The effects
of pre and post-operative procedures on
physiostigmine and apomorphine induced yawing in
rats
Anne Bourson & Paul C
Moser
Merrell Dow Research
Institute, 16, rue d'Ankara, 67084 Strasbourg
Cedex, France
In
previous studies we have exarnined the
effects of dihydropyridine (DHP) calcium channel
blockers on yawning behavior in rats and have
shown that they can potentiate both apomorphine-
and physostigmine-induced yawning.
In order to evaluate the site of this
potentiation, part of these earlier studies
investigated the effect of 6-hydroxydopamine
lesions of the medial forebrain bundle (MFB) on
the interaction between the DHP calcium channel
blocker nifedipine and yawning induced by
either apomorphine or physostigmine. We found
that although sham-lesioned rats showed a normal
nifedipine potentiation of apomorphine induced
yawning, yawning induced by physostigmine was no
longer potentiated by nifedipine. This paper
examines aspects of the operative procedure that
might be responsible for this selective effect
against physostigmine-induced yawning.
[...]
Discussion :
These results show that not only the sham
operation procedure, but also 7 days isolation
or pretreatment with DMI and PB, can prevent the
nifedipine potentiation of physostigmine-induced
yawning. In this respect, the yawning response
to physostigmine differs from that to
apomorphine, which was still potentiated by
nifedipine after the complete sham operation
procedure (Table 1), suggesting that individual
components of the sham operation procedure would
also be ineffective in preventing the effect of
nifedipine.
We consider that the effects we have
described are due to the stress associated with
the procedures used. It is well established that
isolation is a stressful procedure which can
affect many behavioral and physiological
parameters in rats, and it has recently been
demonstrated that 28 days isolation can
significantly attenuate the yawning response to
dopamine agonists. Although the yawning
response to both physostigmine and apomorphine
was reduced by the sham operation procedure,
this effect was particularly marked for
physostigmine, consistent with previous
suggestions that cholinergic agonist-induced
yawning is more susceptible to modulation by
stress than that induced by dopamine
agonists. In addition, sham-lesioning abolished
the nifedipine potentiation of
physostigmine-induced yawning behavior, an
effect mimicked by either isolation for seven
days or pretreatment with DMI and PB. This
suggests that the interaction of nifedipine with
physostigmine-induced yawning is even more
susceptible to modulation by stress than yawning
behaviour itself.
The results obtained with DMI and PB
pretreatment may be due to the stress associated
with anesthesia. The combination of DMI and PB
was used as this was part of the original
protocol for sham-lesioning, the DMI being
included to prevent the uptake of 6-OHDA into
noradrenergic terminals in lesioned rats.
Although it is unlikely that the drug effects
themselves would have lasted 7 days, the
injection of physostigmine on the test day may
have induced a conditioned stress response,
similar to the conditioned emotional response.
Further evidence that this is not a direct
effect of drug treatment comes from the
demonstration that DMI will itself produce
yawning in rats.
As many studies suggest that
apornorphine-induced yawning is mediated via the
cholinergic system, the differences between
apomorphine- and physostigmine-induced yawning
were unexpected, and it is not clear ai present
why mildly stressful events should selectively
affect the interaction of nifedipine with
physostigmine. The dose-response curves for both
apomorphine and physostigmine-induced yawning
follow an inveried U-shape, and while the
apomorphine dose-response curve can be explained
by pre- and postsynaptic effects, that of
physostigmine is due te, secondary drug effects,
such as chewing and behavioral arousal, which
prevent the appearance of yawning.
It is possible that stressful events make
rats more sensitive to such secondary effects,
leading to a suppression of yawning. If these
inhibitory effects are sufficiently strong,
treatment with nifedipine may not be able to
increase yawning. The observations that stress
can markedly affect neurochemical parameters
associated with cholinergic function would
support such a proposal, although further work
is needed to determine the manner in which
stress changes the yawning response to
physostigmine. It should be noted that other
authors have remarked on the greater variability
of physostigmine-induced yawning compared to
apomorphine-induced yawning, particularly
between groups, and have suggested that this
effect of physostigmine is more susceptible to
external influence.
In conclusion, these results show that
relatively mild stress can affect
physostigmine-induced yawning in both a
quantitative manner (reducing the number of
yawns) and a qualitative manner (preventing its
interaction with nifedipine). Both these effects
appear to be specific for physostigmine-induced
yawning, as even when these procedures were
combined in the sham operation they only
slightly reduced apomorphine-induced yawning and
did not prevent its interaction with nifedipine.
It is clear that special attention towards
housing conditions and preinjection routines is
needed when studying yawning behavior, and that
such sources of variation must be eliminated
before accurate conclusions can be drawn frorn
the results. In the present case, for example,
results from stressed rats would suggest that
dihydropyridine calcium channel blockers have a
selective interaction with apomorphine induced
yawning, whereas, in fact, they interact with
both physostigmine- and apomorphine-induced
yawning and the site of this interaction is more
likely to be associated with cholinergic than
dopaminergic neurones.
