Yawning
and suppression of exploration in
amphetamine-treated rats, incompatibility with
the autoreceptor hypothesis
Stahle L, Ungerstedt U
Department of Pharmacology,
Karolinska Institute, Stockholm,
Sweden
Low doses of dopamine agonists have been
reported to reduce schizophrenic morbidity and
symptoms of hyperkinetic disorders. In view of
these clinical findings, it is important to
establish experimental models for effects of low
doses of dopamine agonists and to elucidate the
underlying pharmacological mechanisms. The two
behavioural models most commonly used for
studying the effects of low doses of dopamine
agonists are suppression of exploration in rats
and mice and induction of yawning behaviour in
rats. The presently most widely accepted
hypothesis to explain the mechanism underlying
these responses is the autoreceptor
hypothesis.
According to the autoreceptor hypothesis,
low doses of dopamine agonists cause behavioural
changes by reducing the synaptic levels of
dopamine via selective stimulation of dopamine
autoreceptors. Various effects of dopamine
autoreceptor stimulation may contribute to the
reduced synaptic levels of dopamine such as
decreased dopamine synthesis, decreased dopamine
release and inhibition of the electrical
activity of dopamine neurons.
The dopamine agonists do not, in the low
dose range, elicit the classical signs of
post-synaptic dopamine receptor stimulation,
such as stereotyped behaviour and
electrophysiological changes in striatal
neurons.
Recently, the autoreceptor hypothesis has
been questioned by several research groups.
Their conclusions were based on experiments
using reserpine or x-methyl-p-tyrosine to reduce
the synaptic levels of dopamine, which they
found did not affect the yawning response.
The present study was undertaken to further
test the autoreceptor hypothesis by using
amphetamine to increase the extracellular levels
of dopamine and to test if both yawning and
suppression of exploration could be elicited in
this situation. We found that yawning, as well
as suppression of exploration, can be elicited
by dopamine agonists in rats treated with
amphetamine in doses that are shown to increase
the extracellular levels of dopamine.
[...]
Discussion
The aim of the present study was to test the
hypothesis that both the yawning and the
suppression of exploration induced by dopamine
agonists are caused by a reduction of synaptic
dopamine levels due to stimulation of dopamine
autoreceptors. From this hypothesis, it may be
predicted that if the synaptic levels of
dopamine are increased above baseline then it
should not be possible to elicit either yawning
or suppression of exploratory behaviour.
In the present study we have used an
approach opposite to that of previous studies.
Instead of reducing the basal levels of dopamine
by reserpine or x-methyl-p-tyrosine we increased
the basal levels by amphetamine. Thus, we found
that pretreatment with amphetamine (0.2 mg/kg)
completely counteracted the decrease in
extracellular dopamine levels induced by
pergolide (0.02 mg/kg) and increased the
extracellular levels of dopamine to 300% of
baseline. This small dose of amphetamine was
also sufficiently large to induce a slight
behavioural activation, suggesting that this
dose cause a stimulation of postsynaptic
dopamine receptors.
Yawning behaviour induced by pergolide was
not significantly antagonised by amphetamine
(0.2 mg/kg) pretreatment. However, amphetamine
(0.2 mg/kg) did antagonise the yawning induced
by APO (0.05 mg/kg) although by no more than
30%. Thus, in spite of the fact that the levels
of extracellular dopamine were increased above
baseline it was possible to elicit yawning.
These findings strongly suggest that dopamine
agonist-induced yawning is not due to a decrease
in the extracellular levels of dopamine.
Further evidence against a direct
relationship between the induction of yawning
and reduction of extracellular dopamine levels
is that pergolide (0.02 mg/kg)-induced yawning
was most intense 20-30 min after injection while
the dopamine levels were lowest after between 80
and 100 min. This discrepancy in time has also
been found for APO- and EMD 23448-induced
behavioural effects and dopamine levels which
was interpreted as evidence against a connection
between dopamine levels and behaviour as
discussed in detail elsewhere.
Suppression of exploration induced by APO or
pergolide could not be counteracted by
amphetamine pretreatment. Two different
pretreatment times for amphetamine against
pergolide were used in order to test exploration
at the peak level of dopamine (20 mm) or at the
time point when the behavioural effects of
amphetamine should be at the maximum (30 mm)
according to Sharp et al. (1987). These results
are similar to those on yawning behaviour, in
the sense that it was possible to elicit the
characteristic effects of low doses of dopamine
agonists in spite of the fact that the
extracellular level of dopamine was increased
above baseline. In case autoreceptors were
involved in this response, amphetamine would
have been expected to counteract the APO- or
pergolide-induced suppression of exploration. We
therefore conclude that dopamine agonist-induced
suppression of exploration is not related to
reduced extracellular levels of dopamine.
