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14 février 2002
 Psychiatr &Psychobiol 1988 3, 195-199
Apomorphine-induced yawning in migraine patients: enhanced responsiveness
Induction of yawning by low doses of apomorphine in healthy volunteers
O Blin, P Danjou, D Warot, J Fondarai, AJ Puech
Clinical Pharmacology & CPCET, CHU Timone, 13385 Marseille Cedex 5
The neuropharmacology of yawning Argiolas A, Melis MR
Yawning: an evolutionary perspective Smith EO
A trial of subcutaneously injected apomorphine for parkinsonian
Chat-logomini
Introduction : Yawning is a physiological reflex (Heusner, 1946) which has been incompletely examined, but for which at least one neurobiological step seems to be dopamine-dependent. Dopaminergic agonists induce yawns in animals (Mogilnicka et al., 1977; Serra et al., 1983; Dourish et al., 1985a, b) and this effect is antagonized by atypical (Dubuc et al., 1982) or typical neuroleptics (Nickolson et aL, 1980).

Several neuroanatomical locations of a possible yawn center have been proposed in man: the medulla oblongata, hypothalamus or striatum (Heusner, 1946). Physiological data on sex (Lal et al., 1987) or chronobiological variations (Anias et al., 1984; personal communication) indicate that these seem to modulate the yawning response to apomorphine, and therefore require further research.

Apomorphine, a reference dopaminergic agonist (Ernst, 1967), induces different behavioral and autonomic effects in anirnals, such as hypo or hypermotility, stereotypes (Iicking, gnawing, grooming), increased responsiveness to stimuli, yawning, erection or hypothermia (Puech et al., 1974). These different effects seem to be finked to the activation of different structures (Serra et al., 1983) or different sub-classes of dopaminergic receptors (Costentin et al., 1983). Large sets of data suggest the involvement of dopamine autoreceptor in apomorphine-induced yawnings (Nickolson et al., 1980; Yarnada et al., 1980; Lal et al., 1982 - Gower et al., 1984; Mogilnicka et al., 1984; Stahl~ et al., 1984; Holmgren et al., 1985; Okuyama et al., 1986), but the recent works of Serra (1987) and Morelli (1986) present arguments against the autoreceptor theory. Penile erection and yawning both take place at the same dose and are maximum at 100 lÀg/kg. The ED 50 of apomorphine is scattered with a ratio of 1 to 160 depending on the effect observed (e.g. hypomotility and hypothermia). (Puech et al., 1974; Mogilnicka et al., 1977; Dubuc et al., 1982; Szechtman et al., 1984; Dourish et al., 1985a; Ushijima et al., 1985).

Regarding apomorphine, low doses devoid of emetic properties could be used in man to assess the sensitivity of the receptors implicated in yawning. Until now, only a few studies have been carried out in humans (Corsini et al., 1982; Lal et al., 1982; Nair et al., 1984; Lal et al., 1987), and a very limited dose range, usually between 0.5 mg and 0.7 mg, has been investigated on yawning and erection. This study was a preliminary step in the doserange study of apomorphine, assessing lower doses than those described in the literature, in order to determine the lowest dose that induces yawning in man.

Materiais and Methods : The experimental design was a double-blind placebo controlled (4 x 4) latin square. Each subject was his own control and successively received all of the 4 treatments at 48 hr-intervals after the prion treatment. The study was approved by the local ethics committee (PitiéSalpêtrière).

Subjects : 8 male subjects aged 23 ± 2.3 yr (20-25 yr) and weighing 65.4 ± 4 kg (60-70 kg) were included in the study. They were all physically healthy according to physical examination, EKG and routine biological laboratory blood tests at the time of the experiment. None had a history of mental illness, drug abuse, sleep disturbance or pathological anxiety. Other medications and alcohol and caffeinecontaining beverages were prohibited on the experimental days. All subjects were fully informed of the risks of the protocol and signed a consent forrn. Subjects were tested separately, in order to avoid group interactions and were not told that yawning was recorded.

