Antagonism
of apomorphine-induced yawning by SCH 23390:
Evidence against the autoreceptor hypothesis
M. Morelli, R. Longoni, L. Spina, and G. Di
Chiara
Institute of Experimental
Pharrnacology and Toxicology,
University of Cagliari
Italy
It has been recently suggested that the
yawning syndrome (YWG) elicited in rats by
low doses of dopamine (DA) receptor agonists is
due to stimulation of DA-autoreceptors (Gower et
al. 1984; Stahle
and Ungerstedt 1984). An antagonist of DA
receptors has recently became ovailable, the
benzazepine SCH 23390 (Hyttel 1984), which has
affinity for D-1 receptors about 3 orders of
magnitude higher than for D-2 receptors. Since
DA autoreceptors are of the D-2 type (Hyttel
1984), SCH 23390 is not expected to interact
with DA autoreceptors at concentrations
sufficient to block D-1 receptors; in fact SCH
23390 is a very poor antagonist of putative DA
autoreceptor-mediated effects both in vitro and
in vivo (Hyttel 1984, Gessa et al. 1985). We now
report that apomorphine-induced YWG is
potentiated by a 16 h depletion of central
catecholamine stores with reserpine and is
blocked both in normal and reserpine-pretreated
rats by low doses of SCH 23390,
Materials and methods
Male Sprague-Dawley
rats (Charles River, Italy) of 180-200 g
were administered reserpine (Serpasil, Ciba) at
a dose of 5.0 mg/kg IP and 16 h thereafter the
rats showing the typical reserpine syndrome
consisting of palpebral ptosis, sedation and
hunched-back posture were selected and
transferred to Perspex testing cages (40 x 25 x
15 cm bigh). Control rats were given saline (0.2
rni/kg IP) in place of reserpine. After a 60-min
adaptation period, the rats were pretreated SC
in the flank with saline (0. 1 ml/1 00 g) or
with 0.05 mg/kg SCH 23390 (kindly provided by
Dr. Ongini, Essex-Schering, Italy) dissolved in
saline. Fifteen minutes later the rats were
injected SC in the neck with different doses of
apomorphine and the number of yawnings with or
without stretching was recorded during 45 min of
observation. ED5O with 95% confidence limits
were calculated by logprobit analysis.
Significant differences were determined by
two-tailed Student's t-test following ANOVA.
Results and discussion
Apomorphine showed a bell shaped dose-effect
curve for YWG in normal and reserpinized rats.
In fact, as shown in Table 1, in normal and
reserpinized rats apomorphine maximally
stimulated YWG at doses of 0.080 and 0.025 mg/kg
SC, respectively, with lower or higher doses
being less effective. After doses higher than
0.025 mg/kg SC in reserpinized rats and higher
than 0.080 in normal rats YWG was replaced by
stereotyped hypermotility and sniffing. The ED50
(dose of apomorphine in mg/kg SC eliciting at
least ten yawnings in 50% of the rate) with 95%
confidence limits (in parentheses) was 0.015
(0.09-0.022) in reserpinized rats and 0.063
(0.042-0.094) in non-reserpinized rats.
Pretreatment with 0.05 mg/kg SC SCH 23390
effectively antagonized YWG induced by low doses
of apomorphine both in normal and in
reserpinized rats (Table 1). After doses of
apomorphine higher than those maximally
effective in inducing YWG, SCH 23390
pretreatment apparently facilitated YWG. After
SCH 23390 pretreatment the ED50 (wiht 95%
confidence limits) of apomorphine for YWG in
normal and in reserpinized rat was,
respectively, 0.38 (0.25-0.57) and 0.084
(0.056-0.126).
