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Dopamine agonist-induced yawning in rats: a dopamine D3 receptor mediated behavior
Collins G et al
 
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mise à jour du
28 août 2003
Europ J Pharmacol
1994; 261; 149-155
lexique
Penile erection and yawning induced by 5-HT1c receptor agonists in male rats: relationship with dopaminergic and oxytocinergic transmission  
Roberto Stancampiano, Maria Rosaria Melis, Antonio Argiolas
Department of Neuroscience, University of Cagliari, Cagliari, Italy
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren

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Introduction : penile erection and yawning are two distinct behavioural patterns that often occur concomitantly under certain physiological and experimental conditions. Among substances that induce both penile erection and yawning, dopamine receptor agonists (e.g. apomorphine), oxytocin and adrenocorticotropin (ACTH) are certainly the most widely known.
 
While several lines of experimental evidence suggest that a dopamine-oxytocin link plays a key role in the expression of these behavioural responses, ACTH and related peptides seem to act through a mechanism(s) not involving central dopamine or oxytocin:
  1. both penile erection and yawning are induced by apomorphine and by oxytocin injected in the paraventricular nucleus of the hypothalamus;
  2. apomorphine and oxytocin responses are prevented either by oxytocin receptor antagonists or by electrolytic lesions of the paraventricular nucleus that deplete oxytocin in the central nervous system;
  3. the ACTH effect is not prevented either by oxytocin receptor antagonists or by electrolytic lesions of the paraventricular nucleus.
Recent experimental evidence has shown that penile erection and yawning can also be induced in male rats by drugs that modify serotonin (5-hydroxytryptamine, 5-HT) transmission, in particular, 5-HT receptor agonists that act on the 5-HT1c receptor subtype. It has also been shown that the effect of these drugs on penile erection is often paralleled by increased oxytocin release in plasma. This latter effect seems more related to the stimulation of 5-HT1a and/or 5-HT2 receptors although a role of 5-HT1c receptors cannot be ruled out. In agreement with this hypothesis, the paraventricular nucleus receives a dense 5-HT innervation originating from the raphe nuclei of the medulla oblongata. The above results led to the suggestion that penile erection induced by these drugs is mediated by an increased oxytocinergic transmission.
 
In order to test this hypothesis, we studied: (1) the effect of dopamine and oxytocin receptor antagonists on 5-HT1c receptor agonist-induced penile erection and yawning; and (2) the effect of 5-HT receptor antagonists on apomorphine- and oxytocin-induced penile erection and yawning. [...]
 
Discussion : the present results confirm and extend previous findings showing that m-CPP and TMFPP, but not 8-OH-DPAT, induce penile erection and yawning. In particular, although previous reports were focussed mainly on the ability of these compounds to induce penile erection, our results showed that they are as effective in inducing yawning.
 
Indeed both drugs induced yawning according to a U inverted bell-shaped dose-response curve as found with penile erection. The prevention of m-CPP- and TFMPP-induced penile erection and yawning by mianserin and ritanserin with a potency that follows their potency for blocking 5-HT1c receptors together with the inability of 8-OH-DPAT, a selective agonist of 5-HT1a receptors, to induce these responses are in agreement with the suggested key role of the 5-HT1c receptor subtype in these behavioural responses. However, the failure of the potent oxytocin receptor antagonist, [d(CH2),Tyr(Me)2 Orn8-vasotocin, to prevent such responses does not support the hypothesis that 5-HT1c receptor agonist-induced penile erection is mediated by increased central oxytocinergic transmission.
 
This is in contrast with the ability of 5-HT receptor agonists to increase plasma oxytocin concentration (that is to activate magnocellular oxytocinergic neurons), but is favoured by at least three lines of experimental evidence. The first is that the 5-HT receptor agonist-induced increase of plasma oxytocin is mediated mainly by the stimulation of 5-HT1a and 5-HT2 receptors rather than 5-HT1c receptors located in the hypothalamic supraoptic and paraventricular nuclei. The second is that 8-OH-DPAT, despite its ability to increase plasma oxytocin concentration by stimulating 5-HT1a receptors, not only does not induce penile erection and yawning but also prevents m-CPP-induced penile erection.
 
Although the mechanisms mediating these 8-OH-DPAT responses are unknown, this suggests that increased plasma oxytocin concentrations do not always reflect an increased extrahypothalamic oxytocinergic function and that 5-HT1a and 5-HT1c receptors might have different roles in the expression of penile erection. The third piece of evidence is that m-CPP and TFMPP do not induce penile erection and yawning when injected in the paraventricular nucleus, in contrast to apomorphine and oxytocin.
 
