Apomorphine-induced
yawning in rats is abolished by
bilateral
6-hydroxydopamine lesions
of the
substantia nigra
A.J. Stoessl, C.T. Dourish, S.D.
Iversen
Merck Sharp & Dohme
Research Lab, Harlow, Essex, UK
Yawning is a physiological response
that occurs spontaneously, and is associated
with fatigue and recovery from stress. Numerous
pharmacological agents induce yawning behaviour
in animals, including the peptide hormones ACTH,
a-MSH, prolactin and oxytocin. The cholinergic
agents physostigmine and pilocarpine induce
yawning in association with chewing mouth
movements, and this is inhibited by muscarinic
but not nicotinic blockade. Finally, numerous
investigators have demonstrated yawning and
sexual arousal in response to apomorphine and
other dopamine agonists, at doses presumed to be
selective for presynaptic autoreceptors.
Dopamine agonist-induced yawning is inhibited by
selective D2 antagonists but may be either
attenuated or potentiated by presynaptic
dopamine depletion with reserpine. It has thus
been proposed that yawning results from
disinhibition of striatal cholinergic activity
which is under tonic dopaminergic inhibition,
mediated by selective activation of
autoreceptors located on nigral dopamine cells
or their striatal terminals.
Previous work provided further support for
the hypothesis that nigrostriatal dopaminergic
autoreceptors are necessary for the behaviour
induced by low doses of apomorphine. It was
found that chemical denervation with
intrastriatal 6-hydroxydopamine (6-OHDA)
abolished the yawning-penile erection syndrome
in rats. Two potential problems with that study
required further delineation, however. First, it
is conceivable that the relatively high dose of
6-hydroxydopamine employed (16 µg) could
exert non-selective toxicity, thereby affecting
post-synaptic striatal receptors. SeconD1y, only
a single dose of apomorphine (100 µg/kg SC)
was used. Since the dose response curve for
apomorphine-induced yawning is bell-shaped, a
marked shift of this curve to the left could
explain the failure of apomorphine to induce
yawning in chemically-lesioned animals.
In the present study, we have addressed
these issues by producing cell body lesions of
the substantia nigra using 6-OHDA, and by
examining the effects of a range of doses of
apomorphine.
Discussion
These results clearly indicate that
apomorphine-induced yawning is dependent on
intact nigrostriatal dopamine projections.
Although some yawning following apomorphine was
seen in the lesioned animals, this was greatly
attenuated when compared to controls.
Preservation of a partial response is not
surprising, since the biochemical data indicate
only moderate depletion of striatal dopamine,
suggesting that the lesions were incomplete. The
most logical explanation for these findings is
mediation of the behavioural syndrome by the
action of apomorphine on dopamine autoreceptors
located on presynaptic nigrostriatal terminals
and! or nigral cell bodies. Autoreceptor
activation would result in suppression of tonic
activity in the dopamine neurons and secondary
disinhibition of striatal cholinergic
interneurons. Mediation of yawning by dopamine
terminal autoreceptors seems likely, as yawning
is also abolished by striatal 6-OHDA lesions and
is induced by injections of dopamine agonists
into striatum and nucleus accumbens but not by
injections of these drugs into substantia nigra
or ventral tegmental area. Administration of
dopamine agonists into the accumbens is much
less effective in eliciting yawning than are
striatal infusions. This may explain the
blockade of yawning in our animals, despite
intact dopamine projections to the
accumbens.
It has been argued that the yawning response
is mediated by a special class of high-affinity
post-synaptic dopamine receptors. Attenuation of
the response in chemically denervated animals
could then be explained by post-synaptic
dopamine receptor supersensitivity and induction
of stereotypy in these animals by low (i.e.
putative "autoreceptor") doses of apomorphine.
The present data show that this is unlikely to
be the case, however, for two reasons. First,
the yawning dose response curve was not shifted
to the left in the lesioned animals, but simply
lowered in amplitude. SeconD1y, there were no
significant increases in stereotyped sniffing
and chewing behaviour in the lesioned
animals.
