Drugs
Affecting Dopamine Neurons and Yawning
Behavior
E. Mogilnicka V. Klimek
Institute of Pharmacology,
Polish Academy of Sciences, Cracow,
Poland
The intracerebral injection of ACTH in
mammals induces a peculiar syndrome
characterized by stretching of the body and
intensive yawning. The secretion of the
hypothalamic hormones (releasing and inhibiting
factors) is regulated in large part neuronal
circuits in the hypothalamus and adjacent areas
of the brain and two of the principal
transmitters in these circuits are noradrenaline
(NA) and dopamine (DA) [8]. In rats
apomorphine causes similar symptoms as ACTH
does, therefore it seemed interesting to check
this phenomenon more thoroughly. The effect of
different DA agonists and antagonists was tested
on rats in this respect.
Method : All experiments were performed on
male albino Wistar rats weighing 180-260 g.
Behavioral observations were made while the
animals were individually housed in wire net
cages at room temperature of 20-2l°C. Food
and water were withdrawn during behavioral
observation. Number of yawnings were counted
immediately after DA agonist administration
during 0.5 hr period of time after apomorphine
or piribedil or during 1 hr after d-amphetamine,
nomifensine and L-DOPA.
The DA agonists were used in doses which did
not produce behavioral stimulation. The
neuroleptics were given before the DA agonists
as follows: butaclamol 0.5 hr, spiperone 1 hr,
pimozide 3.5 hr, reserpine 24 hr. All the DA
agonists, except L-DOPA were injected
subcutaneously as aqueous solution. L-DOPA IP as
suspension in 1% Tween 80 was used together with
a decarboxylase inhibitor (Ro 4-4602) given in a
dose of 25 mg/kg IP, 0.5 hr before L-DOPA.
a-Methyltyrosine methylester (a-MT) was injected
IP 5 hr before DA agonists. The statistical
calculations were performed with the U-Whitney
test, groups consisted of 10 rats. Data
represent medians. The following substances were
used: d-amphetamine sulfate (Smith Kline
& French), apomorphine HCI
(Sandoz), butaclamol HCI (Ayerst
Laboratories), L-DOPA (Reanal),
a-methyltyrosine methylester (Sigma),
nomifensine maleate (Hoe 984, Hoechst), pimozide
(Janssen Pharmaceutica), piribedil
(ET-495), Laboratoires Servier),
reserpine (Serpasil, Ciba), Ro 4-4602
(N-D,L-a-seryl-N(2,3,4-trihydroxybenzyl)-hydrazine
hydrochloride, Hoffman-La Roche),
spiperone (Janssen Pharmaceutica).
Results : After small doses of DA
agonists used (apomorphine, piribedil,
amphetamine, nornifensine and L-DOPA) peclfiar
behavior, characterized by
recurrent episodes of
yawning, chewing and penile erection
could be seen. These effects began at
approximately the same time for all drugs, ie.,
10-30 min after injection and lasted up to 30
min for apomorphine and piribedil and about 60
min for the rest of drugs used. Apomorphine,
piribedil and L-DOPA were more effective than
other drugs. Yawning appeared quickly with
high frequency (mean value 10 episodes of
yawning per 0.5 hr). After all drugs frequent
grooming spells (performed with forelegs,
hindlegs or head on the body) were seen during
observation.
The yawning response produced by
apomorphine was completely inhibited by
spiperone (0.1 mg/kg), butaclamol (0.6 mg/kg)
and pimozide (0.4 mg/kg) (Fig. 2). All the
neuroleptics given alone did not induce yawning
in doses used.
In rats injected with apomorphine (0.05
rng/kg) and pretreated with high dose of
reserpine (7.5 mg/kg) yawning movements were
reduced (Fig. 1); simultaneously stereotyped
behavior consisting of continuous explorative
sniffing was observed. Also a-MT (250 mg/kg)
reduced significantly frequency of yawning after
apomorphine but did not influence general
behavior of rats. A similar effect (as a-MT) on
apomorphine induced behavior was produced by
combined treatment with reserpine and a-MT .
Neither reserpine, a-MT nor reserpine plus a-MT
influenced markedly amphetamine induced yawning.
Reserpine did not change frequency of yawning in
nomifensine 0.5 mg/kg treated rats. Pretreatment
with a -MT or reserpine plus ci -MT counteracted
the development of yawning caused by
nomifensine. Nomifensine in a high dose (30
mg/kg) produced stereotyped behavior (sniffing,
licking) but did not induce yawning. The
pretreatment with reserpine counteracted
nomifensine-induced stereotypy whereas frequent
yawning was seen. The combined treatment with
reserpine and a-MT prevented stereotypy as well
as yawning caused by nomifensine.