Since our results are in apparent conflict
with the idea that low doses of dopamine
agonists induce behavioural changes by reducing
the synaptic levels of dopamine, some other
explanation must be sought. Although we cannot
exclude that dopamine agonists alter the release
of a co-transmitter to dopamine (e.g.,
cholecystokinin), we would like to put forward a
more easily testable hypothesis. We suggest that
yawning and suppression of exploration are
mediated by stimulation of populations of
postsynaptic dopamine receptors. These receptors
are probably of the D-2 type because of the
ability of sulpiride to antagonise both
responses. The fact that the apparent
sensitivity of these receptors is considerably
higher than the sensitivity of the receptors
mediating for example stereotyped behaviour can
easily be fitted into the framework of
Stephenson's receptor, theory (1956), which
allows for a receptor reserve. The existence of
a considerable receptor reserve (spare
receptors) in the receptor population
controlling dopamine synthesis has recently been
demonstrated. We suggest that this is also the
case for the receptor populations mediating
yawning and suppression of exploration. An
equivalent suggestion is that the fraction
(percentage) of spare (dopamine) receptors is
larger in the brain structures mediating
suppression of exploration and yawning than
those mediating induction of locomotion and
stereotyped behaviour.
Our hypothesis is further supported by the
finding that a large dose of amphetamine (2
mg/kg), in combination with the D-1 receptor
antagonist SCH 23390 (0.05 mg/kg) induced
yawning. This dose of amphetamine increases the
extracellular dopamine levels approximately 10
times above baseline and it induces strong
stereotyped behaviour. The yawning behaviour
elicited by combined amphetamine plus SCH 23390
treatment was not as intense as that induced by
APO or pergolide alone. Instead, the intensity
of yawning was comparable with that following
combined treatment with APO and SCH 23390 which
causes a 50% reduction in the APO-induced
yawning. The fact that yawning did not appear
unless amphetamine was combined with SCH 23390
may be explained as due to behavioural
competition, i.e., that the amphetamine-induced
stereotyped behaviour obscures yawning.
Stereotypies induced by dopamine agonists and
amphetamine are readily antagonised by SCH 23390
, suggesting a functional interaction between
D-1 and D-2 receptors. The present findings
indicate that a similar but less pronounced
interaction takes place in the mediation of
dopamine agonist induced yawning, as suggested
by Lognoni et al. (1987). Hence, SCH 23390 may
uncover stimulation of yawning mediating
dopamine receptors by dopamine released through
the action of amphetamine. A similar effect has
been described for APO given in a high dose
combined with various neuroleptics.
The use of conscious rats with microdialysis
probe guides implanted made it possible to
simultaneously monitor yawning behaviour and
changes in the extracellular levels of dopamine,
DOPAC, HVA and 5HIAA. However, the extent to
which extracellular levels of dopamine, as
sampled by microdialysis, actually reflect the
levels of dopamine in the synapses is not known.
Unfortunately, there is no method available to
investigate this problem and we are therefore
forced to make the assumption that the level of
dopamine in the dialysate is a function of,
among other factors, the synaptic level of
dopamine. Similarly, it may be questioned
whether or not the doses of amphetamine used in
the present study act in such a way that they
really overcome the decrease in dopamine release
following treatment with APO. It may be that APO
reduces the amount released per nerve impulse
while amphetamine increases the synaptic levels
between release events in the synapse.
Integrated over time the synaptic levels may
appear increased, but this would not be the case
during the transmission process. Again, we have
no way to test this possibility and we are
consequently forced to work under the assumption
that the transmission process in reality is
enhanced by amphetamine + APO compared to
baseline transmission.
In summary, in view of our findings that
dopamine agofists can induce yawning behaviour
and suppress exploratory behaviour when dopamine
neurotransmission is apparently enhanced, we
suggest that these behaviours are not the
consequence of autoreceptor stimulation, but
that they are mediated through a stimulatory
action on postsynaptic dopamine receptors.
-Stahle L,
Ungerstedt U Discrepancy in the time course
of EMD 23448 induced yawning and reduction of
extracellular dopamine Psychopharmacology 1989;
97; 275-276
-Stahle
L Do autoreceptors mediate dopamine
agonist-induced yawning and suppression of
exploration ? a critical review.
Psychopharmacology 1992; 106; 1-13
-Stahle
L, Ungerstedt U Assessment of dopamine
autoreceptor agonist properties of apomorphine,
(+)3ppp and (-)3ppp by recording of yawning
behaviour in rats Europ J Pharmacol 1984; 98;
307-310
-Stahle L,
Ungerstedt U Yawning and suppression of
exploration in amphetamine-treated rats,
incompatibility with the autoreceptor hypothesis
Psychopharmacology 1989; 97; 553-560
