mise à jour du
28 août 2003
Psychopharmacology (Berl)
1992; 108; 1-2; 47-50
5-HT1a receptor agonists prevent in rats the yawning and penile erections induced by direct dopamine agonists
Simon P, B Guardiola et al
Faculté médecine et pharmacie de Rouen, France


(+) S-20499, an amino chromane derivative (8[-4[N-(5methoxychromane-3yl)N-propylaminobutylj azaspiro [4-5] décane-7,9 dione), is a full agonist of 5-H1a receptor for which it displays a high affinity, in the 10(-10) M range. Because most 5-HT1a agonists are also active at the D2 dopamine receptor we have investagated the possible activity of (+) S-20499 on the dopaminergic system. For this purpose binding studies were carried out. Since the compound had significant affinity at both receptors, the intrinsic activity (agonist or antagonist?) was determined in mice by testing the effect of the drug on body temperature; since DA agonists are hypothermie in mice. The observed hypothermia. combined with its antagonism by the D2 antagonist haloperidol, allowed the conclusion that the drug displayed, like 8-OH-DPA, a D2 DA agonist activity.
It was expected therefore that its administration at increasing doses would induce yawning and penile erections but unexpectedly, these were not observed. To explain this discrepancy, the possible influence of the 5-HT1a agonist property on the expression of these two behaviors which are modulated by the stimulation of D2 DA receptors was examined in this present paper. [...]

Discussion : Beside its high affinity for the 5-HT1a receptor, ( + ) S-20499 displays a notable affinity for dopamine D2 receptors. (+) S-20499 induces in mice a hypothermic effect which was reversed by the D2 dopamine receptor antagonist haloperidol, but not by the 5-HT,1a antagonist tertatolol. This indicates an agonist property of (+) S-20499 for the D2 dopamine receptors.

Therefore low doses of (+) S-20499 would be expected to induce yawns and penile erections in rats, whereas high doses would have suppressed these behaviors, since such a biphasic effect is characteristic of direct D2 dopamine receptors agonists (Protais et al. 1983). Yawns and penile erections are claimed to result from the stimulation of DA autoreceptors, with a consequent decrease in dopaminergic transmission. At high doses of DA agonists these effects disappear simultaneously as the restoration of an apparent dopaminergic tone because of the post-synaptic D2 receptors stimulation. Neither yawning nor penile erections were in fact observed after administration of (+) S-20499, over a wide range of doses, in spite of its D2 dopamine agonist activity. Since the drug displays a 100 fold higher affinity for 5-HT1a receptors than for D2 dopamine receptors, it seemed possible that this property might account for this unexpected lack of yawning and penile erections.

This hypothesis was apparently verified since (+) S-20499, together with two other reference 5-HT1a receptor agonists 8-OH-DPAT and buspirone dose dependently inhibited apomorphine-induced yawning and penile erections. The prevention by stimulation of 5-HT1a receptors of yawning and penile erections induced by DA agonists is also supported by the observation that blocking 5-HTIa receptors by tertatolol restored the typical effect of D2 agonists to ( + )S-20499. Although the three tested drugs (buspirone, 8-OH-DPAT and (+) S-20499) are 5-HT, agonists, one may speculate whether any other common property might account for the antagonism of the apomorphine- induced penile erections and yawns. For instance, an antimuscarinic property could lead to such an effect.

Indeed, concerning yawning, a cholinergic link has been shown. This explanation cannot apply, at least for ( + ) S-20499, since at 2 mg/kg dose (fully effective versus apomorphine effects) the drug did not reduce the hypothermic, akinetic or tremorogenic effects of oxotremorine (0.5 mg/kg) in mice (not shown).

On the other hand, it should be remembered that buspirone, in addition to its 5-HT1a agonist activity, also displays a D2 dopamine antagonist activity. Concerning penile erections, for which such a cholinergic link has not been shown, serotonergic transmissions seem to have a complex modulatory effect, since Berendsen et al. (1990) have reported that 5-HT1c agonists induce penile erections.

In conclusion, it appears that in addition to its potent 5-HT1a agonist property, (+) S-20499 displays a significant D2 agonist property, and that the stimulation of 5-HT1a receptors oppose the action of D2 dopamine receptors with regard to yawning and penile erections. A recent microdialysis study by Benloucif and Galloway (1991) indicated that 8-OH-DPAT perfused in rat striatum increased DA release. This might indicate a mechanism of action of 5-HT1a agonists, which could oppose to the inhibition of DA release elicited by low doses of D2 agonists. However, this interaction seen at the striatal level, may not occur in the brain area(s) where DA transmission modulates yawning and penile erections. Finally, one may wonder whether such interactions might extend to various other DA dependent behaviors. The only partial response presently known concerns the stereotyped climbing elicited by apomorphine on which (+) S-20499 was ineffective (unpublished).

Involvement of 5-HT1c-receptors in drug-induced penile erections in rats H Berendsen