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3 mars 2005
1990; 101; 57-61
Involvement of 5-HT 1c-receptors in drug-induced penile erections in rats
H Berendsen, F Jenck, C Broekkamp
Department of CNS Pharmacology, Organon International, The Netherlands


Penile erections (PE) can be induced in rats by the serotonin (5-HT)-releasing compound fenfluramine, 5-HT reuptake inhibitors, the 5-HT agonist mCPP, the 5-HT agonist quipazine in 5-HT2 antagonist-pretreated rats and by 5-hydroxytryptophan (5HTP) in rats pretreated with a monoamine oxydase inhibitor and a peripheral decarboxylase inhibitor. Fenfluramine and mCPP also induce PE in non-human primates. Previously we have investigated the pharmacology of induction of penile erections and suggested that it is probably mediated by the 5-HT 1b receptor. However, recently Pazos et al. (1985) and later Heuring and Peroutka (1987) showed that, in the 5-HT1b binding test, 5-HT1b and perhaps 5-HT1c sites were also labelled. The affinity of various compounds for the 5-HT, receptor has now been described and a number of reference compounds including both mCPP and quipazine appear to bind more strongly to the 5-HT1c, receptor than to one of the other 5-HT receptor subtypes. These developments necessitate a re-evaluation of the interpretation of PE induction. In this paper the effect of a number of 5-HT agonists TFMPP, MK 212, DOl and of the 5-HT antagonists metergoline, cyproheptadine, mesulergine, mianserin and ritanserin, which all share potent 5-HT1c activity, on PE are described. The results strongly suggest that the 5-HT1c rather than the 5-HT,1b receptors are involved in the induction of PE by 5-HT compounds. [...]
Although mCPP and TFMPP have been claimed before to have some selectivity for the 5-HT1b receptor, there is now in vitro as well as in vivo evidence that these drugs also have potent 5-HT1c affinity. Both compounds induce PE. MK 212, which has very poor affinity for the 5-HT1b receptor but binds more potently to the 5-HT1c receptor, also induced PE, whereas the recently described selective 5-HT1b agonist CGS 12066 B was ineffective in this respect. Therefore it seems that the 5-HT1c rather than the 5HT1b receptors are mediating the induction of PE. This is further supported by the effects obtained with DOl which binds potently to the 5-HT2 and 5-HT1c and only weakly to the 5-HT1a and 5-HT1b receptors; DOl induces PE after blockade of the 5-HT2 receptors with spiperone or pirenperone, indicating that its 5-HT1c properties were probably responsible for its PE-inducing effect. The 5-HT antagonists metergoline, cyproheptadine, mesulergine, mianserin and ritanserin potently inhibited mCPP-induced PE. These compounds have high affinity for the 5-HT1c and 5-HT2 receptor in common. Ketanserin, which has a somewhat lower affinity for the 5-HT1c receptor, also less potently antagonized mCPP-induced PE, whereas spiperone, which hardly binds to the 5HT1c receptor, but strongly to the 5-HT1a, 5-HT2 and dopamine receptors, did not affect mCPP-induced PE up to 0.46 mg/kg. At higher doses there may be some effect, but these doses also induce catalepsy. This suggests that blockade of the 5-HT1c receptor might be the most probable explanation for the PE-inhibiting effect of the 5-HT antagonists.
An influence of 5-HT2 receptor activation or blockade on both induction and inhibition of PE cannot be excluded: DOl only induced PE after blockade of the 5-HT2 receptor. The headshakes which are thought to be the result of 5-HT2 receptor activation disappear after blocking the 5-HT2 receptor. It has been reported before that quipazine also induced more PE in 5-HT2 antagonist pretreated rats. The influence of the 5-HT2 receptor may also explain why the effect of MK 212 on PE is stronger than those of mCPP or TFMPP, whereas the latter two compounds show a higher affinity for the 5-HT, receptor than MK212. If selectivity ratios for 5-HT1c versus 5-HT2 receptors are calculated then the sequence for 5-HT, selectivity is MK 212>mCPP>TFMPP> quipazine> DOI and this is also the sequence of potency to induce PE. When the selectivity ratios for the 5-HT1c versus 5-HT2 receptors of the antagonists are calculated, then their selectivity for the 5-HT1c receptor is also closely parallel to their potency to antagonise the mCPP-induced PE. This suggests that 5-HT2 agonistic properties prevent or counteract induction of PE and that concomitant 5-HT2 antagonistic properties makes the antagonist less effective. Indeed DOl-induced PE in rats pretreated with a 5HT2 antagonist and at 2.2 mg/kg some antagonism of mCPP-induced PE was seen. Interaction studies have also been done with the 5-HT1a agonist 8-OH-DPAT and the mixed 5-HT1a/5-HT2 agonist 5MeODMT. Both compounds potently antagonise mCPP-induced PE, indicating that 5-HT1a receptor activation interferes with expression of 5-HT1c receptor activation. Flat body posture induced by these compounds could possibly influence induction of PE but this cannot explain the disappearance of PE by 8-OH-DPAT and 5MeODMT. These drugs inhibit PE already at doses at which flat body posture was not yet seen.
This functional interplay of the 5-HT1c receptor subtypes has been seen before in other experiments: mCPP and DOl prevented induction of lower lip retraction by 8-OH-DPAT and antagonised 8-OH-DPAT-induced hypoactivity and hypothermia. A similar functional interplay of the 5-HT1c receptor with the 5-HT1b receptor is less likely, since simultaneous injection of mCPP with the purported selective 5-HT1b agonist CGS 12066 B did not change the effect of mCPP.
The lack of effect of spiperone on mCPP-induced PE excludes a role for dopamine receptors. In agreement with this, it was previously found that haloperidol at doses which block yawning and penile erections induced by the dopamine receptor agonist apomorphine did not block mCPP-induced PE.
A role for the 5-HT3 receptors is not likely, since GR 38032 F, a 5-HT3 antagonist, had no effect on mCPP-induced PE. A functional interplay with 5-HT1c and 5-HT3 receptors as seen for the 5-HT1c with the 5-HT1a and 5-HT2 receptors cannot be excluded as yet, since a selective 5-HT3 agonist is not available to date. Induction of PE is not the only consequence of activation of 5-HT1c receptors, since it was found that mCPP- and TFMPP-induced hypoactivity and hypophagia are probably also 5-HT1c receptor mediated effects. Our data support the suggestion that the 5-HT1c receptors play an important role in the control of behaviour. The finding that 5-HT releasers and 5-HT uptake inhibitors induce PE further indicates a postsynaptic location of the responsible 5-HT1c receptors. A further implication of these findings is that the 5-HT1c receptors should be studied in the context of depression. The putatively 5-HT1c receptors mediated penile erections are not only induced by the 5-HT uptake inhibitors but also by mCPP the main metabolite of the antidepressant compound trazodone and 5HTP. The 5-HT1c receptor could very well be the common point of action for these antidepressants.
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