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6 novembre 2005
Archiv Int Pharmacody
1984;271:180-188
lexique
Muodification of apomorphine, physiostigmine and pilocarpine indiced yawning after long-term treatment with neuroleptic or cholinergic agents
I Ushijima, K Yamada, T Inoue, T Tokunaga, T Furukawa
Department of neuropsychiatry, School of Medicine, Yamaguchi University, Japan
Chat-logomini
 rat-yawn
 
Abstract : Chronic treatment with haloperidol, physostigmine and scopolamine exerted different effects on the frequency of yawning induced by apomorphine (0.25 mg/kg, i.p.), physostigmine (0.2 mg/kg, i.p.) and pilocarpine (4 mg/kg, i.p.) as compared with chronic treatment with saline. Haloperidol decreased the apomorphine- and physostigmine-induced yawning but not the pilocarpine-induced yawning. Physostigmine reduced only the pilocarpine-induced yawning without affecting the apomorphine- and physostigmine-induced yawning. However, physostigmine showed the most rapid onset- and peaktime of yawning induced by a high dose of physostigmine (0.75 mg/kg, i.p.) as well as that of pilocarpine (8 mg/kg, i.p.), and potentiated apomorphine (1 mg/kg, i.p.)-induced stereotypy, as compared with that observed in the saline group. Scopolamine potentiated the physostigmine- and pilocarpine-induced yawning but not the apomorphine-induced yawning. A single pretreatment with scopolamine (0.5 mg/kg, i.p.), however, depressed these yawning responses. The results suggest that yawning induced by physostigmine, but not by pilocarpine, may be modified by long-term treatment with haloperidol. The stereotypy mediated by the postsynaptic dopaminergic system, but not the yawning mediated by the presynaptic system, may be altered by chronic treatment with physostigmine, while long-term treatment with scopolamine seems to produce a supersensitivity to cholinergic receptors.
 
Introduction
 
Physostigmine, an anticholinesterase agent, and pilocarpine, a cholinergic agonist predominantly acting upon muscarinic receptors, have been reported to elicit yawning in infant rats (Urbá-Holmgren et al., 1977) and in adult rats (Yamada and Furukawa, 1980a). This behavior is inhibited by scopolamine, but not by methyiscopolamine, suggesting that yawning is mediated by stimulation of the central 'muscarinic' receptor (Urbá-Holmgren et al., 1977; Yamada and Furukawa, 1980a, 1981). Moreover, a low dose of apomorphine which produces an inhibition of dopamine release from presynaptic sites, and consequently, results in an activation of cholinergic neurons (Carlsson, 1975; Di Chiara et al., 1976), also elicits yawning in adult rats. Accordingly, a dopaminergic inhibition and a cholinergic activation are concomitantly involved in this yawning behavior (Yamada and Furukawa, 1980a). Physostigmine-induced yawning is potentiated by fluphenazine, a long-acting neuroleptic, but decreased with a high dose of apomorphine. Pilocarpine induced yawning is not affected by either of these drugs (Yamada and Furukawa, 1980b, 1981). A dopaminergic-cholinergic link may be involved in physostigmine-induced yawning but not in pilocarpine-induced yawning.
 
There is evidence supporting a dopaminergic-cholinergic interaction in that the catalepsy elicited by neuroleptic agents 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). With regard to alteration of receptor sensitivity by long-term administration of drugs, it has been reported that chronic treatment with atropine or scopolamine produced a supersensitivity to cholinergic agents (Takeyasu et al., 1979; Gianutsos, 1979). Repeated injections of haloperidol (Dunstan and Jackson, 1977) or treatment with 6-hydroxydopamine (Kato et a!., 1978), elicited a cholinergic hyposensitivity as a consequence of the hyperactivity of cholinergic neurons which are regulated by dopaminergic neurons. In addition, the observation that chronic treatment with cholinergic stimulants attenuates the catalepsy induced by neuroleptics or cholinomimetic drugs (Gianutsos, 1979) suggests that the sensitivity of postsynaptic dopamine receptors may be potentiated and/or that of acetylcholine receptors attenuated.
 
