mise à jour du
16 janvier 2003
Br J Pharmacology
1989; 34; 915-917 
cas cliniques
The effects of pre and post-operative procedures on physiostigmine and apomorphine induced yawing in rats  
 Anne Bourson & Paul C Moser
Merrell Dow Research Institute, 16, rue d'Ankara, 67084 Strasbourg Cedex, France


In previous studies we have exarnined the effects of dihydropyridine (DHP) calcium channel blockers on yawning behavior in rats and have shown that they can potentiate both apomorphine- and physostigmine-induced yawning.
In order to evaluate the site of this potentiation, part of these earlier studies investigated the effect of 6-hydroxydopamine lesions of the medial forebrain bundle (MFB) on the interaction between the DHP calcium channel blocker nifedipine and yawning induced by either apomorphine or physostigmine. We found that although sham-lesioned rats showed a normal nifedipine potentiation of apomorphine induced yawning, yawning induced by physostigmine was no longer potentiated by nifedipine. This paper examines aspects of the operative procedure that might be responsible for this selective effect against physostigmine-induced yawning. [...]

Discussion :

These results show that not only the sham operation procedure, but also 7 days isolation or pretreatment with DMI and PB, can prevent the nifedipine potentiation of physostigmine-induced yawning. In this respect, the yawning response to physostigmine differs from that to apomorphine, which was still potentiated by nifedipine after the complete sham operation procedure (Table 1), suggesting that individual components of the sham operation procedure would also be ineffective in preventing the effect of nifedipine.

We consider that the effects we have described are due to the stress associated with the procedures used. It is well established that isolation is a stressful procedure which can affect many behavioral and physiological parameters in rats, and it has recently been demonstrated that 28 days isolation can significantly attenuate the yawning response to dopamine agonists. Although the yawning response to both physostigmine and apomorphine was reduced by the sham operation procedure, this effect was particularly marked for physostigmine, consistent with previous suggestions that cholinergic agonist-induced yawning is more susceptible to modulation by stress than that induced by dopamine agonists. In addition, sham-lesioning abolished the nifedipine potentiation of physostigmine-induced yawning behavior, an effect mimicked by either isolation for seven days or pretreatment with DMI and PB. This suggests that the interaction of nifedipine with physostigmine-induced yawning is even more susceptible to modulation by stress than yawning behaviour itself.

The results obtained with DMI and PB pretreatment may be due to the stress associated with anesthesia. The combination of DMI and PB was used as this was part of the original protocol for sham-lesioning, the DMI being included to prevent the uptake of 6-OHDA into noradrenergic terminals in lesioned rats. Although it is unlikely that the drug effects themselves would have lasted 7 days, the injection of physostigmine on the test day may have induced a conditioned stress response, similar to the conditioned emotional response. Further evidence that this is not a direct effect of drug treatment comes from the demonstration that DMI will itself produce yawning in rats.

As many studies suggest that apornorphine-induced yawning is mediated via the cholinergic system, the differences between apomorphine- and physostigmine-induced yawning were unexpected, and it is not clear ai present why mildly stressful events should selectively affect the interaction of nifedipine with physostigmine. The dose-response curves for both apomorphine and physostigmine-induced yawning follow an inveried U-shape, and while the apomorphine dose-response curve can be explained by pre- and postsynaptic effects, that of physostigmine is due te, secondary drug effects, such as chewing and behavioral arousal, which prevent the appearance of yawning.

It is possible that stressful events make rats more sensitive to such secondary effects, leading to a suppression of yawning. If these inhibitory effects are sufficiently strong, treatment with nifedipine may not be able to increase yawning. The observations that stress can markedly affect neurochemical parameters associated with cholinergic function would support such a proposal, although further work is needed to determine the manner in which stress changes the yawning response to physostigmine. It should be noted that other authors have remarked on the greater variability of physostigmine-induced yawning compared to apomorphine-induced yawning, particularly between groups, and have suggested that this effect of physostigmine is more susceptible to external influence.

In conclusion, these results show that relatively mild stress can affect physostigmine-induced yawning in both a quantitative manner (reducing the number of yawns) and a qualitative manner (preventing its interaction with nifedipine). Both these effects appear to be specific for physostigmine-induced yawning, as even when these procedures were combined in the sham operation they only slightly reduced apomorphine-induced yawning and did not prevent its interaction with nifedipine. It is clear that special attention towards housing conditions and preinjection routines is needed when studying yawning behavior, and that such sources of variation must be eliminated before accurate conclusions can be drawn frorn the results. In the present case, for example, results from stressed rats would suggest that dihydropyridine calcium channel blockers have a selective interaction with apomorphine induced yawning, whereas, in fact, they interact with both physostigmine- and apomorphine-induced yawning and the site of this interaction is more likely to be associated with cholinergic than dopaminergic neurones.