Other investigators have examined the
effects of dopamine depletion on agonist-induced
yawning, using reserpine and/or
a-methyl-para-tyrosine. M ogilnicka and Klimek
(1977) reported that both drugs attenuated the
yawning induced by a single dose (50 µ/kg
SC) of apomorphine, while Yamada and Furukawa
(1980) observed increased yawning following 250
µg/kg IP. Morelli et al. (1986) found that
16-h pretreatment with reserpine shifted the
apomorphine-induced yawning dose response curve
to the left, but the same group have recently
shown that 6-h pretreatment with reserpine
(sufficient to result in 95% dopamine depletion)
shifts the yawning dose response curve for other
dopamine agonists (BHT 920, LY 171555 &
(+)-3-PPP) to the right. The effects of
reserpine on autoreceptor-mediated responses are
uncertain at this time. Clearly, reserpine
treatment cannot be considered equivalent to
chemical denervation with 6-OHDA. This is
particularly well demonstrated by the induction
of spontaneous yawning in rats receiving
reserpine 24 h earlier, a response not seen in
our 6-OHDA denervated animals.
Although it is attractive to postulate that
these findings provide further support for the
view that yawning is elicited by auto
receptor-mediated inhibition of tonic
dopaminergic cell firing and secondary release
of striatal cholinergic activity, a number of
observations are not adequately explained by
this hypothesis, and require further comment.
First, although racemic and (+)-3-PPP induce
yawning, the (-)enantiomer, which is a selective
agonist at autoreceptors, and a postsynaptic D2
antagonist , does not. Although such an agent
should clearly result in marked disinhibition of
striatal cholinergic neurons, its in vivo
effects are complex. Thus, (- )-3-PPP stimulates
contralateral circling in animals with
unilateral 6-OHDA lesions, an action
characteristic of post-synaptic dopamine agonist
activity, but increases striatal dopamine
synthesis and turnover, suggesting antagonist
activity. Furthermore, (-)-3-PPP-induced
suppression of locomotor activity is insensitive
to D2 blockade, and the (-)-enantiomer, but not
(+)-3-PPP, is a weak serotonin antagonist and
this may also influence yawning behaviour.
One other difficulty with the hypothesis
that apomorphine-induced yawning is
presynaptically mediated is the demonstration
that it can be blocked by treatment with the
selective D1 antagonist SCH-23390, as well as D2
antagonists. It has been argued that this is
evidence against the pre-synaptic mediation of
yawning, as D1 receptors have generally been
thought to be located post-synaptically. The
selective D1 agonist SKF-38393 does not induce
yawning. Hoever, SCH-23390 does increase the
firing rate of nigral dopamine neurons, although
it fails to attenuate apomorphine-induced
inhibition of nigral cell firing and recent
autoradiographic evidence suggests that
SCH-23390 may in fact bind to nigral
dopaminergic neurons. Furthermore, SCH-23390 was
ineffective in further decreasing dopamine
agonist-induced yawning in reserpinized animals,
and yet attenuated the yawning induced by B-HT
920 (a selective dopamine autoreceptor agonist
in non-denervated animals; even in animals with
kainate lesions of the striatum. These findings
suggest to us that D1 and D2 receptors may be
coupled presynaptically as well as
postsynaptically, as has been previously
suggested by others.
Finally, the relationship between the role
of dopamine autoreceptors and peptide hormones
in the induction of yawning is far from clear.
Laping and Ramirez (1986a) have recently
demonstrated that prolactin induces yawning, and
have furthermore shown that this is abolished
(as is that induced by apomorphine) by 6-OHDA
lesions of the nigrostniatal tract. This
suggests that prolactin may have an inhibitory
effect on the dopaminergic neurons, similar to
that resulting from stimulation of
autoreceptors. Melis and colleagues (1986) have
reported induction of yawning by oxytocin and
have localized this response to the
paraventricular nucleus of the hypothalamus.
Furthermore, they have found that apomorphine is
also extremely potent when microinjected into
this region. On the basis of other work, they
suggest that hypothalamic oxytocin neurons lie
downstream to dopaminergic terminals in the
response, since apomorphine-induced yawning was
blocked by pretreatment with an oxytocin
antagonist. Stimulation of oxytocin mechanisms
may elicit yawning by an action on ACTH , a
peptide which has been known for many years to
produce yawning. While dopamine-oxytocin
interactions in the hypothalamus may indeed be
one potential means for expression of the
yawning response, they do not explain its clear
reliance on an intact nigrostriatal dopamine
system, as demonstrated in this paper and
previously, unless one postulates that the
nigrostriatal lesions abolish the response by
non-specific effects on motor activity. This
would appear to be unlikely, in view of the
induction of spontaneous yawning by a dose of
reserpine (5 mg/ kg) sufficient to produce
catalepsy. One can only speculate that yawning
may either result from activation of a number of
independent brain mechanisms, or that there is
some final common pathway which is recruited by
many converging routes, perhaps culminating in
hippocampal spreading depression.
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