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.
