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mise à jour du 10 juillet 2003
Effects of single and repeated treatment with antidepressants on apomorphine-induced yawning in the rat: the implication of alpha-1 adrenergic mechanisms in the D-2 receptor function
A. Delini-Stula, C. Hunn
Research Laboralories, Pharmaceuticals Division, Ciba_Geigy Basle. Switzerland


Yawning behaviour, induced by low doses of apomorphine, is considered to be a functional expression of a selective stimulation of dopamine (DA)-receptors, which in contrast to the earlier assumptions (Yamada and Furukawa 1980, Stahle and Ungerstedt 1984), appear to be localised at the postsynaptic neuronal membrane (Serra et al. 1986, Morelli et al. 1986; Stahle and Ungerstedt 1989). There is convincing evidence demonstrating that yawning is dominantly mediated by D-2 type receptors (Protais et al. 1983, Holm and Ôgren 1985), but a contributory role of D-1 receptors bas also been suggested by more recent findings (Stahle and Ungerstedt 1989). Recently Mogilnicka et al. (1986) reported that desipramine, imipramine and some other antidepressants induce yawning behavior in rats. This effect was selectively antagonized by DA-receptor blocking drugs. Therefore, it appeared to be of doparninergic origin and unrelated to NA- or 5-HT inhibiting properties of the investigated drugs.

Several antidepressants and electroconvulsive treatment were, however, found to reverse the apomorphine induced hypomotility in rats, which is also of dopaminergic origin and thought to result from the stimulation of the same receptors as involved in the mediation of yawning (Serra et al. 1979, 1981).

Antidepressants lack direct effects on DA receptors and the mechanisms of these observed effects have, up to now, remained unexplained. The aim of the present study was to test the assumption that, by virtue of their NA-enhancing properties, antidepressants nevertheless indirectly modulate D-2 receptors activated by low doses of apomorphine.

Yawning behaviour was selected as a suitable model for this purpose. Even though this might be an overinterpretation, there are reasons to assume that yawning reflects the vigilance state of the animals.

The effects of chiral drugs, the (+)- and (-)-enantiomers of oxaprotiline and of highly selective 5-HTuptake inhibitors citalopram and ifoxetine (Waldmeier et al. 1986) were compared to standard antidepressants (desipramine, imipramine, maprotiline), which, however, display different NA- and 5-HT-uptake inhibiting profiles. Of the two chiral compounds the ( + )-oxaprotiline is a stereospecific and highly selective inhibitor of NA-uptake, whereas the ( -)-oxaprotiline (levoprotiline) lacks any influence on NA or 5-HT-uptake (Waldmeier et al. 1982). In distinct difference to (+)-oxaprotiline, levoprotiline also fails to down-regulate beta-adrenergic receptors or NA-induced depression of cortical neurons after chronic administration (Delini-Stula et al. 1983). In addition to these drugs, adrafinil (CRL 40 028), a central acting alpha-1 receptor agonist (Rambert et al. 1986), and prazosin, a selective alpha-1 receptor antagonists, were also tested. [...]


The results of this study indicate that apomorphine-induced yawning is consistently modified only by those antidepressants which primarily affect noradrenergic transmission. However, none of these drugs showed an intrinsic enhancement of yawning. This is in contrast to the observation of Mogilnicka et al. (1986), who found that desipramine and, to a lesser extent, imipramine induced yawning in rats. The reason for this discrepancy is unclear, but does not seem to be due to different doses of the drugs, since they were about the same in her and our study. Selective 5-HT-uptake inhibitors citalopram and ifoxetine failed to show consistent or significant effects in the interaction with apomorphine, either after acute or repeated administration. They showed, however, some intrinsic enhancing action on yawning. It is worth mentioning that ifoxetine is a highly selective, but atypical, inhibitor of 5-HT-uptake in that it exerts its action only centrally and is practically devoid of any direct antagonistic action on brain receptors (Waldmeier et al. 1986).