Discussion : The present observations
showed that drugs stimulating the DA neurons in
different ways, given to the rats in low doses,
not producing the typical symptoms of behavioral
excitation (hypermotility, rearing, stereotypy),
induced yawning often accompanied by penile
erection. Yawning appeared after apomorphine
and piribedil, drugs directly influencing DA
receptors, amphetamine and nomifensine, drugs
with DA releasing and DA uptake inhibiting
properties as well as after L-DOPA, precursor of
DA. Frequency of yawning was much higher after
apomorphine or piribedil when compared with the
remaining drugs used. The yawning performance
was antagonized by spiperone, pimozide,
butaclamol, specific DA receptor blockers used
at smaller doses than those inducing catalepsy.
These results suggest that the yawning
activity may, at least, partly depend on
dopaminergic component. Similar conclusions
could be drawn from the results of experiments
with partly or completely monoamines depleted
rats. Reserpine and a-MT given together
completely deplete DA from its nerve terminals
and in such treated rats amphetamine and
nomifensine did not induce yawning. It seems
therefore that in DA agonists evoked yawning
release of DA and inhibition of DA uptake
displayed by these drugs may be of some
importance.
In the present study it was also found that
pretreatment of rats with a-MT reduced
apomorphine induced yawning. We have no
explanation for this observation since
apomorphine is supposed to act directly on DA
receptors. It seems also that for performance of
yawning only minute DA-ergic stimulation is
necessary. Doses of DA agonists higher than
those used in our experiments provoke symptoms
characteristic for strong stimulation of DA
receptors. Nomifensine, acting via release of DA
from reserpine sensitive pools, in 30 mg/kg
produced stereotypy consisting of sniffing and
licking. In the reserpinized rats the same dose
induced intensive yawning instead of stereotypy,
probably acting on newly synthesized DA.
Carlsson et al. suggested that DA agonists are
able to activate two types of DA receptors (pre-
and postsynaptic) resulting in behavioral
inhibition and activation. It seems that
apomorphine at the dose used in these
experiments (0.05 mg/kg) influences mainly
presynaptic DA receptors but some level of
stimulation of postsynaptic DA receptors may
occur too. In reserpine pretreated rats the DA
receptor stimulation produced by apomorphine
could be shifted more into direction of
postsynaptic receptors, due to supersensitivity
developed, and therefore it manifests in
sniffing.
In conclusion, our results indicate that
yawning appears after DA agonists and that
blockade of DA receptors counteracts this
effect. Obviously, more detailed studies will be
needed before anything conclusive can be said
the exact nature of this
phenomenon. Appearance
yawning may be useful in screening studies
because indicate a dopaminergic component of
action of investigated drugs.
-Hipolide DC; Lobo
LL; De Medeiros R; Neumann B; Tufik S
Treatment with dexamethasone alters yawning
behavior induced by cholinergic but not
dopaminergic agonist. Physiol Behav 1999; 65;
4-5; 829-32
-Hipolide
DC, Tufik S Paradoxical sleep deprivation in
female rats alters drug-induced behaviors
Physiol Behav. 1995; 57; 6; 1139-1143
-Mogilnicka E,
Klimek V Drugs affecting dopamine neurons
and yawning behavior. Pharmacol Biochem Behav
1977; 7; 303-305
-Molgilnicka
E REM sleep deprivation changes behavioral
response to catecholaminergic and serotoninergic
receptor activation in rats Pharmacol Biochem
Behav 1981; 15; 1; 149-151
-Neumann BG,
Troncone LR, Braz S, Tufik S Modifications
on dopaminergic and cholinergic systems induced
by the water tank technique: analysis through
yawning behavior Arch Int Pharmacodyn Ther 1990;
308; 32-8
-Stoessl
AJ Effects of ageing on the behavioural
responses to dopamine agonists: decreased
yawning and locomotion, but increased stereotypy
Brain Research 1989; 495; 20-30
-Tufik S et
al Effects of stress on drug induced yawning
Physiology & behavior 1995; 58; 1;
1881-184
-Tufik S
Does REM sleep deprivation induce subsensitivity
of presynaptic dopamine or postsynaptic
acetylcholine receptors in the rat brain?
European Journal of Pharrnacology 1987; 140;
215-219
Mogilnicka E,
Klimek V Drugs affecting dopamine neurons
and yawning behavior. Pharmacol Biochem Behav
1977; 7; 303-305
R Brus
, R Szkilnik, RM Kostrzewa Nitric oxide (NO)
and central dopamine (DA) D3 receptor reactivity
to quinpirole in rats Act Neurobiol Exp 1996;
56; 15-19
Kostrzewa RM and R
Brus Is dopamine-agonist induced yawning
behavior a D3 mediated event? Life Sci 1991; 48;
26; 129
Kostrzewa
RM, Brus R. Ontogenic homologous
supersensitization of quinpirole-induced yawning
in rats. Pharmacol Biochem Behav.
1991;39(2):517-519.
Eguibar
JR et al Behavioral differences between
selectively bred rats: D1 versus D2 receptors in
yawning and grooming Pharmacology; Biochemistry
and Behavior 2003; 74; 827-832
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
