haut de page

mise à jour du
8 janvier 2004
1986; 90; 9-13
Involvement of septal and striatal dopamine D2 receptors in yawning behavior in rats 
Katsushi Yamada, Tatsuo Furukawa
Department of pharmacology, School of medecine, Fukuoka University


Previous observations show that apomorphine exerts biphasic effects on behavior, ie., yawning and hypomotility at low doses, and stereotypy and hypermotility at higher doses. Low doses of apomorphine preferentially activate presynaptic dopamine autoreceptors, which results in an inhibition of dopamine release and decrease of its synthesis, while higher doses stimulate postsynaptic receptors. Accordingly, we have proposed that the yawning elicited by low doses of dopamine receptor agonists is due to an activation of presynaptic dopamine autoreceptors, whereas stereotypy induced by higher doses may be attributed to a stimulation of postsynaptic dopamine receptors
In addition, previous investigations have pointed out the involvement of the cholinergic systein in yawning behavior. Physostigmine, an anticholinesterase agent, and pilocarpine, a muscarinic receptor agonist, induce yawning behavior which is abolished by scopolamine, a muscarinic receptor antagonist, but not by mecamylamine, a nicotinic receptor antagonist. Scopolamine also completely inhibited the yawning induced by small doses of apomorphine.
Assuming that small doses of apomorphine produce an inhibition of dopamine release from presynaptic sites which results in an activation of cholinergic neurons, apomorphine-induced yawning can result from secondary activation of cholinergic neurons, and dopaminergic inhibition and cholinergic activation are proposed to be concomitantly involved in yawning behavior.
In vitro experiments indicate the presence of at least two subtypes of dopamine receptors, D-1 and D-2, according to the nomenclature proposed by Kebabian and Calne (1979). The D-1 receptor is associated with adenylate cyclase and can be labelled with the neuroleptic thioxanthene ligands piflutixol or flupentixol, whereas D-2 receptors are independent of adenylate cyclase and can be labelled with the butyrophenone ligands spiroperidol or 'haloperidol. Using this classification, it has been shown that the standard dopamine agonist apomorphine has effects on both types of dopamine receptors in vitro, but the functional consequences in vivo of this mixed effect are unclear.
In the present study, we attempted to evaluate the relative importance of D-1 and D-2 receptors in the effects of dopamine receptor agonists including apomorphine in eliciting yawning behavior. Furthermore, we investigate whether or not intracerebral injections of dopamine receptor agonists in the brain areas in which a dopaminergiccholinergic neuron link has been reported, could induce yawning. [...]
Discussion The present study confirmed our previous finding that both apomorphine and piribedil induce yawning at very low doses for which the dose-response curves showed a bellshaped form and stereotypy at higher doses
Recently, it was found that haloperidol reduced the yawning induced by apomorphine at doses much smaller than those needed for inhibition of stercotypy or hyperactivity. These support our previous proposal that the yawning induced by dopamine receptor agonists may be mediated by stimulation of presynaptic dopamine receptors.
This conclusion is further supported by prescrit results and the other observations showing that the compounds 3-PPP and TL-99, which have been reported to stimulate dopamine autoreceptors induced yawning. Only the lower dose range of 3-PPP was tested in the prescrit study but our findings agree with those of Hjorth et al. (1981), concerning the stimulating properties of presynaptic dopamine receptors of the drug. These agents at doses used did not induce stereotypy or hyperactivity, in contrast to apomorphine and piribedil, which indicates that 3-PPP and TL-99 do not stimulate postsynaptic dopamine receptors, responsible for this behavior. Consequently, yawning may not be mediated by the saine postsynaptic dopamine receptors.
It has been reported that SK & F 38393 is a dopamine agonist with a novel profile of action in that it does not affect dopamine turnover in the brain or cause stereotypy or emesis but does stimulate dopamine-sensitive adenylate cyclase in vitro and causes contralateral rotation in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway. In addition, SK & F 38393 does not inhibit dopamine release in brain slices. Thus, SK & F 38393 is apparently devoid of autoreceptor stimulating actions and is a putative dopamine D-1 receptor agonist
In the present study, SK & F 38393 failed to elicit yawning behavior, as shown by Gower et al. (1984). On the other hand, a distribution of dopamine D-2 receptors at both presynaptic and post synaptic sites of dopamine neurons in the striatum of rats has been reported. Very recently, Plantje et al. (1985) also reported that stimulation of dopamine D-2 receptors inhibited the electricallyevoked release of [H]-dopamine in rat neostriatum and entorhinal cortex.
