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mise à jour du
22 février 2009
Pharmacological Reports

Central interaction between physostigmine
and histamine during yawning in rats
Esmaeal Tamaddonfard, Hamid Soraya, Nasrin Hamzeh-Gooshchi
Section of Physiology, Department of Basic Sciences, Faculty of Veterinary Medicine, Urmia University, Iran


In this study, the effects of intraperitoneal (ip) injection of physostigmine, subcutaneous (sc) injection of atropine, and intracerebroventricular (icv) injections of histamine, chlorpheniramine (H1-receptor antagonist), and ranitidine (H2-receptor antagonist) in separate and combined treatments were investigated during yawning in rats. Physostigmine at a dose of 0.25 mg/kg produced the highest number of yawns. Atropine, used alone, was without effect, but physostigmine (0.25 mg/kg, ip)-induced yawning was blocked by pretreatment with atropine (1 mg/kg, sc).
Histamine at the doses of 10, 20 and 40 g produced yawning. Chlorpheniramine and ranitidine, used alone, had no effect, whereas pretreatments with chlorpheniramine and ranitidine at the same dose of 80 g prevented histamine (40 g, icv)-induced yawning. The suppressive effect of chlorpheniramine was more than that of ranitidine. Histamine (10 and 40 g, icv) enhanced, whereas chlorpheniramine and ranitidine at the same dose of 80 ?g suppressed, physostigmine (0.25 mg/kg, ip)-induced yawning. Atropine (1 mg/kg, sc) not only suppressed histamine-induced yawning, but also enhanced the inhibitory effect of chlorpheniramine, but not of ranitidine on yawning induced by histamine.
These results indicate that muscarinic receptors mediate yawning induced by physostigmine. Histamine central H1, and to a lesser extent H2 receptors, may be involved in histamine-induced yawning. Cholinergic muscarinic receptors, as well as histaminergic H1 and to a lesser extent H2 receptors, may also be involved in the interaction between brain acetylcholine and histamine.
Yawning, as a common physiological event, occurs with a low frequency in humans and animals and is under coordinated control of several neurotransmitters and neuropeptides such as dopamine, excitatory amino acids, serotonin, nitric oxide, noradrenaline, -aminobutyric acid (GABA), adrenocorticotropic hormone-related peptides, prolactin, urotensin, oxytocine and opioid peptides at the central nervous system level [2]. Several lines of pharmacological evidence suggest that acetylcholine is involved in the expression of the yawning. This evidence includes, for example, findings that cholinomimetic drugs (e.g., physostigmine and pilocarpine) induce yawning in rats and muscarinic receptor antagonists that cross the blood-brain barrier, such as atropine and scopolamine, but not the nicotinic receptor antagonist, mecamylamine, prevent yawning induced by dopamine D 2 receptor antagonists [15, 19, 23, 40].
On the other hand, additional evidence suggests that the brain histamine may also be involved in the induction of yawning. It was found that microinjection of histamine into the paraventricular nucleus (PVN) of the brain produced yawning in the pentobarbital sodium anesthetized rats [33]. In the study of Seki et al. [33], the involvement of histamine H 1 receptors in histamine-induced yawning was clarified. In addition, Seki et al. [32] reported a suppressive effect of prylamine (H 1-receptor antagonist) in the light-induced yawning response in rats. Brain histamine, through its H 1, H2 and H3 receptors, influences the release and function of other neurotransmitters as well as neuropeptides such as dopamine, GABA, serotonin, acetylcholine, oxytocin and orexins [8, 17, 25].
In the higher functions of the brain such as arousal, learning and memory the interaction between histaminergic and cholinergic systems has been documented [6]. Moreover, it has been reported that brain histamine, through its central H 1, but not H2 receptors mediates neostigmine-induced hyperglycemia in rats [20]. In addition, it was reported that central histamineinduced hyperglycemia was suppressed by icv injection of atropine [21]. Therefore, the present study was designed to investigate the interaction between physostigmine and brain histamine during yawning in rats. To clarify the involvement of histaminergic and cholinergic receptors in yawning, the effects of histamine H 1 and H2 receptor antagonists, chlorpheniramine and ranitidine, respectively, and atropine (a muscarinic antagonist) were also examined.
