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26 mai 2005
Eur J Pharmacol
1984; 103; 81-89
Yawning-penile erection syndrome as a model for putative dopamine autoreceptor activity
Gower AJ, Berendsen H et al.
Department of CNS pharmacology, Organon, The Nederlands


Yawning can be elicited in experimental animals by the dopamine agonists, apomorphine, norpropolnorapomorphine and lisuride. Furthermore apomorphine-induced yawning can be antagonised by doamine antagonists: haloperidol, fluphenazine, spiperone, butaclamol, pimozide and sulpiride. Thus, drug-induced yawning apparently involves doamine receptors.
Apomorphine has biphasic effects on behaviour, decreasing motor activity at low doses and causing stimulant effects such as hyperactivity and stereotypy at high doses. The stimulant effects have been attributed to a postsynaptic agonist action whereas the motor inhibition is believed to be mediated by activation of central dopamine autoreceptors. This latter hypothesis is derived from the close correlation between the doses which inhibit motor activity and the doses which reduce dopaminergic activity, including synthesis, in the brain.
Since yawning is elicited by low doses of the dopamine agonists it has been proposed that this response may be mediated via a dopamine autoreceptor. If such a suggestion is correct and the elicitation of yawning is a characteristic common to dopamine autoreceptor agonist, it would provide a behavioural model for evaluating potential new autoreceptor agonists. Such a model would be useful in view of current thinking that dopamine autoreceptor agonists may represent a novel class of antipsychotic agents. Apomorphine and n-propyl norapomorphine have been reported to alleviate schizophrenic symptoms in man.
In order to investigate drug-induced yawning as a possible model for dopamine autoreceptor agonist activity, we determined the ability of several drugs to elicit yawning. We evaluated the effect of both the established dopamine agonists, apomorphine and n-propyl norapomorphine and of some new dopamine agonists. These new drugs included TL-99, 3-PPP racemate and pergolide which share certain dopaminergic actions such as their ability to inhibit the accumulation of DOPA in gamma-butyrolactone-treated rats but which differ in other respects. For example, pergolide causes stereotyped hyperactivity whereas TL-99 and 3-PPP do not. We also tested SK&F 38393. This is a dopamine agonist with a novel profile of action in that it does not affect dopamine turnover in the brain or cause emesis or stereotypy but does stimulate dopamine-sensitive adenylate cyclase in vitro and cause contralateral rotation in rats prepared with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway. In addition we tested clonidine which, like the dopamine agonists, reduces locomotor activity but has no properties which can be ascribed to a dopamine mimetic action. At the same time we investigated the ability of all these drugs to produce penile erections since such an effect has been described in association with drug induced yawning. We report here that physostigmine, a drug without dopamine agonist activity but which induces yawning, can be differentiated from dopamine agonists by its lack of ability to cause penile erection. Finally we evaluated the effects of some antagonists against drug-induced yawning and penile erection.
In addition to apomorphine and NPA, that are already known to induce yawning, pergolide, 3-PPP, TL-99 and N,N-dipropyl A-5 ,6-DTN all caused pronounced yawning. The yawning occurred at low doses and was always accompanied by an increase in penile erections. In accordance with previous findings the responses elicited by morphine were prevented by pretreatment with haloperidol and sulpiride. Pergolide, N,N-dipropyl A -5,6-DTN and 3-PPP were also antagonised by haloperidol. It has already been shown that haloperidol and sulpiride antagonise NPA-induced yawning and NPA-induced penile erection. Due to lack of TL-99, the antagonism of the effects of his drug could not be tested. These data plus dditional evidence cited in the introduction indicate that both responses are mediated via a dopamine receptor.
There is a close resemblance between the potencies of these drugs in causing yawning and their potencies in biochemical tests considered to identify dopamine autoreceptor activity. The order of potency for the dopamine agonists in causing the YE syndrome at peak effect was NPA- N,Ndipropyl A-5,6-DTN, pergolide, apomorphine TL-99, 3-PPP. The same order of potency was obtained by Martin et al. (1982) for the ability of these drugs to inhibit the accumulation of striatal DOPA caused by gamma-butyrolactone and NSD 1015 treatment. There is a striking similarity between the optimal doses for causing yawning and the ED50s cited by Martin. Using a different index which may also indicate autoreceptor activity. Feenstra et al. (1980) reported that N,N-dipropyl A-5,6-DTN caused a 70% depletion of striatal homovanillic acid at a concentration of 0.06 µmol/kg i.p., equivalent to 15.6 µg/kg. This is close to the optimal dose (20 µg/kg) of this drug for eliciting yawning. Furthermore the potencies of the dopamine agonists in this study are dissociated from their potencies for eliciting other dopamine mediated behaviours such as emesis, stereotypy and rotation.
SK&F 38393 did not cause yawning and or slightly enhanced penile erections. This drug do not reduce dopamine turnover or inhibit dopamine release in brain slices; SK&F 38393 is thus parently devoid of autoreceptor activating action.
