Dopamine agonist-induced yawning in rats: a dopamine D3 receptor mediated behavior
Collins G et al






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31 décembre 2002
1980; 67; 39-43
Direct evidence for involvement of dopaminergic inhibition and cholinergic activation in yawning
Katsushi Yamada, Tatsuo Furukawa
Department of pharmacology, School of medecine, Fukuoka University


It has been reported that the characteristic yawning behavior appears after intracerebral injection of adreno-corticotrophic hormone (ACTH), melanocytestimulating hormone (MSH) or beta-lipotrophic hormone (beta-LPH) in many animals, such as monkeys, dogs, cats, rabbits, rats and mice (Gessa et al., 1966, Baldwin et al., 1974; Gispen et al., 1975; Rees et al., 1976). In infant rats, cholinergic agonists also elicited yawning (Urba Holmgren et al., 1977), suggesting that yawning is due to cholinergic stimulation. However, few studies have been made on the neurological mechanisms involved in yawning which still remain to be elucidated.

There is evidence that catalepsy elicited by neuroleptic agents, which are dopamine antagonists, is blocked by anticholinergic agents (Costail and Olley, 1971 ; Maj et al., 1976), and that the nigro-striatal dopaminergic neurons inhibit the striatal cholinergic neurons (Trabucchi et al., 1975; Agid et al., 1975; Roth and Bunney, 1976). Apomorphine may be a directacting dopamine receptor agonist (Andén et al., 1967; Carlsson, 1975), and, at a low dose, produces an inhibition of dopamine release from presynaptic sites that results in activation of cholinergic neurons (Carlsson, 1975; Chiara et al., 1976). Consequently apomorphine, at a low dose, ought to elicit yawning.

In the present investigation, we found that apomorphine did elicit yawning in adult rats and we attempted further to understand the neurological mechanism involved. [...]

Discussion : Low doses of apomorphine induced yawning without producing typical symptoms of behavioral excitation, such as stereotypy and hypermotility. Yawning was accompanied by penile erections which were similar to those seen in the sexual arousal elicited by ACTH, MSH or beta-LPH in rats (Colbern et al., 1977) and rabbits (Bertolini et al., 1969; Baldwin et al., 1974). Higher doses of apomorphine produced stereotypy. It bas been proposed that apomorphine exerts biphasic effects on behavior, i.e., decrease of motor activity at low doses, and stereotypy and hypermotility at higher doses (Carlsson, 1975; Strômbom, 1976, Chiara et al., 1976).
It has also been reported that low doses of apomorphine preferentially activate presynaptic dopamine autoreceptors, which results in an inhibition of dopamine release and consequent decrease in its synthesis, whereas higher doses stimulate postsynaptic receptors (Roberts et al., 1975, Groves et al., 1975, Walters and Roth, 1976). Accordingly, yawning elicited by low doses of apomorphine seems to be due to an activation of presynaptic dopamine autoreceptors, while stereotypy induced by higher doses may be attributed to a stimulation of postsynaptic dopamine receptors as previously proposed (Kelly et al., 1975).
Apomorphine-induced yawning was not inhibited by the predominantly peripherally acting methylscopolamine but was blocked by scopolamine, an anticholinergic agent. Physostigmine, an anticholinesterase agent, and pilocarpine, a direct acetylcholine agonist, also elicited yawning in adult rats, as observed previously in infant rats with cholinergic agents (Urba-Holmgren et al., 1977). This was abolished by scopolamine but not by methylscopolamine, suggesting that yawning is mediated by activation of cholinergic neurons in the brain. Recently bilateral intranigral injection of picrotoxin combined with SC injection of apomorphine, 0.2 mg/kg, was found to induce simultaneous catalepsy and yawning in rats (Olianas et al., 1978), suggesting that the nigro-striatal dopaminergic neurons are involved. There is also accumulated evidence that the nigro-striatal doparninergic neurons inhibit the striatal cholinergic neurons (Trabucchi et al., 1975, Roth and Bunney, 1976, Choi and Roth, 1978), while a dopaminergic-cholinergic link is lacking in the mesolimbic area such as the nucleus accumbens septi and tuberculum olfactorium (Consolo et al., 1977, 1978). Therefore, in apomorphine-induced yawning, in addition to an inhibition of dopamine release resulting from activation of presynaptic dopamine autoreceptors, a consequent activation of cholinergic neurons seems to be concomitantly involved.

Further studies on inhibitory and stimulative effects of certain drugs corroborate the prescrit proposal that yawning may be induced through activation of cholinergic neurons which are regulated by dopaminergic neurons. Reserpine, an amine depletor (Furukawa et al., 1976, 1979; Yamada and Furukawa, 1979), markedly increased not only the apomorphine-induced yawning, with little increase in stereotypy, but also the physostigmine- and pilocarpine-elicited yawnings. This increase in yawning thus seems to be due to an inhibition of dopamine release resulting from a presynaptic depletion of dopamine produced by reserpine.

On the other hand, fluphenazine, a long-acting neuroleptic, blocks both pre- and postsynaptic dopamine receptors (Nowycky and Roth, 1977; Choi and Roth, 1978; Yamada et al., 1979). In the present study, fluphenazine decreased the apomorphine-induced yawning, markedly increased the physostigmineinduced yawning, but failed to affect the pilocarpineinduced yawning. This inhibitory effect of the dopamine antagonist on the apomorphine-induced yawning can be explained by the blockade of presynaptic dopamine autoreceptors. While the effects of physostigmine, an indirect cholinergic agonist, seein to depend on the status of cholinergic neurons. Modification of the cholinergic system by dopaminergic agents can alter the effects of physostigmine (Guyenet et al., 1975; Dunstan and Jackson, 1977). Accordingly, blockade of postsynaptic dopamine receptors by the dopamine antagonist and a consequent activation of cholinergic neurons may account for the stimulatory effect on the physostigmine-induced yawning. With regard to alteration of receptor sensitivity by long-term administration of a drug, it bas been reported that chronic treatment with atropine for 21 days produced a supersensitivity to direct cholinergic agents (Takeyasu et al., 1979), whereas repeated injections of haloperidol (Dunstan and Jackson, 1977) or treatment with 6hydroxydopamine (Kato et al., 1978), elicited a cholinergic hyposensitivity as a eonsequence of hyperactivity of cholinergic neurons which are regulated by dopaminergic neurons. However, since fluphenazine failed to potentiate the pilocarpine-induced yawning in this study, it seems not to induce an alteration in postsynaptic sensitivity to direct acetylcholine agonists after 24 h.

From these results, it is suggested that the sites of action of neuroleptics on pre- or postsynaptic dopamine receptors can be determined by observing their inhibitory or stimulatory effects on yawning induced by aportiorphine or physostigmine.

The yawning elicited by intracranial injection of peptides, such as ACTH, MSH and f~-LPH, appeared with a time lag of about 40 - 60 min and then lasted for 1 - 2 h (Ferrari, 1958; Ferrari et al., 1963; Gessa et al., 1967; Izumi et al., 1973; Baldwin et al., 1974). ACTH and MSH were also considered to activate cholinergic neurons in the brain (Torda and Wolff, 1952, Marx, 1975). In fact, the ACTH-induced yawning was suppressed by chlorpromazine or atropine (Ferrari et al., 1963) suggesting a possible involvement of dopaminergic and cholinergic neurons. It is therefore probable that the effect of the peptides may involve other neurological mechanisms, presumably dopaminergic and/or cholinergic neurons, when they ceicit yawning beliavior.

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