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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 1 mai 2003
Psychopharmacology (Berl)
1995; v 120; n 4; p376-383
lexique
Post-synaptic 5-HT1A receptor involvemement in yawning and penile erections induced by apomorphine, physostigmine and MCPP in rats
Protais P, Windsor M, Mocoer E, Comoye E
Laboratoire de physiologie UFR Médecine-Pharmacie Rouen France

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Apomorphine and mCPP induced yawning associated with penile erections in rats, whereas physostigmine induced only yawns. Apomorphine-induced yawning and penile erections were antagonized by low doses of raclopride, whereas physostigmine-induced yawning and mCPP-induced effects were only partly inhibited at high doses of raclopride. Scopolamine as well as clozapine antagonized yawning and penile erections induced by apomorphine, mCPP and physostigmine. Similarly, the 5-HT1A agonists 8-OH-DPAT and S 14506 inhibited yawning and penile erections induced by apomorphine, mCPP and physostigmine, and at similar doses induced lower lip retraction and hyperreactivity to handling. The beta/5-HT1A antagonist tertatolol reversed the inhibitory effects of 8-OH-DPAT and S 14506 on drug-induced yawning and penile erections and increased apomorphine- and physostigmine-induced yawn frequency but not penile erection frequency. Like tertatolol, propranolol increased apomorphine- and physostigmine-induced yawn frequency, whereas ICI 118551 increased only physostigmine-induced yawning. 8-OH-DPAT- and S 14506-induced lower lip retraction and hyperreactivity to handling were also significantly antagonized by tertatolol. Finally, p-chlorophenylalanine pretreatment produced about 95% depletion in 5-HT in hypothalamus, hippocampus, striatum and frontal cortex and modified neither the responses of the inducing drugs nor the inhibitory effects of 8-OH-DPAT and S 14506 on drug-induced yawning and penile erections. These data suggest (i) that a final cholinergic mechanism blocked by scopolamine and clozapine is involved, in drug-induced yawning and penile erections, (ii) that the effects of S 14506 depend upon stimulation of 5-HT1A receptors, (iii) that the inhibitory effects of 5-HT1A agonists on yawning and pende erections probably occurred at final steps on the pathways involved in the expression of yawning and penile erections and that these effects could be related to other effects of the 5-HT1A agonists, (iv) that a tonic inhibitory P influence could interfere with the expression of yawning but not with that of penile erections and (v) that presynaptic 5-HT1A receptors do not seem to play an important role in the inhibitory effects of 5-HT1A agonists on druginduced yawning and penile erections in rats.

Introduction

Several neurotransmitters appear to be involved in yawning and pende erections in rats. Even if it is likely that the two behaviours are independent, they were reported as both induced by classical neurotransmitters agonists such as dopamine (DA) agonists, as well as by neuropeptides such as ACTH, (alpha-MSH and oxytocin. In contrast, muscarinic receptors agonists cholinesterase inhibitors appear to induce only yawning. In the case of serotoninergic agonists, it was essentially reported that a serotoninergic link was involved in yawning and that mCPP, a metabolite of trazodone acting at both 5HT1B abd 5HT2C receptors, induced yawning, mCPP and other 5HT2C receptors agonists also appeared potent in inducing penile erections, whereas 5HT1A and 5HT2A agonist were reported to inhibit mCPP-induced penile erections.

In the course of studies on S 14506, a highly potent 5-HT1A agonist, we observed inhibition of apomorphine-induced yawning and pende erections. In another study, it was observed that S 14506 inhibited some dopamine agonist-induced behaviours by blocking D2 dopamine receptors. The aim of the present study was to determine the pharmacological specificity of the inhibition exerted by S 14506 on apomorphine-induced yawning and penile erections and to extend our initial observation to yawning and penile erections induced by physostigmine and mCPP. For this purpose, S 14506 as essentially compared to the prototypic 5-HTI A agonist, 8-OH-DPAT. The selective D2 dopamine antagonist raclopride, the muscarinic antagonist scopolamine and the atypical neuroleptic clozapine were used to quantify the specificity of drugs inducing yawning and penile erections. [...]
 
Discussion : The present results confim previous work pointing to the involvement of dopaminergic, cholinergic and serotoninergic synapses in both yawning and penile erections in rats. However, there are differences between the ability of apomorphine, physostigmine and mCPP to induce the two responses.
 
Yawning was induced by apomorphine, physostigmine and mCPP. The antagonism by scopolamine of yawning induced by the three compounds suggests that a cholinergic link was likely as a final step on the neuronal pathways involved in this behaviour. The effects of raclopride confirmed the dopaminergic origin of apomorphine-induced yawning, and that physostigmine and mCPP probably acted downstream from DA receptors to induce yawning. Contrary to raclopride, clozapine inhibited the effects of apomorphine, physostigmine and mCPP on yawning at roughly similar doses. Since clozapine acts as an antagonist at various muscarinic receptor subtypes ) in addition to its antagonist activities at DA Dl and D2 receptors and at 5-HT2c receptors, it is likely that the effects of clozapine resulted either from its anticholinergic component (similarly to scopolamine) or that, in spite of the differences in affinity at various receptors observed in in vitro binding studies, clozapine acted in vivo at roughly similar doses on these various receptors.

Yawning induced by apomorphine, physostigmine and mCPP was inhibited by 8-OH-DPAT and S 14506. This inhibitory effects probably resulted from the stimulation of 5-HT1A receptors, since the two compounds were described as 5-HT1A agonists at doses used in the present stuldy. DA receptor antagonist properties of S 14506 were observed at far higher doses. Furthermore, at the doses used in the present study, 8OH-DPAT and S 14506 elicited lower lip retraction, an effect described as resulting from the stimulation of 5-HT1A receptors, and hyperreactivity to handling.