All these findings show that the receptor involved in the induction of yawning and penile erections has characteristics in common with the dopamine autoreceptor. One would expect that postsynaptic dopamine receptor blockers should induce the YE syndrome by reducing functional activity on the dopamine receptor. Although some potentiation by fluphenazine and haloperidol of physostigmine-induced yawning has been observed, there is no report of a true YE syndrome being elicited by a neuroleptic by itself. This could be related to additional effects of these drugs on other receptors such as noradrenergic, serotonergic or cholinergic or to a lack of specificity for subpopulations of dopamine receptors. Our results do not imply that the YE syndrome is mediated by autoreceptors per se since we have no evidence concerning the location, but rather that the receptors involved have similar characteristics.
3-PPP is a racemic mixture of two isomers, each having a different profile of activity. At low doses (+ )-3-PPP inhibits DOPA formation in y-butyrolactone-treated rats and reduces locomotor activity, indicating a presynaptic autoreceptor action. At higher doses (+ )-3-PPP has effects which point to postsynaptic receptor agonist activity: it increases levels of striatal acetylcholine (ACh) and causes hyperactivity. The YE syndrome observed with this isomer is therefore consistent with the possibility that (+ )-3-PPP is a selective dopamine autoreceptor agonist at low doses. The (-)-isomer appears to be both weaker and less selective in its actions at dopamine receptors. There is, as with (+ )-3-PPP, evidence indicative of an autoreceptor agonist action. However, unlike (+ )3-PPP, this isomer also behaves as a postsynaptic blocker in that it antagonises dopamine stimulation of dopamine-linked adenylate cyclase and also decreases striatal ACh levels. The inability of (- )-3-PPP to cause significant yawning and penile erections is consistent with its reported profile of activity.
The negative results obtained with clonidine indicate that stimulation of alpha2-adrenoceptors does not cause yawning or penile erections. The lack of effect also shows that yawning is not concomitant with reduced activity. This demonstrates that, in terms of selectivity, there is a great advantage in using the YE syndrome instead of hypomotility as a behavioural index of autoreceptor agonist activity. These findings are particularly pertinent in the case of reports that TL-99 and N,N-dipropyl A-5,6 DTN possess substantial a2-agonist activity especially since Horn et al. showed that the hypomotility caused by TL-99 was, in fact, mediated in part by activation.
Physostigmine also caused yawning, confirming previous findings. It is distinct from dopamine agonists because it had no effect on penile erections. The antagonism of apomorphine yawning by atropine supports previous findings and suggests that a cholinergic-dopaminergic linked system in the striatum is involved in yawning induction.
The observation that A-5,6 DTN did not produce yawning or penile erections is relevant to the search for the site at which drugs act to cause the YE syndrome. A-5,6 DTN causes stereotypy, hyperactivity and rotation when given intracerebrally showing that it has potent dopaminergic activity but it fails to penetrate into the brain after systemic injection. It is tempting to suggest that the failure of A-5,6 DTN to elicit the YE syndrome is evidence that the responses are centrally nduced. Such a conclusion is however premature n the absence of evidence indicating whether A5,6-DTN possesses dopamine autoreceptor activity r alternatively whether it elicits yawning and penile erections following intracerebral injection. There is evidence that the YE syndrome is mediaed centrally as domperidone, a specific peripherthy acting dopamine antagonist, did not prevent apomorphine-induced yawning and penile erections. This result substantiates previous findings by Benassi-Benelli et al. (1979) who reported that penile erections induced by apomorphine or NPA were not antagonised by domperidone.
In addition to the drugs included in this study, other agents are known to cause yawning with or without an increase in penile erections. For example, ACTH and related peptides will induce a YE syndrome in animals although these effects are not elicited on peripheral injection. Glutamate diethyl ester, a glutamate antagonist, injected i.p. has been reported to cause yawning; its effects on penile erections are not known. While these compounds represent a possible source of false positives, they are at present readily distinguishable chemically from known dopamine agonists. On the other hand ACTH- or glutamate antagonist-induced yawning may involve a dopamine receptor.
The slight enhancing effect of SKF 38393 on penile erections but with yawning not affected suggests that the neuromechanisms mediating the two responses may be separable. Not only do the results obtained with physostigmine clearly support such a hypothesis but we have also found that naloxone inhibited apomorphine-induced yawning but potentiated apomorphine-induced penile erections (to be published). A similar potentiation by naloxone of NPA-induced penile erections was reported by Ferrari and Baggio (1982). However, despite the indications that the two responses can be separated, our studies show that the elicitation of yawning accompanied by penile erections may indicate the activation of a particular class of dopamine receptors.
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-Gower J, Berendsen H et al. Yawning-penile erection syndrome as a model for putative dopamine autoreceptor activity Eur J Pharmcol 1984; 103; 81-89
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