The importance of NA component in the inhibition of yawning is strengthened by the stereoselectivity of action of the (+)-enantiomer of oxaprotiline. Also, apart from being a potent and selective, NA-uptake inhibitor (+)-oxaprotiline is pharmacologically a rather specific acting drug. It shows weak or no affinity for beta-adrenergic, dopaminergic, 5-HT-2 and, most importantly, cholinergic receptors (for references see Delini-Stula 1986 and unpublished). A cholinergic link in the initiation of yawning has been demonstrated by Yamada and Furukawa (1980) and anticholinergic properties of a drug might have been implicated in the suppression of this behaviour. Complete lack of an effect of the (-)enantiomer levoprotiline further indicates that H-1 receptor blockade (which both compounds have in common) is of no relevance to yawning. Further, it does not seem that any direct enhancing effect on postsynaptic D-2-receptors is implicated in this inhibitory action. As several recent studies have shown, both (+) and (-)enantiomers have:

- a) a common property to increase amphetamine- and apomorphine-induced stereotypies after single doses of 10 and 30 mg/kg IP with (-) form being even more active than the (+)-one (Delini-Stula and Mogilnicka 1988),
- b) after chronic administration both drugs equally enhance behavioral stimulation induced by d-amphetamine and dopamine (Maj and Wedzony 1988)
- c) enhanced behavioural stimulation after chronic treatment with (-)-enantiomer could be antagonized by sulpirid (Delini-Stula et al. 1988).

The absence of acute effects of imipramine and maprotiline seems, however, to contradict the implication of noradrenergic mechanisms in the modulation of yawing.

Both drugs are also inhibitors of NA uptake, and maprotiline even a selective one. However, both drugs directly act upon various other receptor and transmitter systems as well. Particularly, they have rather prominent alpha-1 receptor blocking properties. If our assumption is true, than it is plausible to explain the lack of their acute effects on yawning, among others, by the counterbalancing alpha 1 receptor blockade. However, after subchronic treatment with these drugs yawning was markedly and significantly inhibited. This is compatible with the reported increased functional sensitivity of alpha-1 receptors observed after repeated administration of antidepressants (Mogilnicka et al. 1987). Of interest, in this respect, is that no change in specific 3H-prazosin binding was observed after subchronic treatment with antidepressants, but some findings suggest that increased responsiveness of alpha-1 receptors relates to their increased preference for the agonists (Menkes et al. 1983). In the case of imipramine, a part of its subchronic effect could be due to the increased accumulation of desipramine to which it is metabolized under in vivo conditions. The implication of noradrenergic mechanisms and, specifically, alpha-1 receptors in the modulation of yawning is, however, more directly supported by clear-cut opposite effects of adrafinil and prazosin.

The pharmacological profile of adrafinil, the 2/(diphenylmethyl)-sulfinyl/N-hydroxyacetamide, indicates that this compound possesses selective central alpha-l adrenergic agonistic properties. The central action of adrafinil is evidenced by the fact that behavioural activation is not paralleled by signs of peripheral sympathetic overstimulation. Selective alpha-1 adrenergic properties are, on the other hand, supported by the fact that behavioural hyperactivity, without features of stereotypies, could be antagonized by alpha-adrenergic antagonists such as phenoxybenzamine, prazosin and yohimbine, but it is unaffected by propranolol or pimozid (Duteil et al. 1979; cf. Weetman 1980; Rambert et al. 1986). Our own investigations corroborate these rindings. We also found that adrafinil in doses of 30-120 mg/kg increases organized exploratory and locomotor activity of rats in the open field, enhances the plus-maze behaviour of mice and reduces the acquired immobility in rats. This behavioural activation, as reported by other authors, was qualitatively different from that induced by dopamineagonistic drugs. Particularly, it was lacking stereotyped features (Delini-Stula and van Riezen, unpublished).

Altogether, the results of our study indicate that, by virtue of their noradrenergic-enhancing properties, antidepressants inhibit yawning behaviour induced by apomorphine. The findings also offer indirect evidence that the function of D-2 dopamine receptors, activated by low doses of apomorphine, is under modulatory control of alpha-1 adrenoceptors. The attractivness of this assumption consists in that is suggests a link between the alpha-1 adrenergic and D-2 receptors and their mutual involvement in the control of vigilance. Certainly, this assumption needs further and more direct supportive evidence.