Ushijima I, Mizuki Y, Soeda K, Kishimoto O,
Hara T, Yamada M
Depart Psychiatry. Yamaguchi
University. Japan
Abstract :
This study served to examine the
differential effects of age (rats aged 2 or 12
months) on behavioral responses induced by
bromocriptine and apomorphine. Intraperitoneal
(i.p.) injection of bromocriptine or apomorphine
produced a lower frequency of yawning responses,
in 12-month-old rats than in 2-month-old rats.
Apomorphine produced a more pronounced
stereotyped behavior in 12-month-old rats than
in 2-month-old rats. Apomorphine, at 0.1 mg/kg
administered after bromocriptine (1.0-20 mg/kg)
potentiated yawning behavior. The frequency of
yawning in 2-month-old rats was pronounced at
2.5 mg/kg of bromocriptine but only at 5 mg/kg
12-month-old rats. Apomorphine (0.1 mg/kg) did
not produce perioral behavior in 2-month-old
rats but did in 12-month-old rats. The
apomorphine (1.0 mg/kg)-induced stereotypy was
stimulated dose dependently by bromocriptine in
2-month-old-rats but not in 12-month-old rats.
Bromocriptine did not produce this behavior when
administered alone. Pretreatment of 2-month-old
rats with reserpine, a catecholamine depletor,
plus alpha-methyl-p-tyrosine, a tyrosine
hydroxylase inhibitor, inhibited the yawning
induced by bromocriptine but potentiated that
induced by apomorphine. Such treatment did not
significantly alter either bromocriptine or
apomorphine-induced yawning responses in
12-month-old rats. The apomorphine-induced
stereotypy in 2-month-old rats was markedly
potentiated by catecholamine depletion but was
not affected in 12-month-old rats. These results
suggest that the increasing effect on stereotypy
and decreasing effects on yawning in the
12-month-old rats seem to result in an
alteration of potency and of the ratio of D-2
versus D-1 receptor activity.
Introduction
It has been reported that the behavioral,
stereotypy-inducing actions of apomorphine are
increased in aging rats. These authors also
observed that the duration of action of
apomorphine greater in rats aged 20-24 months
than in rats aged 2 months suggesting that
either increased levels in brain or decreased
elimination of apomorphine may be important
factors contributing to the marked ircrease in
behavioral sensitivity to apomorphine with
increasing age in the rat. On the other hand,
direct binding studies with 3H-ligands indicate
an age-related decline in the density of
dopamine receptors in rat striata and human
striata. The decline of 3H-antagonist binding is
progressive with age and losses in receptor
density can be detected at midlife. Dopamine
agonist binding in striatum declines more
rapidly with age than does antagonist binding.
The major part of the decline of 3H-agonist
binding appears to occur before midlife in rats.
The total D-2 receptor population, as defined by
[3 H]spiperone binding, declined
progressively from 3 to 24 months, and
age-related changes were restricted to D-2
receptor density in mice. We found that
pretreatment with reserpine plus
a-methyl-p-tyrosine markedly potentiated the
yawning and stereotyped behaviors induced by
apomorphine, a dopamine receptor (both D-1 and
D-2 receptors) agonist, whereas this treatment
inhibited the yawning induced by bromocriptine,
a selective dopamine D-2 agonist.
Apomorphine-induced stereotypy was stimulated by
bromocriptine, which does not produce this
behavior when administered alone. Jenkins and
Jackson (1985) also reported that bromocriptine
has no behavioral efficacy per se at the
postsynaptic dopamine receptor and that it
requires either dopamine or the administration
of an exogenous agonist such as apomorphine for
the expression of its effects. The purpose of
the present study was to demonstrate the effects
of age on yawning and stereotyped behaviors
which are mediated mainly by D-2 and D-1
dopainine receptors in rats. This study was also
designed to investigate whether age-related
changes in these behaviors were primarily
determined by dopamine D-1 or D-2 receptor
activity, or by dopamine synthesis (tyrosine
hydroxylase activity).
Discussion
The study showed that the yawning behavior
induced by bromocriptine and apomorphine
decreased in 12-month-old rats whereas the
apomorphine-induced stereotypy was incr eased,
as compared with that of 2-month-old rats.
Apomorphine exerts biphasic effects on bahavior
i.e. yawning and hypomotility at low doses and
stereotypy and hyperlocomotion at higher doses.
This, bahavior has been suggested to be mediated
by cholinergic activation secondary to the
inhibition of dopamine transmission by
activation of presynaptic autoreceptors.