This study shows that the ED50 for
apomorphine-induced YWG is significantly
lowered, as indicated by the non-overlapping 95%
confidence limits, by a 17-h depletion of
catecholamine stores with reserpine and is
significantly increased by pretreatment with a
low dose of SCH 23390 in normal and in
reserpine-pretreated rats. These results
indicate that 17-h reserpine pretreatment
potentiates wthe ability of apomorphine to
induce YWG while SCH 23390 pretreatment blocks
it. The ability of a 17-h reserpine pretreatment
to potentiate apomorphine-induced YWG appears
analogous to the potentiation of apomorphine
stereotypy induced by reserpine pretreatment and
can be explained as post-synaptic
supersensitivity consequent to the
reserpine-induced interruption of DA
transmission (Di
Chiara and Gessa 1978). The ability of SCH
23390 to block apomorphine-induced YWG in
reserpinized rats is in keeping with a
post-synaptic origin of this behavioural
syndrome; in fact SCH 23390, at low doses, is
expected to be devoid of effects on D-2
receptors in general (Hyttel 1984) and on DA
autoreceptors in particular both in vitro
(Hyttel 1984) and in vivo (Gessa et al.
1985).
The finding that SCH 23390 reduced
apomorphine-induced YWG also in reserpinized
rats is in agreement with the observation that
SCH 23390 potently blocks apomorphine stereotypy
not only in normal rats but also in rats
pretreated with reserpine (Arnt 1985; Breese and
Mueller 1985). Since SCH 23390 seems to acquire
in vivo D-1 specificity after 24-h
reserpine-a-methyltyrosine-induced depletion of
catecholamines (Breese and Mueller 1985), our
observation could be interpreted to indicate
that D-1 receptors contribute to the YWG
induced by apomorphine in reserpinized
rats.
The observation that SCH 23390 facilitates
YWG after high doses of apomorphine can be
explained if one considers that these doses are
in the descending part of the bellshaped
dose-response curve for apomorphine-induced YWG.
At these doses of apomorphine, the expression of
YWG is reduced as a result of the emergence of
competing behavioural items (locomotion,
sniffing). Accordingly, the ability of SCH 23390
to potentiate YWG at high doses of apomorphine
is a reflection of an overall shift to the right
of the bell-shaped dose-response curve for
apomorphineinduced YWG which in turn might be
the result of the DA-receptor blockade by SCH
23390.
Our results directly contradict the
hypothesis that apomorphine produces YWG by
acting on DA autoreceptors. In fact, if this
hypothesis were true, reserpine pretreatment
would have abolished the ability of apomorphine
to induce the behaviour and SCH 23390, in view
of its D-1 specificity, would have been
ineffective at low doses. Indeed, the
autoreceptor hypothesis of DA agonist-induced
YWG is based solely on the fact that this
behaviour is evoked by low doses of DA agonists
and is blocked by (-)sulpiride at doses which
are considered specific for DA autoreceptors
(Gower et al. 1984; Stahle and Ungerstedt 1984).
It is conceivable, however, that the same dose
of DA agonist could elicit DA
autoreceptor-mediated effects or post-synaptic
effects depending on the baseline activity of
the animals; indeed low doses of apomorphine
elicit hypomotility and sedation in rats exposed
to a novel environment (Di Chiara and Gessa
1978) while inducing YWG in well adapted
rats.
The effectiveness of (-)sulpiride as an
antagonist of apomorphine YWG (Stahle and
Ungerstedt 1984) simply indicates that this
effect is at least in part mediated by D-2
receptors but does not allow any conclusion on
their location. The ability of SCH 23390 to
block apomorphine-induced YWG suggests that not
only D-2 receptors but also D-1 receptors can be
operative in eliciting this behavioural
syndrome. Therefore, blockade of DA
agonist-induced YWG is a further addition to the
list of those effects of SCH 23390 like
sedation, hypomotility and catalepsy (Morelli
and Di Chiara 1985), blockade of conditioned
avoidance responding, blockade of DA-agonist
induced hypothermia (Carboni et al. 1986) and
stereotypy, which were previously considered as
typical of D-2 antagonists. IC as it seems,
these effects are due primarily to blockade of
D-1 receptors by SCH 23390 we should conclude
that the central functions of D-1 receptors are
largely superimposable to those of D-2 receptors
or/and that a certain degree of D-1 receptor
stimulation is essential for the full
behavioural expression of D-2 receptor
activation.
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