mise à jour du
1 janvier 2004
European Journal of Pharmacology
Effects of adenosine receptor agonists and antagonists on physostigmine-induced yawning
MR Zarrindast, R Adeli , S Hosseini-Semnani, M Sharifzadeh
Department of pharmacology, school of medecine
Teheran University of medical sciences
Teheran Iran
Index de tous les travaux de MR Zarrindast


Introduction Yawning behaviour has been suggested to be a physiological response associated with fatique and recovery from stress (Barbizet, 1958; Stoessl et al., 1987). Although yawning is a curious and still little understood behaviour which is displayed in many vertebrate species (Baenninger, 1987), it is nonetheless a discrete and easily quantifiable behaviour that can be used as a model for the understanding of various central nervous system functions. Current models based on pharmacological experiments suggest that cholinergic and dopaminergic systems induce yawning behaviour in rats. Interaction between cholinergic and dopaminergic systems in yawning behaviour (Mogilnicka et al., 1984; Zarrindast and Poursoltan, 1989) and also between dopaminergic (Brown et al., 1991) or cholinergic systems (Brown et al., 1990) with an adenosine mechanism has been shown.

Adenosine plays a functionally important role in nervous tissue as a regulator of neural activity (Phillis and Wu, 1981; Snyder, 1985). Adenosine inhibits neural firing and release of neurotransmitters such as acetylcholine, gamma-aminobutyric acid, dopamine, norepinephrine and glutamate in the brain (Harms et al., 1979; Fredholm and Hedqvist, 1980; Stone, 1981; Dolphin and Archer, 1983; Spignoli et al., 1984; O'Regan and Phillis, 1987). Adenosine receptors have been divided into A1 and A2 subtypes by Van Calker et al. (1979), based on the ability of adenosine analogs to inhibit or stimulate adenyl cyclase. Both receptors are present in the central nervous system (Daly, 1985; Fredholm, 1982). A1 adenosine receptors widely distribute in brain, whereas A2 receptor sites are localised in dopamine-rich brain areas such as striatum, nucleus accumbens and olfactory tubercle (Bruns et al., 1986). The striatum may be one of the sites involved in yawning induced by drugs (Yamada et al., 1986). A1 and A2 adenosine receptors are prescrit in the striatum, which has been shown to regulate acetylcholine release (Brown et al., 1990). Our previous work has shown that the adenosine receptor antagonist, theophylline, inhibits yawning behaviour in rats (Zarrindast and Poursoltan, 1989; Zarrindast and Nasir, 1991).

In the present study, we have tested the effects of adenosine receptor agonists on yawning induced by the anticholisterase agent, physostigmine. [...]

Discussion In the present work, both intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) administration of thecholinesterase inhibitor, physostigmine, induced dosedependent yawning. The response induced by i.p. injection of the cholinergic drug was decreased by both i.p. or i.c.v. administration of the muscarinic receptor antagonist, atropine. The data indicate that a central cholinergic stimulation mechanism is involved in physostigmine-induced yawning. This is in agreement with a previous report that activation of cholinergic mechanisms can induce yawning (Zarrindast and Poursoltan, 1989). Septal and striatal dopamine D2 receptors has been suggested to be involved in yawning in rats (Yamada et al., 1986). It has been also shown that yawning induced by a doparmnergic mechanism is mediated through cholinergic activation (Carlsson, 1975; Di Chiara et al., 1976). Accordingly, it can be suggested that septal and striatal cholinergic systems are the sites of physostigmine-induced yawning.

The prescrit results show that the adenosine receptor agonists, N 6_CyClohexyladenosine (Moos et al., 1985) and NECA (Heffner et al., 1989), when administered either peripherally or centrally, decreased the behaviour induced by a cholinergic agent, physostigmine, suggesting interactions of central adenosine mechanism(s) with cholinergic-induced yawning behavior.

Adenosine actions have been detected at both presynaptic and postsynaptic sites (Proctor and Dunwiddie, 1983; Lee et al., 1984; Schubert and Lee, 1986). Both adenosine A1 and A2 receptors are present in the striatum, and are localized to cholinergic nerve terminals. The former have been shown to inhibit acetylcholine release. In contrast, adenosine A2 receptor cause stimulation of acetylcholine release (Richardson and Brown, 1987; Brown et al., 1990). It has been shown that N 6_cyclohexyladenosine and NECA have affinity for both adenosine A, and A 2 receptors (Stone, 1985). Considering the cholinergic nature of yawning induced by physostigmine (Urba-Hoimgren et al., 1977; Zarrindast and Poursoltan, 1989), a possibility may exist that A1 activation by N'-cyclohexyladenosine or NECA decreases the release of acetylcholine and in turn reduces the behaviour. The adenosine A1 receptor antagonist, 8-phenyltheophylline, did not alter the physostigmine response, but prevented the inhibition of the yawning induced by N 6_CyClohexyladenosine. This may support the suggestion that adenosine A1 activation causes a decrease in the cholinergic-induced yawning.
In contrast to 8-phenyltheophylline, the adenosine receptor antagonist, theophylline, decreased the yawning induced by physostigmine. 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). Thus there is the possibility that blockade of adenosine A2 receptors by theophylline decreased the release of acetylcholine. This possibility is supported by the finding of Brown et al. (1990) that A 2 stimulation is able to increase acetyl choline release in the striatum. Since N'-cyclohexyladenosine and NECA have no selective affinity for adenosine A1 or A2 receptors (Stone, 1985), selective adenosine receptor agonists may be needed to clarify the exact mechanism involved. High doses of theophylline inhibit phosphodiesterase; considering that activation of adenosine A1 receptors decreases cAMP levels (Van Calker et al., 1979), should stimulation of adenosine A1 receptors be responsible for inhibition of yawning, the increase in cAMP caused by theophylline cannot be part of the mechanism of the effect on yawning.