The results of the present study show that physostigmine at the low (0.625 mg/kg) and high (1 mg/kg) doses was without effect, whereas at the doses of 0.125, 0.25 and 0.5 mg/kg, with the highest response at the dose of 0.25 mg/kg, physostigmine produced yawning. Physostigmine is a major alkaloid found in the seeds of the fabaceous plant Physostigma venenosum, and it is a powerful and reversible acetylcholine esterase inhibitor that effectively increases the concentration of acetylcholine in the sites of cholinergic transmission [43]. Physostigmine, as a cholinomimetic agent, at the dose range of 0.05&endash;1 mg/kg has been frequently used in the study of the involvement of the cholinergic system in behavioral and physiological events. Most research has reported that physostigmine at the doses of 0.1&endash;0.3 mg/kg, especially at the dose of 0.2 mg/kg, produces an increased yawning response [15, 24, 36, 41, 42].
Physostigmine at higher doses (0.5&endash;2 mg/kg) produces tremor, fasciculation, salivation, tongue protruding, hypothermia and defecation [7, 22, 23, 29, 36, 37]. In the present study, atropine prevented physostigmine-induced yawning. This finding is in agreement with those from other investigations [7, 15, 34]. It would appear that physostigmine-induced yawning and the inhibitory effect of atropine on the yawning induced by physostigmine may occur at a central level. Distigmine, a peripherally acting cholinesterase inhibitor, did not produce any yawning, whereas E2030 and donepezil, with marked preferential central cholinergic activities, relative to peripheral activities, produced more yawning and scopolamine, a centrally acting antimuscarinic drug, inhibited E2030-iduced yawning [23].
The results presented here indicate that icv injection of histamine produced yawning. Histamine H 1 and H 2 blockers, chlorpheniramine and ranitidine, respectively, produced no yawning response in the absence of histamine, but in the presence of histamine, chlorpheniramine and to a lesser extent ranitidine prevented histamine-induced yawning. This indicates that both histamine central H 1 and H2 receptors are involved in yawning induced by brain histamine. The cell bodies of the histaminergic neuron system are concentrated in the tuberomammillary nucleus of the hypothalamus and send out axons to innervate the entire central nervous system [17, 31]. The areas known to be involved in the induction of yawning (e.g., hippocampus, PVN, pituitary gland, nigrostriatal system, locus cereleus, nucleus of solitary tract, the dorsal motor nucleus of the vagus nerve, ventrolateral medulla and spinal cord) [2, 30], are also innervated by the brain histamine system [31].
It has been found that microinjection of histamine into the medial, but not into the lateral and caudal parts of the PVN produces a yawning response in anesthetized rats [33]. It was reported that after microinjection of trifluoromethyl toluidide dimaleate, an H 1-receptor agonist, into the PVN, yawning was produced, while pyrilamine (H 1-receptor antagonist) prevented histamine-induced yawning [33]. In addition, dimaprit, an H 2-receptor agonist, produced yawning after microinjection into the PVN, but cimetidine (H 2-receptor antagonist) did not prevent histamine-induced yawning [33]. Icv injection of pyrilamine blocked the yawning induced by light stimulation, suggesting a role for brain histamine H 1 receptors in modulating light-induced yawning [32]. In this regard, Gower et al. [16] reported that the H 1-receptor antagonist, dexchlorpheniramine, inhibited apomorphine-induced yawning. Moreover, Ferrari and Baggio [14] found that cimetidine but not ranitidine, injected ip antagonized the yawning induced by apomorphine. In our study, the route of ranitidine injection, the yawning inducing agent, and the conscious level of the animal may affect the results obtained from ranitidine.
However, further studies are required to identify the histamine H 2-receptor action on the yawning response. Yawning is a complex arousal defense reflex located in the reticular brainstem with a peripheral and central arch, whose aim is to reverse brain hypoxia [38]. On the other hand, the involvement of the brain histamine in the arousal regulation has been documented [8]. Seki et al. [33] reported an arousal shift in the electrocorticogram after microinjection of histamine into the PVN. Therefore, it seems that the histamine-induced yawning observed in the present study may be associated with the action of histamine on the area involved in the activation of yawning/arousal mechanisms.
The results of the present study indicate that brain histamine produced an additive effect on physostigmine-induced yawning, and histamine H 1 and H2 blockers suppressed the yawning induced by physostigmine. On the other hand, atropine suppressed histamine-induced yawning and enhanced the suppressive effects of chlopheniramine but not for ranitidine on the yawning induced by histamine. These data therefore indicate that brain histamine, through its H 1 and H 2 receptors, might have an excitatory effect on acetylcholine function, and that cholinergic muscarinic receptors might interact with central H 1 but not H 2 histaminergic stimulation of yawning. Microinjection of histamine into the basolateral amygdala increased the escape latency in acquisition and avoidance tasks [1].
