Assessment
of dopamine autoreceptor agonist properties of
apomorphine, (+)3ppp and (-)3ppp by recording of
yawning behaviour in rats
Stahle L, Ungerstedt U
Department of pharmacology,
Karolinska Institute. sSockholm, Sweden
Schizophrenic morbidity has been reported to
be reduced by low doses of apomorphine (APO).
Such low doses of APO are considered to
slectively stimulate dopamine auto receptors
leading to a decrease of dopamine release. In
humans it has been found thate a low, non emetic
dose of APO induced yawning. APO also induced
yawning in rats and the behaviour is believed
tio reflect autoreceptor stimulation.
Consequently it may be used to assess drugs
potentially active on dopamine
autoreceptors.
The presebt study was undertaken to
investigate the yawning dose-ressponse to APO
and the sensitivity of this yawning to
sulpiride, a neuroleptic that may be a selective
blocker of dopamine autorecptors at the doses
tested here. The enantiomers of the recently
synthetised compound
3-(3-hydroxyphenyl)-N-n-propyl piperidine
(3-PPP) are believed to be active on dopamine
autoreceptors and their ability to induce
yawning was therefore tested. We report the
inability of (-)-3-PPP to induce yawbning, while
(+)-3-PPP was as efficient as APO in this
respect. [...]
Discussion : The present study
confirm the finding that invery low doses APO
indices yawning. This has also been observed in
man. Yawning in rats is believed to reflect
stimulation of dopaminergic autoreceptors.
Sulpiride, considered to selectively block these
autoreceptors at low doses blocked this effect
in a dose-dependent manner, giving evidence for
the dopaminergic nature of the yawning
response and its possible mediation by
autoreceptors. It is not plausible that the
response could be due to stimulation of
peripheral dopamine receptors since domperidone
does not antagonise APO induced yawning.
3-PPP has been developed as a selective
autoreceptor agonist and its recent resolution
into the (+)- and (-)-enantiomers revealed that
(+)-3PPP may be an autoreceptor agonist at low
doses while higher doses also stimulate
postsynaptic receptors. Only the lower dose
range was tested in the present study but our
findings agree with those of Hjorth et al.
(1982) concerning the autoreceptor stimulating
properties of the drug. However, (-)-3-PPP did
not mimic the effect of a low dose of APO in the
present study. Hjorth et al. (1982) suggested
that the (-)form may stimulate autoreceptors at
low doses and block postsynaptic receptors at
higher doses.
It was also recently reported that both
enantiomers reduce exploratory locomotion when
they are given intraaccumbens. The present
findings give no clear evidence for autoreceptor
stimulating properties of (-)-3PPP. This
conclusion is also supported by the recent
finding that the (+)-enantiomer, but not the
(-)-enantiomer, reduced the in vivo release of
dopamine and DOPAC from the striatum.
Furthermore, sulpiride does not antagonize the
behavioural suppression of (-)-3-PPP as is the
case for other dopamine agonists). Thus,
evidence from several different models used to
assess stimulation of dopamine autoreceptors
cast doubt upon the ability of (-)-3-PPP to
stimulate dopamine autoreceptors selectively. In
contrast the yawning behaviour induced by
(+)-3-PPP is sensitive to sulpiride suggesting
that the same mechanism is responsible for the
effects of APO and (+)-3-PPP.
In summary, the present study supports the
idea that yawning behaviour may be used as an
index of dopamine autoreceptor stimulation.
Using this model it was found that (+)-3-PP but
not (-)-3-PPP may posess autoreceptor
stimulating properties comparable with those of
a low dose of APO.
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201-209 9
