Yawning
Induced by the Selective Dopamine D2 Agonist
N-0437 is Blocked by the Selective Dopanrine
Autoreceptor Antagonist (+)-UH
232
Cooper SJ, Rusk IN, Barber DJ
Yawning and stretching responses were
elicited in rats by a small dose (0.3 mg/kg) of
the highly selective dopamine D2 agonist.
N-0437. The responses were blocked by the highly
selective dopamine autoreceptor antagonist,
(+)-UH 232 (3.0 mg/kg), but not by raclopride at
a dose which selectively blocks postsynaptic D2
receptors. The results strongly confirm the view
that yawning and stretching are
behavioral responses elicited by stimulation of
presynaptic D2 receptors
Small doses of dopamine agonists elicit a
behavioral syndrome comprising yawning,
forepaw-stretching, and penile grooming in male
rats. It has been proposed that these effects
are due to selective agonist activity at
dopamine autoreceptors , although evidence
against this view has also been put forward. One
means to determine the mechanism by which
dopamine agonists elicit yawning and the
other responses would be to use selective
dopamine autoreceptor antagonists to see if the
response to the agonists could be blocked.
Recently, dopamine receptor antagonists have
been characterised in an extensive series of in
vivo biochemical and behavioral experiments.
Hence, in the present report, we examined the
effectiveness of one dopamine autoreceptor
antagonist, (+)-UH 232, in blocking the
responses to a small dose of a selective
dopamipe agonist.
The dopamine agonist chosen for this study
is the highly specific dopamine D2 agonist,
N-0437. In small doses, it has been reported to
act preferentially at dopamine autoreceptors. We
have observed that at 0.3 mg/kg IP, N-0437
induced hypomotility, which is indicative of
autoreceptor activation, whilst at 1.0 and 3.0
mg/kg it produced mild forms of behavioral
stereotypy (sniffing, oral activity) which
denote postsynaptic receptor-mediated effects.
Hence, our aim was to determine if N-0437 at 0.3
mg/kg also elicits yawning and associated
responses, and then to test for antagonism with
(+)-UH 232. As a control measure, raclopride, a
highly-selective D2 receptor antagonist (8) was
also tested at a dose which selectively blocks
postsynaptic dopamine-mediated responses. This
should have little or no effect on drug-elicited
yawning.
Results
The highly selective D2 agonist, N-0437,
elicited yawning at a small dose of 0.3
mg/kg. Individual differences were considerable,
although in the first test there was a median
value of 36 yawns in the 60 min period of
observation. The maximum value was 76, and this
rose slightly to 84 and 80 in subsequent tests.
There were no significant differences for any
time interval between the three N-0437 tests.
The selective dopamine receptor antagonist,
(+)-UH 232, significantly reduced the rate of
yawning induced by N-0437 down to a
baseline value, over the 60-min test. Its
antagonistic effect was present within the first
20-min period. In contrast, raclopride (0.03
mg/kg) had no effect on N-0437induced
yawning.
Stretching occurred at substantially lower
rates than yawning. Nevertheless, a
similiar pattern of drug effects emerged. N-0437
significantly increased the incidence of
stretching; the effect was antagonized by (+)-UH
232, but not by raclopride.
At the doses used, neither dopamine
antagonist induced either yawning or
stretching (data not shown).
Discussion
Using a novel, selective dopamine
autoreceptor antagonist, (+ )-UH 232, the
present results provide strong confirmation of
the view that yawning and stretching
responses elicited by N-0437 are mediated by
dopamine autoreceptors. Antagonism at
postsynaptic dopamine D2 receptors had no effect
on the elicited yawning and stretching
responses.
Recently, N-0437 has been resolved into its
enantiomeric forms. (- )N-0437 acts as an
agonist at both pre- and postsynaptic dopamine
receptors, while (+)N-0437 behaves as an
antagonist at autoreceptors involved in the
release of dopamine, and as a weak antagonist at
postsynaptic dopamine receptors. In confirmation
and extension of the present data, we have
demonstrated that (- )N-0437 elicits
yawning (peak effect, 36 yawns in 60 mm).
whereas (+)N-0437 does not (Timmerrnan, Rusk.
Horn and Cooper, submitted). The action of
N-0437 to elicit yawning is therefore
stereoselective, and requires agonis t activity
at presynaptic autoreceptors involved in the
control of dopamine release to induce the
behavioral effect.
Although many investigators have proposed
that small doses of dopamine agonïsts
elicit yawning through a selective action
at dopamine autoreceptors, there has been
dissent from this view. Morelli et al. reported
that the dopamine D1 antagonist, SCH 23390,
antagonized yawning induced by
apomorphine. They concluded that the locus of
the antagonism may involve
postsynaptically-situated dopamine D1 receptors.
However, it should be noted that SCH 23390 also
binds to 5-HT2 receptors in the brain. Since
serotonergic mechanisms may have a facilitatory
role with respect to apomorphine-induced
yawning, the pharmacological significance
of the report by Morelli et al. is somewhat
unclear. Furthermore, Gower et al. were unable
to elicit yawning responses with the
selective dopamine D1 agonist, SK&F 38393.
Our results, in contrast, firmly indicate that
agonist activity at presynaptic dopamine D2
receptors is necessary to elicit yawning
and stretching responses.
It is interesting to note that spontaneous
yawning in the rat shows circadian
variation. Yawning is most frequent in
the late light and early dark period. This
coincides with lowest turnover rates for
dopamine in the rat brain. As the night period
proceeds, dopamine release in nucleus accumbens
and striatum increases dramatically , and,
therefore, autoreceptor sensitivity would be
expected to decline. As a result, behavioral
responses mediated by dopamine autoreceptors
should prove more difficult to obtain during the
later parts of the dark period. Future
experiments could examine relationships between
the phase of the day-night cycle, and behavioral
responsiveness to dopamine autoreceptor
stimulation and antagonism.
Investigations into behavioral responses
mediated by dopamine autoreceptors may have
clinical relevance. Szechtman et al. have
recently reported that a small dose of
apomorphine induced yawning responses in
men, and the drug effect showed sensitization
with repeated injections. Since sensitization
processes may be involved in the development and
exacerbation of psychosis, Szechtman et al.
suggest that further studies on yawning
may provide a useful means to study dopaminergic
mechanisms involved in schizophrenia. Using a
selective dopamine autoreceptor antagonist, our
data firmly link yawning responses to
presynaptic dopamine receptor activation, and
indicate that autoreceptor mechanisms deserve
close experimental scrutiny in relation to
neural processes underlying psychosis.
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