Furthermore, there is evidence suggesting that
acetylcholine release is controlled by the
dopamine D-2-receptor. Recently, we found that
bromocriptine-induced yawning was inhibited by
sulpiride, a selective dopamine D-2 receptor
antagonist. The yawing was characterized by the
head moving downward similarly to the effects
produced by apomorphine. The fact that
apomorphine-induced yawning responses are also
inhibited by sulpiride suggests that presynaptic
dopamine autoreceptors may be similar to
presynaptic D2 receptors. Most recently, SCH
23390, a selective D1 receptor blocker,
prevented apomorphine-induced yawning.
Increasing D-1 receptor activity intact adult
rat with the selective agonist SK&F an
potentiate stereotyped responses to the
selective D-2 agonist RU 24213. It was suggested
that dopamine receptors mediating yawning and
stereotypy may include not only D-2 but probably
also D-1 receptors. However, it appears from
this study that since the frequency of yawning
induced by bromociptine was more pronounced than
that induced by apomorphine, the yawning
behavior is mainly mediated via D-2 receptor
activity. Furthermore, apomorphine-induced
stereotypy was stimulated in a dose-dependent
manner by bromocriptine which did not produce
this behavior when administered alone.
Bromocriptine-induced yawning was also
potentiated by a low dose of apomorphine.
Bromocriptine but not apomorphine appears to
require another dopamine receptor agonist for
the induction of stereotypy. This suggests a
dissimilarity in the mode of action of
bromocriptine and apomorphine. The ability of
dopamine agonists to induce yawning and
stereotyped behaviors seems to depend upon the
ratio and potency of D-2 versus D-1 receptor
activity.
The yawning behaviors induced by
bromocriptine and by lower doses of apomorphine
were decreased with increasing age. The
frequency of apomorphine (0.1 mg/kg)-induced
yawning as potentiated by the combination with
bromocriptine was pronounced in 2-month-old rats
at the 2,5mg/kg dose of bromocriptine but at the
5 mg/kg dose in 12-month-old rats, suggesting
that dopamine D-2 receptor activity may be
attenuated in 12-month old rats. Conversely,
despite the age associated loss of striatal
dopamine receptors, apomorphine-induced
stereotypy in rats which is mediated by
stimulation of post-synaptic dopamine receptors
(including D-1 and D-2) was potentiated with
increasing age and appeared as perioral
movement. Apomorphine (0.1mg/kg) did not produce
stereotypy in 2- or in 12 month-old rats but
when combined with bromocriptine it increased
the stereotypy shownas discontinuous sniffing,
the cumulated scores for stereotypy of
12-month-old being higher than those 2-month-old
rats. The stereotypy induced by apomorphine (1.0
mg/kg) in 2-month-old rats was potentiated by
bromocriptine in a dose-dependent manner, but
was unaltered in 12-month-old rats, suggesting
that the activity of postsynaptic dopamine D-2
receptors mediating stereotypy was also
attenuated with advancing age.
Rosengarten et al. (1983) have shown that
abnormal mouth movements in rats can be induced
by selective D-1 receptor stimulation by SKF
38393 or by selective blockade of the D-2
receptor with sulpiride or spiroperidol. It
appears, therefore, that these perioral
movements are mediated by the D-1 receptor and
by an imbalance in D-1 and D-2 responsiveness.
Moreover, these authors found that whereas rats
treated with apomorphine alone displayed
stereotypy, the rats pretreated with sulpiride
showed perioral movements. The
apomorphine-induced perioral behavior that we
observed in 12-month-old rats may have been due
to a relative increase of dopamine D-1 receptor
activity secondary to the attenuation of
dopamine D-2 receptor activity.
Combined pretreatment with reserpine and a
methyl-p-tyrosine in 2-month-old rats inhibited
bromocriptine-induced yawning and potentiated
apomorphine-induced yawning, as compared with
their respective control groups. This was
consistent with the results of our previous
experiments. Catecholamine depletion in
12-month-old rats did not produce a significant
difference from the control group. The
apomorphine-induced stereotyped behavior of
12-month-old rats was less pronounced than that
of 2-month-old rats if the rats were pretreated
with reserpine plus a-methylp-tyrosine. The
inhibitory effect of reserpine plus
a-methyl-p-tyrosine on bromocriptine-induced
yawning behavior may have been due to the lack
of endogenous dopamine, whereas the stimulatory
effect of these drugs on apomorphine-induced
yawning and stereotypy may be due to dopamine
depletion based on the inhibition of dopamine
synthesis and stimulation of presynaptic
dopamine D-2 receptor activity. Furthermore,
important factors in the occurrence of yawning
include not only dopamine D-2 receptor
stimulation but also stimulation of D-1
receptors. The increasing effect on stereotypy
and decreasing effect on yawning in 12-month-old
rats seem to result from an alteration of the
potency and the ratio of D-2 versus D-1 receptor
activity.