The basolateral amygdala receives abundant cholinergic innervation from the nucleus basalis mangocellularis [10]. Moreover, in the ventral striatal neurons, histamine increased while -fluoromethylhistidine, a suicide inhibitor of histidine decarboxylase, decreased the release of acetylcholine [27]. By whole-cell current-clamp recording, it was shown that histamine excited the septohippocampal cholinergic neurons [39]. It was reported that in the ventral striatal neurons, thiazolylethylamine (TEA, H 1-receptor agonist) and dimaprit (H2-receptor agonist) enhanced the release of acetylcholine, while blockade of histamine H 1 and H2-receptors with triprolidine (H 1-receptor antagonist) and impromidine (H 2-receptor antagonist) produced opposite effects [28]. On the other hand, cholinergic nucleus basalis neurons projecting to the cortex were excited by histamine mostly via H 1 but also via H2 receptors [18]. In addition, blockade of medial septum-diagonal band H 2 receptors with cimetidine was found to antagonize the release of acetylcholine produced by H 3 receptor antagonist, whereas triprolidine, an H 1 receptor antagonist was without effect [5].
Betahistine, as a partial histamine H 1 receptor agonist, was reported to increase acetylcholine from the cortex of freely moving rats [12]. It has been reported that mepyramine and cimetidine failed to alter acetylcholine spontaneous release from the cortex: however, H 1 but not H2 receptor antagonists antagonized the releases of acetylcholine elicited by histamine [11]. In freely moving rats, intraseptal administrations of thioperamide and ciproxifan, H 3 receptor antagonists increased the release of acetylcholine from the hippocampus and cimetidine inhibited the effects of thioperamide and ciproxifan [3, 4].
Central pretreatments with pyrilamine and atropine suppressed central histamineinduced hyperglycemia and suggested that histamine H 1 receptors and muscarinic cholinergic neurons are involved in histamine-induced hyperglycemia [21]. Bugajski and G1dek, [9] have suggested that cholinergic muscarinic receptors interact with central H 1 and H 2 histaminergic stimulation during the increased pituitary-adrenocortical response in stressed rats. The discrepancies between findings of H 2 receptors involvement in acetylcholine release and function may be associated with the fact that histamine, via H 2 receptors, inhibits activity of dopaminergic and GABAergic neurons, thus indirectly modulating the release of acetylcholine. Moreover, histamine also slightly increases acetylcholine release through H 2 receptors, possibly located on cholinergic neurons [27, 28].
In conclusion, the results of the present study suggest that the central histaminergic and cholinergic systems interact with each other in the modulation of yawning. Cholinergic muscarinic receptors as well as histaminergic H 1, and and to a lesser extent H2 receptors, are involved in the interaction between brain acetylcholine and histamine.
-Argiolas A; Melis MR The neuropharmacology of yawning Eur Pharmacol 1998;343(1):1-16
-Bourson A; Moser PC Yawning induced by apomorphine; physostigmine or pilocarpine is potentiated by dihydropyridine calcium channel blockers Psychopharmacology (Berl) 1990;100(2):16-20
-Collins GT, JM Witkin et al Dopamine agonist-induced yawning in rats: a dopamine d3 receptor mediated behavior. J Pharmacol Exp Ther 2005;314(1):310-9.
-Gower AJ Effects of acetylcholine agonists and antagonists on yawning and analgesia in the rat Europ J Pharmacology 1987;139:79-89
-Kimura H; Yamada K; Nagashima M; Furukawa T Involvement of catecholamine receptor activities in modulating the incidence of yawning in rats.Pharmacol Biochem Behav 1996;53(4):1017-21
-Ogura H, Kosasa T, Kuriya Y, Yamanishi Y Central and peripheral activity of cholinesterase inhibitors as revealed by yawning and fasciculation in rats. Eur J Pharmacol. 2001;415(2-3):157-64
-Okuyama S et al Relation between yawning behavior and central serotonergic neural system in rats Naunyn-Schmiedebergs'Arch Pharmacol 1987;335:667-672
-Sato-Suzuki I; Kita I; Oguri M; Arita H Stereotyped yawning responses induced by electrical and chemical stimulation of paraventricular nucleus of the rat Journal of Neurophysiology, 1998;80(5):2765-2775
-Sato-Suzuki I, I Kita, Seki Y, M Oguri, H Arita Cortical arousal induced by microinjection of orexins into the paraventricular nucleus of the rat Behavioural Brain Research 2002;128:169-177
-Seki Y, Y Nakatani, et al Light induces cortical activation and yawning in rat Behav Brain Res 2003;140(1-2):65-73
-Seki Y, Sato-Suzuki I, et al Yawning/cortical activation induced by microinjection of histamine into the paraventricular nucleus of the rat. Behav Brain Res. 2002;134(1-2):75-82.