This also suggests that ascending serotoninergic projections from raphe nuclei to the paraventricular nucleus are not involved in the expression of these m-CPP- and TFMPP-induced responses. Likewise, the failure of the blockade of dopamine receptors by haloperidol to modify m-CPPand TFMPP-induced penile erection and yawning rules out the possibility that these responses are mediated by increased central dopaminergic activity. These results are in line with the inability of spiperone to prevent m-CPP-induced penile erection in male rats, but contrast with previous findings by the same group showing that m-CPP-induced yawning was prevented by haloperidol. The reason for this discrepancy is unknown, since similar times and doses of haloperidol and m-CPP were used in both studies, although the possibility cannot be ruled out that it is related to other different experimental conditions.
 
All together, the results discussed above suggest that 5-HT1c receptor agonists induce penile erection and yawning by activating neuronal circuits different from those activated by dopamine receptor agonists and/or oxytocin. However, the above results do not rule out the possibility that 5-HT1c receptor agonists act at sites located after dopamine and oxytocin in the cascade of neuronal events mediating penile erection and yawning. The reduction of penile erection by mianserin and ritanserin is in agreement with this hypothesis at least for this behavioural response. This also raises the possibility that a neuronal dopamine-oxytocin-5-HT link is involved in the control of penile erection.
 
Interestingly, two pathways that might be candidates for such a link, one, oxytocinergic originating in the paraventricular nucleus, and another, serotoninergic originating in the nucleus paragigantocellularis of the ventral medulla (e.g. the pars alpha of the gigantocellular reticular nucleus of the ventral medulla, have been recently identified. In particular the former structure facilitates and the latter inhibits penile erection, but both send projections to the lumbar spinal cord in the region of the spinal nucleus of the bulbocavernosus. It is consistent with this possibility that
  1. electrolytic lesions of the paraventricular nucleus, that destroy all central oxytocinergic projections including those reaching the spinal cord abolish apomorphine- and oxytocin-induced penile erection
  2. electrolytic lesions of the nucleus paragigantocellularis facilitate penile reflexes and copulatory behaviour in male rats
  3. drugs that enhance 5-HT transmission, especially 5-HT2 receptor agonists, impair these sexual responses
Since 5-HT1c receptor agonists injected in the paraventricular nucleus do not induce penile erection whereas mianserin and ritanserin reduce it when it is induced by apomorphine or oxytocin, it is tempting to speculate that the paraventricular nucleus-spinal oxytocinergic pathway induces the sexual response by favouring the stimulation of 5-HT1c receptors in the spinal nucleus of the bulbocavernosus. These receptors might be located post-synaptically because penile erection is also induced by 5-HT releasers and uptake blocker.
 
Alternatively the stimulation of these spinal 5-HT1c receptors might be achieved by a paraventricular nucleus-medullary oxytocinergic pathway controlling the spinal serotoninergic pathway in the ventral medulla. Accordingly, several nuclei containing oxytocinergic innervation originating in the paraventricular nucleus, i.e. the nucleus ambiguus, the lateral reticular nucleus and the olivas, are located close to the nucleus paragigantocellularis.
 
Despite the possibility discussed above that a dopamine-oxytocin-5-HT link is involved in the control of penile erection, the failure of 5-HT1c receptor antagonists to prevent apomorphine- or oxytocin-induced yawning suggests that 5-HT1c receptor agonists induce this response by means of a mechanism not involving dopamine or oxytocin, thereby excluding the involvement of a dopamine-oxytocin-5-HT link in the expression of yawning. The finding also provides additional evidence that penile erection and yawning, that often appear concomitantly in different experimental and pharmacological conditions, can be differentially regulated.
 
The best known evidence for different regulation of apomorphine- and oxytocin-induced penile erection and yawning is perhaps provided by the effects of sex steroids on these responses in hypophysectomized and castrated rats:
  1. hypophysectomy and castration abolish both responses
  2. testosterone restores penile erection but not yawning in hypophysectomized and castrated male rats
  3. estradiol benzoate restores yawning but not penile erection in castrated male rats,
  4. 5a-dihydrotestosterone restores apomorphine-induced yawning but not penile erection in castrated male rats. However, this latter finding has been recently questioned and is in contrast with the above mentioned inability of testosterone to restore yawning in castrated male rats.
In conclusion, the presentt results show that penile erection and yawning induced by 5-HT1c receptor agonists is not mediated by increased central dopaminergic or oxytocinergic transmission, and suggest the existence of a dopamine-oxytocin-5-HT link involved in the control of penile erection and not necessarily of yawning in male rats.

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