-Fugikawa
M; Yamada K; Nagashima M; Furukawa T
Involvement of beta-adrenoreceptors in
regulation of the yawning induced by
neuropeptides; oxytocin and alpha-melanocytes
stimuling hormone in rats. Pharmacol Biochem
Behav 1995; 50; 339-343
-Furukawa
T Yawning behavior for preclinical drug
evaluation Meth Find Exp Clin Phamacol 1996; 18;
2; 141-155
-Kimura H;
Yamada K; Nagashima M; Matsumoto S Role of
adrenergic neuronal activity in the yawning
induced by tacrine and NIK-247 in rats.Pharmacol
Biochem Behav 1992; 43; 4; 985-91
-Kimura
H; Yamada K; Nagashima M; Furukawa T
Involvement of catecholamine receptor activities
in modulating the incidence of yawning in
rats.Pharmacol Biochem Behav 1996; 53(; 4;
1017-21
Ogura
H, Kosasa T, Kuriya Y, Yamanishi Y Central
and peripheral activity of cholinesterase
inhibitors as revealed by yawning and
fasciculation in rats. Eur J Pharmacol. 2001;
415; 2-3; 157-64
-Serra
G , Collu M and Gessa GL Yawning is elicited
by D2 dopamine agonists but is blocked by D1
antagonist Psychopharmacology 1987; 91;
330-337
-Serra G,
Gessa GL Hypophysectomy prevents yawning and
penile erection but not hypomotility induced by
apomorphine Pharmacology Biochemistry &
Behavior 1983; 19; 917-919
-Serra G
et al Cycloheximide prevents apomporphine
induced yawning, penile erection and genital
grooming in rats European Journal of
Pharmacology1983; 86; 279-282
-Kostrzewa RM
and R Brus Is dopamine-agonist induced
yawning behavior a D3 mediated event? Life Sci
1991; 48; 26; 129
-Ushijima I,
Mizuki Y, Yamada M Multifocal sites of
action involved in dopaminergic-cholinergic
neuronal interactions in yawning
Psychopharmacology (Berl) 1988; 95; 34-7
-Ushijima
I et al, Muscarinic and nicotinic effects on
yawning and tongue protruding in the rat
Pharmacol Biochem Behavior 1984; 21;
297-300
-Ushijima
et al modification of apomorphine,
physiostigmine and pilocarpine induced yawning
after long term treatment with neuroleptic or
cholinergic agents Arch Int Pharmacodyn 1984;
271; 180-188
-Ushijima
I et al Characteristics of yawning behavior
induced by apomorphine, physostigmine and
pilocarpine Arch Int Pharmacodyn 1985; 273;
196-201
-Ushijima,
I., Y. Mizuki, et al. Behavioral effects of
dilazep on cholinergic, dopaminergic, and
purinergic systems in the rat. Pharmacol Biochem
Behav 1992;43(3): 673-676.
-Ushijima I,
Mizuki Y, et al Effects of age on behavioral
responses to dopamine agonists in the rat. Eur J
Pharmacol. 1987;138(1):101-106.
-Ushijima
I, Mizuki Y, Yamada M. The mode of action of
bromocriptine following pretreatment with
reserpine and alpha-methyl-p-tyrosine in rats.
Psychopharmacology (Berl).
1988;95(1):29-33.
-Yamada K,
Furukawa T Direct evidence for involvement
of dopaminergic inhibition and cholinergic
activation in yawning Psychopharmacology 1980;
67; 39-43
-Yamada K,
Furukawa T The yawning elicited by
alpha-melanocyte-stimulating hormone involves
serotonergic -dopaminergic - cholinergic neuron
link in rats Naunyn-Schmiedeberg's Arch
Pharmacol 1981; 316; 155 -160
-Yamada K et
al Involvement of septal and striatal
dopamine D2 receptors in yawning behavior in
rats Psychopharmacology 1986; 90; 9-13
-Yamada K
et al Possible involvement of differing
classes of dopamine d2 receptors in yawning and
stereotypy in rats Psychopharmacology 1990; 100;
141-144
-Yamada K,
Furukawa T Behavioral studies on central
dopaminergic neurons. especially jumping,
stretching, body shaking and yawning behavior J
PharmacoBio dynamics 1980; 3; S16-S18