-Ushijima I et al, Muscarinic and nicotinic effects on yawning and tongue protruding in the rat Pharmacol Biochem Behavior 1984;21:297-300
-Ushijima et al modification of apomorphine, physiostigmine and pilocarpine induced yawning after long term treatment with neuroleptic or cholinergic agents Arch Int Pharmacodyn 1984;271:180-188
-Ushijima I et al Characteristics of yawning behavior induced by apomorphine, physostigmine and pilocarpine Arch Int Pharmacodyn 1985;273:196-201
-Ushijima, I., Y. Mizuki, et al. Behavioral effects of dilazep on cholinergic, dopaminergic, and purinergic systems in the rat. Pharmacol Biochem Behav 1992;43(3): 673-676.
-Ushijima I, Mizuki Y, et al Effects of age on behavioral responses to dopamine agonists in the rat. Eur J Pharmacol. 1987;138(1):101-106.
-Yamada K, Furukawa T Direct evidence for involvement of dopaminergic inhibition and cholinergic activation in yawning Psychopharmacology 1980;67:39-43
-Yamada K, Furukawa T The yawning elicited by alpha-melanocyte-stimulating hormone involves serotonergic -dopaminergic - cholinergic neuron link in rats Naunyn-Schmiedeberg's Arch Pharmacol 1981;316:155 -160
-Yamada K et al Involvement of septal and striatal dopamine D2 receptors in yawning behavior in rats Psychopharmacology 1986;90:9-13
-Yamada K et al Possible involvement of differing classes of dopamine d2 receptors in yawning and stereotypy in rats Psychopharmacology 1990;100:141-144
-Yamada K, Furukawa T Behavioral studies on central dopaminergic neurons. especially jumping, stretching, body shaking and yawning behavior J PharmacoBio dynamics 1980;3:S16-S18
-Yamada K, Matsumoto S, Nagashima M, Kumagai M, Matsuo N, Furukawa T Stimulatory effects of beta-adrenoceptor blockers on the yawning induced by dopaminergic and cholinergic agonists in rats. Japanese J Pharmacology 1987;43:supp53p
-Yamada K, S Matsumoto, M Nagashima, K Shirakawa, T Furukawa Potentiation of yawning responses to the dopamine receptor agonists B-HT 920 and SND 919 by pindolol in the rat J Neural Transm 1990;79:19-24
-Zarrindast MR, Poursoltan M Interactions of drugs acting on central dopamine receptors and cholinoceptors on yawning responses in the rat induced by apomorphine, bromocriptine or physostigmine Br J Pharmacol 1989;96(4):843-848
-Zarrindast, MR, Jamshidzadeh A Inhibitory effect of morphine on yawning induced by cholinoceptor and dopamine D2 receptor activation in rats Br J Pharmacol 1992;105(3):675-678
-Zarrindast MR, Toloui V, Hashemi B Effects of GABAergic drugs on physostigmine-induced yawning in rats; Psychopharmacology (Berl) 1995;122:297-300
-Zarrindast MR, Fazli-Tabai S, Semnanian S, Fathollahi Y Influence of different adrenoceptor agonists and antagonists on physostigmine-induced yawning in rats. Pharmacol Biochem Behav 1999;62(1):1-5
-Zarrindast MR, M Ghazi-Khansari, et al Effects of lead exposure on licking and yawning behaviour in rats Pharmacol toxicol 1998;83:120-124
-Zarrindast MR et al Effects of adenosine agents on apomorphine-induced yawning in rats Psychopharmacology 1995;122:292-296
-Zarrindast MR et al Effects of adenosine receptor agonists and antagonists on physostigmine-induced yawning Europ J Pharmacology 1995;276:3-7
-Zarrindast MR et al The effect of electroconvulsive shock seizures on behaviour induced by dopaminergic agonists and on immobility in the Porsolt test Europ Neuro Psychopharmacol 2004;14(6):509-514
-Zarrindast M, K Nojoomi et al Nitric oxide agents and apomorphine induced rat behaviors Pharmacology 2004;71:169-173