Bromocriptine, which has been reported to inhibit the prolactin secretion from the anterior pituitary via a stimulation of dopamine D-2 receptors, induced decrease of motor activity and DOPAC levels and reversed the -methyltyrosine-induced decline of dopamine in mice, suggesting that bromocriptine can stimulate presynaptic dopamine receptors.
In the present study, yawning was also evoked by bromocriptine. Sulpiride, considered to selectively block presynaptic dopamine D-2 receptors at low doses inhibited the yawning responses induced by apomorphine, piribedil, 3-PPP or bromocriptine, giving evidence for the involvement of dopamine D-2 receptors in yawning behavior.
On the other hand, as mentioned above, physostigmine and pilocarpine elicit yawning and then the yawning induced by dopamine receptor agonists is antagonized by scopolamine but not by mecamylamine, suggesting that a cholinergic-dopaminergie linked system is involved in yawning induction
Various lines of evidence suggest that the nigro-striatal dopaminergic neurons inhibit the striatal cholinergic neurons, while a dopaminergic-cholinergic link is lacking in the mesolimbic area such as the nucleus accumbens and olfactory tubercle. There is also accumulated evidence that the mesoseptal dopaminergic neurons seem to play an inhibitory role in the control of the septal-hippocampal cholinergic neurons
The septal-hippocampal cholinergic neurons have been proposed to be necessary to elicit a specific stretching-yawning syndrome following a-MSH, since intraventricular injection of a-MSH increased the acetylcholine turnover rate in the hippocampus of rats and did not alter the dopaminergic neuron activity in the dopaminecontaining nerve terrninals such as septum, striaturn and nucleus accumbens.
Therefore, in the present experiment, dopamine receptor agonists such as apomorphine, piribedil and 3-PPP were injected into the striatum and septum, yawning responses being markedly evoked after the intracerebral injections. The local application of apomorphine into the nucleus accumbens of rats has been reported to inhibit the hyperactivity induced by intra-accumbens amphetamine.
Injection of apomorphine or 3-PPP into the nucleus accumbens also reduced spontaneous locomotor activity, and the mechanisms of action of dopamine receptor agonists appear to be a selective activation of presynaptic dopamine receptors. Therefore, the yawning elicited by the striatal or septal application of apomorphine, piribedil or 3-PPP may be mediated via a stimulation of presynaptic dopamine receptors which results in decrease of dopamine release.
The results suggest that the yawning induced by low doses of apomorphine, piribedil, 3-PPP, TL-99 or bromocriptine is related to the stimulation of dopamine D-2 receptors in the rat striatum and septum.
-Fugikawa M; Yamada K; Nagashima M; Furukawa T Involvement of beta-adrenoreceptors in regulation of the yawning induced by neuropeptides; oxytocin and alpha-melanocytes stimuling hormone in rats. Pharmacol Biochem Behav 1995; 50; 339-343
-Furukawa T Yawning behavior for preclinical drug evaluation Meth Find Exp Clin Phamacol 1996; 18; 2; 141-155
-Kimura H; Yamada K; Nagashima M; Matsumoto S Role of adrenergic neuronal activity in the yawning induced by tacrine and NIK-247 in rats.Pharmacol Biochem Behav 1992; 43; 4; 985-91
-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
-Matsumoto S, Yamada K, Nagashima M, Matsuo N, Shirakawa K, Furukawa T Potentiation by serotonergic inhibition of yawning induced by dopamine receptor agonists in rats.Pharmacol Biochem Behav 1989; 32; 3; 815-8
-Serra G , Collu M and Gessa GL Yawning is elicited by D2 dopamine agonists but is blocked by D1 antagonist Psychopharmacology 1987; 91; 330-337
-Serra G, Gessa GL Hypophysectomy prevents yawning and penile erection but not hypomotility induced by apomorphine Pharmacology Biochemistry & Behavior 1983; 19; 917-919
-Serra G et al Cycloheximide prevents apomporphine induced yawning, penile erection and genital grooming in rats European Journal of Pharmacology1983; 86; 279-282
-Kostrzewa RM and R Brus Is dopamine-agonist induced yawning behavior a D3 mediated event? Life Sci 1991; 48; 26; 129
-Ushijima I, Mizuki Y, Yamada M Multifocal sites of action involved in dopaminergic-cholinergic neuronal interactions in yawning Psychopharmacology (Berl) 1988; 95; 34-7
-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.
-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 [GenSect] 1990; 79; 19-24