induction of PE by D2-like agonists was provided by the evaluation of apomorphineinduced PE in the WT and D4R KO mice.
 
Not only was apomorphine equally effective at inducing PE in the WT and D4R KO mice, but the pro-erectile effect of apomorphine was also dose-dependently inhibited by the D3-selective antagonist, PG01037, in both the WT and D4R KO genotypes. Although species differences precluded comparisons of the effects of agonists and antagonists on yawning and PE to be made in mice as D2-like agonists do not induce yawning in mice (Li et al., submitted), when taken together with the pharmacologic data collected in rats, these data provide strong support for a role for the D3, but not D4 receptor in the induction of PE by D2-like agonists in rodents. To summarize, a series of D2-like agonists and antagonists with varying degrees of selectivity for the D2, D3, or D4 receptors were assessed for their capacity to modulate PE and yawning in rats. Similar to the effects of apomorphine, all D3-preferring agonists induced dose-dependent increases in PE and yawning over a similar range of low doses, with the inhibition of PE and yawning occurring at higher doses; D4-selective agonists failed to induce PE or yawning.
 
The D3-selective antagonist, PG01037, and D2- selective antagonist, L-741,626, had similar effects on PE and yawning, with PG01037 selectively shifting the ascending limbs, and L-741,626 selectively shifting the descending limbs of the dose-response curves for apomorphine- and pramipexoleinduced PE and yawning. Additionally, dose-dependent inhibition of pramipexoleinduced PE was observed with a series of D2-like antagonists with a wide range of selectivities for the D3 and D2 receptors, an effect that corresponded to their capacity to inhibit pramipexole-induced yawning, but was not observed with D4-selective antagonists. Furthermore, the pharmacologic evaluation of the pro-erectile effects of D2- like agonists was validated in D4R KO mice. Not only was apomorphine was equally effective at inducing PE in both WT, and D4R KO mice, but the induction of PE by apomorphine was dose-dependently inhibited by the D3-selective antagonist, PG01037 in both genotypes. In conclusion, although inferences with regard to the receptors mediating the pro-erectile effects of D4-selective agonists could not be made, these studies provide convergent evidence in support of a role for the D3 receptor in the induction of PE by D2-like agonists, with the inhibition of PE observed at higher doses resulting from the concomitant activation of the D2 receptor.
 
-Collins C, Truccone A et al. Pro-erectile Effects of Dopamine D2-like Agonists are Mediated by the D3 Receptor in Rats and Mice. J J Pharmacol Exp Ther 2009
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Li SM, Collins GT et al. Yawning and locomotor behavior induced by dopamine receptor agonists in mice and rat. Behav Pharmacol. 2010; 21(3): 171&endash;181.
 
Distribution of dopamine D3 receptor expressing neurons in the human forebrain:
comparison with D2 receptor expressing neurons
Gurevich EV, Joyce JN.
Neuropsychopharmacology 1999;20(1):60-80

Based on studies in the rat, Sokoloff et al. have made the valuable suggestion that the D3 receptor is a particularly important target for antipsychotics in the mesolimbic DA system. These study in the human demonstrates that the distribution of D3 receptors and D3 mRNA-bearing neurons is consistent with relative segregation of the D3 subtype to the limbic striatum as well as it primary and secondary targets and many sources of its afferents.