mise à jour du
1 janvier 2004
Effects of adenosine agents on apomorphine-induced yawning in rats
MR Zarrindast, F Fatehi, M Mohagheghi-Badi
Department of pharmacology, school of medecine
Teheran University of medical sciences
Teheran Iran
Index de tous les travaux de MR Zarrindast


Introduction Yawning behaviour is a curious and still little understood response which is induced in many vertebrate species (Baenninger 1987). The most widely held hypothesis is that yawning serves as a form of respiration induced by high levels of carbon dioxide in the blood. At least in humans, it has been shown that neither oxygen nor carbon dioxide levels contribute to yawning rates (Provine et al. 1987).
Yawning can be elicited in experimental animals by a number of dopamine agonists including apomorphine and bromocriptine (Mogilnicka and Klimek 1977; Baggio and Ferrari 1983; Zarrindast and Poursoltan 1989). The involvement of central cholinergic mechanisms in the behaviour has also been suggested (Urba-Holmgren et al. 1977; Yamada and Furukawa 1980; Ushijima et al. 1984; Zarrindast and Poursoltan 1989). Our previous experiments showed that the yawning produced by dopminergic or cholinergic agents was inhibited by the adenosine receptor antagonist theophylline (Zarrindast and Poursoltan 1989). We also found that a central adenosine mechanism interacts with physostigmine induced yawning (Zarrindast et al. 1995). Septal and striatal dopamine receptors have been proposed to be involved in yawning behaviour in rats (Yamada et al. 1986). The behaviour seems to be mediated through D2 dopamine receptors in rats (Protais et al. 1983; Gower et al. 1984; Longoni et al. 1987, Zarrindast and Poursoltan 1989). Interactions between adenosine and the dopaminergic system (Brown et al. 1991) and adenosine with the D2 dopamine mechanism have also been shown (Murayama et al. 1990).
In the present study, the effects of adenosine agents on yawning induced by apomorphine have been investigated.


In the present work, both SC and ICV injections of apomorphine induced dose-dependent yawning. This is in agreement with previous reports that peripherally (Dourish et al. 1985; Zarrindast and Poursoltan 1989) or centrally administered apomorphine into areas such as caudate nucleus (Dourish et al. 1985), septum and the paraventricular nucleus (Melis et al. 1987) can induce this behaviour and that central dopaminergic system (Urba-Holmgren et al. 1982) may be related to the display of yawning behaviour. However, the behaviour can also be induced by cholinergic agents (Urba-Holmgren et al. 1977; Yamada and Furukawa 1980, Ushijima et al. 1984; Zarrindast and Poursoltan 1989). Our previous experiments (Zarrindast et al. 1995) showed that physostigmine-induced yawning was reduced by adenosine drugs. The purpose of this study was to focus on the influence of adenosine agonists and antagonists on apomorphine-induced yawning. The behaviour bas also been proposed to be centrally mediated (Dourish and Huston 1985) and due to septal and striatal D2 receptor activation (Yamada et al. 1986). Adenosine has been shown to function as a neuromodulator or a neurotransmitter in many areas of the mammalian CNS (Phillis and Wu 1981; Snyder 1985). There are at least two types of adenosine receptor subtypes; the A1 adenosine receptors inhibit adenylyl cyclase whereas the A2 adenosine receptors stimulate adenylyl cyclase (for review sec Stiles 1986, Fredholm and Dunwiddie 1988). Both A1 and A2 adenosine receptors are present in striatum.

The presen results indicate that adenosine agonists NECA (Heffner et al. 1989) and CHA (Moos et al. 1985) have the capability to reduce the yawning induced by apomorphine dose dependently. These data suggest that adenosine receptor activation exerts a negative influence on the apomorphine-induced yawning behaviour. The results may support those of others (Murayama et al. 1990, Brown et al. 1991) that suggest interaction between adenosine and dopaminergic mechanisms. It has been shown that NECA have affinity for both adenosine A1 and A2 receptors (Stone 1985). Although, the drug has been shown to have more affinity for A2 then A1 adenosine receptor subtypes (Heffner et al. 1989). CHA has been shown to be a selective and potent A1 adenosine agonist (Moos et al. 1985). Since the A1 adenosine antagonist 8-PT (Smellie et al. 1979; Jacobson et al. 1985) decreased the inhibitory effect of both drugs, the response induced by the both adenosine agonists seems to be mediated through the activation of the adenosine A2 receptor mechanism. 8-PT by itself did not alter apomorphine induced yawning, suggesting that there is no active negative influence of A1 adenosine on yawning.

The present data showed that, in contrast to 8-PT, theophylline decreased yawning induced by apomorphine. Our previous studies have shown that theophylline reduced several behaviours, such as yawning induced by dopaminergic and cholinergic drugs (Zarrindast and Poursoltan 1989), pecking induced by apomorphine in chickens (Zarrindast and Nasir 1991) and catalepsy induced by NECA or CHA (Zarrindast et al. 1993). Theophylline has been proposed to be an adenosine receptor antagonist (Bruns et al. 1986) which may exert a greater A2 antagonist effect (Ferre et al. 1991). The possibility may exist that blocking the A2 adenosine receptor unmasks A1 receptor subtype and in turn, elicits inhibition of apomorphine-induced yawning.

Theophylline is a phosphodiesterase inhibitor. Since the A1 adenosine agonist CHA, which decreases cAMP, also attenuates the behaviour, the inhibition of yawning through an increase in cAMP levels seems unlikely. Methylxanthines have also been proposed to have direct dopaminergic properties (Wanatabe and Uramboto 1986, Herrera-Marschitz et al. 1988, Casas et al. 1989), and they may also release catecholamines (Lin et al. 1980). Since other behaviours, such as pecking in chickens (Zarrindast and Namdari 1992), and licking in rats (Zarrindast et al. 1992) which are induced by D1/D2 dopaminergic systems, are attenuated by theophylline (Zarrindast and Nasir 1991; Zarrindast and Sharifzadeh 1995), the dopaminergic mechanism of theophylline cannot be included. However, to clarify the exact mechanism involved, more studies are required.