Drugs : The three doses of apomorphine (0. 1 mg, 0.2 mg 0.4 mg) and the placebo were prepared by a nurse not participating in the study, then the dose was administered imrnediately. The active drug or the placebo were injected subcutaneously under a vol of 1 ml at the level of the deltoiki muscle.

Dependent variables : Yawning was monitored continuously by direct observation, and was defined as an unvoluntary opening of the mouth followed by at least one deep inhalation before mouth closing. Haemodynamic parameters were monitored every 3 min for 15 min and then every 15 min until 60 min. Measurements were performed by an automatic tensiometer Dinamap, using the oscillometric method; all results were printed on line. All subjects remained supine during the experiment, except at 9, 30, 45 and 60 min after the injection when orthostatic blood pressure was measured. A fall in systolic blood pressure of > 20 mm Hg was considered to be significant. Visual analog scales (VAS) assessing sedation, anxiety and depression were used. Scales were composed of 10-cm horizontal lines with a 10-mm central area corresponding to the usual state. These VAS were adapted from Hindmarch & Gudgeon (1980). Self-ratings were collected every 15 min. Side-effects were assessed using some closed questionnaires filled out by the experimenter. Lacrimation, rhinorrhea, palor and nausea were assessed at 15-min intervals. Erections were self-reported by subjects who were aware of this possible effect of apomorphine. Each item was assessed from 0 (absent) to 4 (maximum).

Time course : Subjects arrived at the laboratory at 0830; they had received no food or drink since the previous evening meal. Blood pressure was monitored at this time and subjects rested in a supine position until the subcutaneous injection 30 min later.

Statistical analysis : The number of yawns were analyzed as a non-parametric variable with Kruskall and Wallis one-way analysis of variance for overall effect. At each time, inter-treatment comparisons were carried out using a Wilcoxon two-tailed test. Parametric variables such as the lag tirne before the first yawn were analyzed with a 2-factor ANOVA (subject, treatment) and treatments were compared with Student's two-tailed t-test.

Results : Yawning was observed in 7 out of 8 subjects with 0.2 mg apomorphine and in 5 out of 8 subjects with 0. 1 mg apomorphine, 0.4 mg apomorphine and placebo. Orthostatic hypotension, bradycardia and Iacrimation were observed under the active treatment but not under placebo. The lag time before the first yawn was modified by the active treatment (F = 2.73, P < 0. 0 1), but only 0.2 mg apomorphine showed different results from placebo (t = 2.08, P < 0. 05). Mean lag time (± SD) before yawn was 37.75 (± 21.13) min for placebo, 28.50 (± 26.20) 0.1 mg apomorphine, 17.37 (± 18.03) 0.2 mg apomorphine, and 28.87 (±25.97) for 0.4 mg apomorphine. When yawns were compared at each 10-min interval, differences were located at the 10-20 min interval. The dose-effect relationship between the dose of apomorphine injected and the number of yawns at 10-20 min, showed a clear saturation of the Hill function starting from the first 0.1 mg dose.

Discussion and Conclusion : In humans, small doses of apomorphine seem able to stimulate the subclass of dopaminergic receptors involved in yawning. As the number and the duration of yawns we observed were not different under the 3 doses regimen (0.1, 0.2 and 0.4 mg of the drug), the effects were probably observed at the "plateau" of the dose-response curve. As 0.1 mg had already saturated the response, the use of lower doses is required to confirm the existence of a linear area of the dose-response relationship located between zero and 0. 1 mg. As the present work concerned examination of the dose inducing 50% of the maximum effect (ED 50), preliminary to the assessment of dopaminergic sensitivity in man, this determination has yet to be assessed. The use of yawning as an index of dopaminergic receptor sensitivity seems to be an easy and ethical way suitable for determining, in vivo, the global reactivity of an organism, and could be used both in patients and in healthy subjects.