The present experiments were performed to clarify the possible role of the dopaminergic and cholinergic systems in mediating the effects of chronic treatment with haloperidol, physostigmine and scopolamine on yawning induced by apomorphine, physostigmine or pilocarpine.
 
Results
 
Yawning induced by apomorphine, physiostigmine or pilocarpine
In animals chronically treated with saline, floowed by low dose of apomorphine (0.25 mg/kg), yawning began within 5 min (mean, 4.3 mm), reached a maximum after 10-20 min (mean, 15 mm) and usually ceased within 60 min. Stereotypy did not appear. After a high dose of 1 mg/kg, stereotypy began within 10 min (mean, 8.5 mm), reached a peak after 20 min (mean, 19.5 mm), and usually disappeared within 60 min. There was no occurrence of yawning in this condition. After a low dose of physostigmine (0.2 mg/kg) and pilocarpine (4 mg/kg), yawning began at about 10 min (mean, 7.8 mm), reached a peak after 20-30 min (mean, 24.4 mm), and terminated within 60 min. There was no occurrence of chattering. At higher doses of physostigmine (0.75 mg/kg) and pilocarpine (8 mg/kg), chattering appeared immediately after the drug administration, reached a maximum 5 min later and, lasted for 10 mm; while yawining occurred at about 20 min (mean, 19.1 mm), reached a maximum 40-60 min (mean, 53 mm) later, and ceased within 90 min after the drug administration.
 
 
Effects of chronic treatment with haloperidol, physostigmine and scopolamine on yawning induced by apomorphine, physostigmine or pilocarpine
Following chronic haloperidol treatment, the frequency of pilocarpine (4 mg/kg)-induced yawning was unaffected, while apomorphine (0.25 mg/kg)and physostigmine (0.2 mg/kg)-induced yawning was decreased.
 
Following chronic physostigmine treatment, the frequency of pilocarpineinduced yawning was reduced, while that of apomorphine and physostigmine was unaffected.
 
Following chronic scopolamine administration, the frequency of physostigmine- and pilocarpine-induced yawning was markedly increased while apomorphine-induced yawning was not affected, when compared with the respective saline groups. However, a single pretreatment with scopolamine (0.5 mg/kg) completely inhibited these yawning responses. These results are summarized in Table I.
 
 
Effects of chronic treatment with physostigmine on the sensitivity of cholinergic receptors
Following chronic treatment with physostigmine, the frequency of yawning induced by 0.2 and 0.75 mg/kg of physostigmine was not modified, as compared to chronic treatment with saline. At 0.75 mg/kg of the agent, the onset (11 mm)- and peak (23.5 mm)time of the yawns were significantly more rapid rather than those of the saline group. In contrast, with 4 mg/kg and 8 mg/kg of pilocarpine, the frequency of the yawns was inhibited, but the onset and duration of the yawns were similar to those induced by physostigmine (0.2 and 0.75 mg/kg). The chatters induced by high doses of physostigmine (0.75 mg/kg) and pilocarpine (8 mg/kg) were attenuated by repeated treatment with physostigmine (data not shown). The frequency, onset-, and peak-time of the yawns induced by a low dose of apomorphine (0.25 mg/kg) was not affected by repeated treatment with physostigmine (data not shown).
 
 
Effects of acute and chronic treatment with haloperidol, physostigmine or scopolamine on the sensitivity of dopaminergic receptors
 
The stereotypy induced by apomorphine (1 mg/kg, i.p.) was inhibited by a single administration of haloperidol (0.2 mg/kg, i.p.) or physostigmine (0.25 mg/kg, i.p.) and was increased by repeated treatments with these drugs. Acute treatment with scopolamine also increased the apomorphine-induced stereotypy whereas repeated treatment with the drug tended to decrease this behavior, but not significantly.
 
Discussion
 
Apomorphine, physostigmine and pilocarpine have been reported to elicit yawning behavior in rats. The doses which produced the highest frequency of yawning were 0.25 mg/kg, 0.2 mg/kg and 4 mg/kg, respectively (UrbáHormgren et al., 1977; Yamada and Furukawa, 1980a). Rats given chronic treatment with haloperidol, physostigmine and scopolamine exhibited different yawning behavior induced by apomorphine, physostigmine and pilocarpine.
 