 
Hyperreactivity to handling is not classically studied as a component of the behavioural 5-HT syndrome. However, this reactivity to handling is frequently observed in animals treated with various serotoninergic drugs. In the present study, this phenomenon appeared of high importance since it is well known that rats stressed during injections usually have a low frequency of yawning. Therefore, it may be asked whether hyperreactivity to handling could reflect a state of stress and therefore non-specifically inhibit drug-induced yawning. 8-OH-DPAT- and S 14506 induced inhibition of drug-induced yawning, lower lip retraction and hyperreactivity to handling were antagonized by the beta/5-HT1A antagonist tertatolol.
 
In fact, tertatolol was able not only to oppose the inhibition by 8-OH-DPAT and S 14506 of apomorphine and physostigmine induced yawning but also to increase the effects of these two yawning inducing drugs. Such a potentiation by tertatolol was not found on mCPP-induced yawning or on the components of the behavioural 5-HT syndrome which were only partially antagonized by 5 mg/kg tertatolol. Since potentiation by tertatolol of apomorphine- and physostigmine-induced yawning could be observed simultaneously with partial antagonism by tertatolol of hyperreactivity to handling, this tends to suggest that hyperreactivity to handling and inhibition of yawning were not really related.

That tertatolol increased apomorphine- and physostigmine-induced yawning could be due to permanent inhibition of yawning linked either to a serotoninergic tone and a basal stimulation of 5-HT1A receptors or to a catecholaminergic tone and a basal stimulation of beta-adrenoreceptors. In order to test the influence of an inhibition of yawning through the tonic stimulation of 5-HTIA receptors, drug-induced yawning was studied in rats pretreated with the serotoninergic depletor pCPA.

 
The virtually complete depletion of 5-HT in various brain areas possibly involved in yawning, weakly increased physostigmine-induced yawning but did not modify apomorphine-induced yawning. Our data contrast with those of Okuyama et al. (1987) and of Matsurnoto et al. (1989), suggesting a potentiation of DA agonist-induced yawning following pCPA pretreatment. These discrepancies could be due to differences especially in the procedure of administration of pCPA and in the extent of the 5-HT depletion. In our study, the changes in monoamine levels induced by the pCPA pretreatment permitted the conclusion that 5-HT transmission was virtually abolished, whereas other forms of monoamine neurotransmission were unaffected. Therefore, it seems that, if a tonic stimulation of 5-HT1A receptors inhibited yawning, its influence was weak, and that the beta-adrenergic antagonist component of tertatolol was probably involved in the potentiation of apomorphine-and physostigmine-induced yawning by thisbeta/5-HT1A antagonist. This conclusion is consumed by previous data with various adrenoreceptor antagonists (Yarnada et al. 1989) similar to our results with tertatolol and propranolol, by the increased physostigmine-induced yawning in rats treated with the selective P2 antagonist ICI 118.551 and by the decreased yawn frequency reported in rats pretreated with the P2 agonist salbutamol.
 
However, since tertatolol and propranolol increased apomorphine- and physostigmine-induced yawning in a more marked manner than ICI 118 551, we cannot exclude that simultaneous blockade of fl adrenoreceptors and of 5HT receptors could be responsible for tertatolol and propranolol effects. Indeed, pretreatment with pCPA could also suppress a tonic facilitatory serotoninergic influence involved in the expression of yawning. The interpretation for the involvement of the fi-adrenergic antagonist properties of tertatolol in the potentiation of apomorphine-and physostigmine-induced yawning is nevertheless further suggested by the fact that low doses of 8-OH-DPAT, which could stimulate preferentially presynaptic 5-HTIA receptors, and therefore decrease the serotoninergic tone, were unable to increase apomorphine and physostigmine-induced yawning. In addition, since the 8-OH-DPAT and S 14506-induced inhibition of drug-induced yawning was not modified in pCPA-pretreated rats, it is like that postsynaptic 5-HT1A receptors are much more involved in this effect than presynaptic 5-HT1A receptors. It seems possible to draw the same conclusion 8-OH-DPAT- and S 14506-induced lower lip retraction and hyperreactivity to handling. However, our conclusion must be confirmed by further experimente using silent and selective antagonists since it was reported that pCPA pretreatment could modify the activity of drugs (ritanserin) on dopaminergic neurons.

Roughly similar results were obtained on penile erections. Despite the inability of physostigmine to induce penile erections, the antagonism by scopolamine, and also by clozapine, of penile erections induced by apomorphine and mCPP suggest that a final cholinergic link is also involved in this behaviour. In a manner similar to that observed on yawning, we conclude that postsynaptic 5-HT1A receptors are likely to be involved in 8-OH-DPAT- and S 14506-induced inhibition of drug induced penile erections. However, drug-induced penile erections appeared more sensitive to the effects of 5-HT1A agonists and did not seem to be modulated by beta adrenoreceptors, since beta antagonists were unable to increase apomorphine- and mCPP-induced penile erections.

In conclusion, our results (i) suggest that both inducing drugs exerted their effects by a final cholinergic mechanism blocked by scopolamine and clozapine, (ii) confirm the 5-HT1A agonist properties of S 14506, (iii) indicate that the inhibitory effects of 5-HT1A agonists on yawning and penile erections probably occurred at final steps on the pathways involved in the expression of yawning and penile erections and that these effects could be related to other effects of the 5-HT1A agonists, (iv) suggest that presynaptic 5-HT1A receptors do not seem to play an important role in the inhibitory effects of 5-HT1A agonists on drug-induced yawning and penile erections in rats and (v) confirm that tonic inhibitory P2 influence could interfere with the expression of yawning but not with that of penile erections.

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