SKF 38393
potentiates yawning induced by LY 171555:
further evidence against the autoreceptor
hypothesis of yawning
L Spina, R Longoni, A Mulas, G di
Chiara
Institute of experimental
pharmacology and toxicology, Univesity of
Cagliari, Italy
Dopamine (DA) receptor agonists active on
D-2 receptors share the property of eliciting
yawning in rats (Protais
et al. 1983; Gower et al. 1984; Longoni
et al. 1987a). The receptors mediating this
effect have been initially identified as
"autoreceptors" on the basis of the observation
that this behaviour is elicited by DA-agonists
devoid of behavioural stimulant effects and is
blocked by DA receptor antagonists active at D-2
receptors (Gower et al. 1984;
Stahle and Ungerstedt 1984; Ferrari 1985).
As supporting evidence for the latter view has
been regarded the fact that DA-agonists also
elicit yawning in the low-dose range, i.e. at
doses superimposable to those eliciting typical
autoreceptor effects such as hypomotility and
sedation (Gower et al. 1984; Stahie and
Ungerstedt 1984; Serra et al. 1986).
In contrast with this hypothesis, we first
suggested that yawning is due to stimulation of
D-2 receptors located on structures
post-synaptic to the dopaminergic ones (Morelli
et al. 1986); this suggestion was based on the
observation that yawning induced by the D-1 D-2
agonist apomorphine was reduced by blockade of
D-1 receptors with the specific D-1 antagonist
SCH 23390 and potentiated by a 12 h reserpine
pretreatment (Morelli
et al. 1986). From these results it appeared
that agonist-induced yawning responds to certain
pharmacological treatments in much the same way
as a typical post-synaptic D-2 response such as
hypermotility and stereotypy, which is also
blocked by SCH 23390 (Longoni et al. 1987 b) and
shows supersensitivity after a subacute
reserpine pretreatment (Di Chiara and Gessa
1975).
If this hypothesis is correct, yawning in
response to specific D-2 agonists should be
under permissive control by endogenous DA acting
on D-1 receptors (Longoni et al. 1987b). In
aggreement with this possibility, the D-1
antagonist SCH 23390 also reduces the yawning
elicited by D-2 agonists such as LY 171555 and
BHT-920 (Longoni et al. 1987a). It remains to be
established, however, if yawning, like typical
post-synaptic D-2 responses, is potentiated by
concurrent administration of a D-1 receptor
agonist (Mashurano and Waddington 1986; Longoni
et al. 1987 b). Here we report the results of
such investigation.
Materials and methods
Male Sprague-Dawley rats (Charles River,
Calco, Como, Italy) weighing 180-200 g were
housed six per cage and kept in a temperature
and humidity controlled room under a 12 h
light/dark cycle (6 a.m.-6 p.m.) with food (rat
chow) and water ad lib. After reception from the
supplier the rats were allowed about 1 week to
recover before the experiment. Experiments were
performed between 4 p.m. and 6 p.m.
The day before the experiment the rats were
transferred to individual wire mesh cages (40x25
x 15 cm high) for adaptation. Yawning was
measured blindly by direct observation by two
independent observers as number of yawns in a
60-min period.
The following drugs were used: LY 171555
(Eli Lilly Co., USA), SCH 23390 (Essex-Schering,
Italy). SKF 38393 (Smith, Kline and French, USA)
dissolved in saline (0.1 mg/ 100 g) and
administered SC.
Analysis of variance (ANOVA) followed by
student's t-test for individual comparison or
Dunnett's t-test for multiple comparisons was
applied to evaluate the significance of the
results obtained.
Results and conclusions
Figure 1 shows the dose-response curve for
LY 171555-induced yawning in control rats and in
rats pretreated with SKF 38393 (2.5 mg/kg SC 15
min before LY 171555); clearly, pretreatment
with SKF 38393 increased the incidence of
yawning over the whole range of the LY 171555
dose-response curve with a resulting shift to
the left.
SKF 38393 by itself failed to elicit yawning
at any of the doses tested (2.5, 5.0 and 10.0
mg/kg SC). The potentiating effect of SKF 38393
(2.5 mg/kg SC) on yawning was abolished by low
doses of SCH 23390 (0.012 mg/kg SC 10 min before
LY 171555) which in turn failed to affect
yawning elicited by LY 171555 (0.025 mg/kg SC)
alone (LY 171555: 3.8±0.5; SKF 38393+LY
171555: 9.6±1.3; SCH 23390+SKF 38393+LY
171555: 3.2±0.5*; SCH 23390+LY 171555:
4.2±0.6; mean±SEM of yawns recorded in
five rats during 1 h after SKF 38393;
*p<ØQ5 as compared to SKF 38393+LY
171555).
The main finding of the present study is
that administration of low doses of the D-1
agonist SKF 38393, while failing to elicit
yawning by itself, facilitated the expression of
yawning as a result of stimulation of D-2
receptors by the D-2 agonist LY 171555. That the
effect of SKF 38393 was due to stimulation of
D-1 receptors is demonstrated by the observation
that it was abolished by low doses of the D-1
antagonist SCH 23390 which failed to affect
yawning by LY 171555 alone. These results show
that stimulation of D-1 receptors exerts a
facilitatory influence on the expression of
yawning in much the same way as observed for the
expression of typical post-synaptic responses
such as hypermoility and stereotypy (Longoni et
al. 1987b).
Therefore, these results support the
contention that yawning, rather than an
autoreceptor-mediated response, is a
post-synaptic response.
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Spina, R
Longoni, A Mulas, G di Chiara SKF 38393
potentiates yawning induced by LY 171555:
further evidence against the autoreceptor
hypothesis of yawning Psychopharmacology 1989;
98; 567-568