Following haloperidol treatment, pilocarpine-induced yawning was unaffected, while apomorphine and physostigmine-induced yawning were reduced.
 
The stereotypy induced by high doses of apomorphine was potentiated. The inhibitory effect on apomorphine- and physostigmine-induced yawning may be accounted for by the supersensitivity of postsynaptic dopamine receptors induced by the chronic treatment with the dopamine antagonist and a consequent inhibition of cholinergic neurons. It appears that the effects of physostigmine seem to depend upon the status of cholinergic neurons and modification of the cholinergic system by dopaminergic agents can alter the effects of physostigmine (Dunstan and Jakson, 1977; Guyenet et al., 1975; Yamada and Furukawa, 1980a, 1981). Repeated injections of haloperidol may produce a cholinergic subsensitivity as a consequence of the hyperactivity of cholinergic neurons which are regulated by dopaminergic neurons. However, since the chronic treatment with haloperidol failed to inhibit pilocarpine induced yawning, the postsynaptic sensitivity of cholinergic neurons to a direct acetylcholine agonist pilocarpine may be unaltered by chronic haloperidol in the dopaminergic cholinergic neuron system.
 
As a result of physostigmine treatment, apomorphine- and physostigmine induced yawning were unaffected, while pilocarpine-induced yawning was decreased. After a single injection of a high dose of physostigmine (0.75 mg/kg) or pilocarpine (8 mg/kg), chattering appeared first, while yawning occurred only after the chattering behavior had almost ceased. The onset- and peak-time of yawning induced by the high dose of physostigmine (0.75 mg/kg) was delayed, as compared with 0.2 mg/kg of the agent in a previous study (Ushijima et al., 1984). It is probable that yawning is produced by a weaker stimulation of central cholinergic neurons whereas chattering is due to stronger stimulation of these neurons. However, following chronic treatment with physostigmine, the onset and the peak-time of yawning induced by a high dose of physostigmine (0.75 mg/kg) was faster than that seen in the saline group. In addition, chattering behavior was decreased, suggesting that the sensitivity of cholinergic receptors is probably attenuated. The effect of physostigmine on the onset and the peak-time of pilocarpine-induced yawning was also similar to the physostigmine-induced yawning. The yawning induced by a low dose of apomorphine, which preferentially stimulates presynaptic dopamine autoreceptors, was not affected by physostigmine. However, the stereotypy induced by a high dose of apomorphine which stimulates postsynaptic dopamine receptors (Kelly et al., 1975), was potentiated. From these results, it is suggested that chronic treatment with physostigmine may produce subsensitivity of cholinergic receptors and supersensitivity of postsynaptic dopamine receptors while not affecting the sensitivity of presynaptic dopamine autoreceptors.
 
Following scopolamine treatment, physostigmine- and pilocarpine-induced yawning was potentiated. It is suggested that scopolamine may induce cholinergic receptor supersensitivity which would be manifested by an increase in the response to physostigmine or pilocarpine. Although a single administration of scopolamine completely depressed yawning behavior, as has been previously reported (Urbi-Holmgren et al., 1977; Yamada and Furukawa, 1980a), and potentiated the stereotypy induced by a high dose of apomorphine, repeated treatment with the drug failed to modify both the yawning and stereotypy as compared with the saline group. This finding suggested that repeated treatment with scopolamine may alter the sensitivity of postsynaptic dopamine receptors as well as that of cholinergic receptors. Since apomorphine-induced yawning is mediated via an enhanced acetylcholine release, and consequently, via an increased stimulation of the acetylcholine receptor, it would be expected that chronic scopolamine would also affect apomorphine-induced yawning. Accordingly, it was found that chronic treatment with scopolamine also changes the sensitivity of the dopaminergic system. The results suggest that the sensitivity of postsynaptic dopamine receptors, but not that of presynaptic aûtoreceptors, may be modified by chronic treatment with physostigmine. In addition, chronic treatment with haloperidol may modify the sensitivity of cholinergic receptors affected by physostigmine, but not that affected by a direct acetylcholine receptor agonist, pilocarpine.
 
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