Abstract : This study examined the
effects of 1,4-bis[3-(3,4,5-trimethoxy
benzoyloxy)-propyl] perhydro-1,4-diazepine
(dilazep; Comelian) on central dopaminergic,
cholinergic, and purinergic neuronal systems in
rats. Intraperitoneal injections of dilazep (1-5
mg/kg) produced yawning responses, the most
effective dose being 2 mg/kg. Dilazep
potentiated physostigmine-induced yawning but
not pilocarpine- and bromocriptine-induced
yawning. Dilazep-induced yawning was not
affected by low doses of haloperidol or
sulpiride, but was completely inhibited by
atropine, a muscarinic M1 receptor antagonist.
Dilazep-induced yawning, as well as
physostigmine-induced yawning, were markedly
inhibited by pretreatment with SK & F 38393,
a dopamine D1 receptor agonist, and were
potentiated by SCH23390, a dopamine D1 receptor
antagonist that alone does not elicit yawning.
Caffeine, an adenosine receptor antagonist,
inhibited dilazep- and physostigmine-induced
yawning responses but N6-cyclohexyl adenosine
(CHA) and N6-(L-phenylisopropyl, adenosine
(L-PIA), adenosine A1 receptor agonists, were
inactive. These results suggest that because the
effects of dilazep on central cholinergic
neurons are similar to those of physostigmine
dilazep may potentiate indirectly the action of
endogenous acetylcholine. Cholinergic neurons
activated by dilazep may be modulated by
postsynaptic dopamine D1 receptor activity but
may not be affected by dopamine D2 receptor
activity. Furthermore, the stimulatory effects
of dilazep on cholinergic neuron may not be due
to an inhibition of dopamine D1 receptors via
purinergic (adenosine A1 receptor) stimulation
by dilazep.
Introduction: DILAZEP (Comelian; 1
,4-bLs[3-(3,4,5-trimethoxy
benzoyloxy)propyl]perhydro- 1 ,4-diazepine)
has been proposed to increase coronary blood
flow and potentiate the dilating effect of
adenosine on coronary vessels. Because dilazep
also has a dilating effect on central vessels,
probably via inhibiting adenosine uptake, the
drug has been proposed as a valuable therapeutic
agent in cerebrovascular dementia. Dilazep and
N6-(L-phenylisopropyl) adenosine (L-PIA:
adenosine A, receptor agonist) inhibit
aggressive behaviors induced by high doses of
clonidine, which antagonizes adenosine A,
receptors. On the other hand, the memory
dysfunction associated with senile dementia of
the Alzheimer type has been associated with a
deficiency and loss of cholinergic neurons. An
adenosine receptor antagonist, theophylline,
inhibits physostigmine-induced yawning
behaviors, which result in activation of central
cholinergic neurons.
Yawning behaviors induced by physostigmine,
a cholinesterase inhibitor, and pilocarpine, a
direct acetylcholine receptor agonist, in rats
are essentially mediated through the stimulation
of central muscarinic receptors but not
nicotinic receptors. On the other hand, yawning
can also be elicited by apomorphine, a D1/D2
agonist, and bromocriptine, a D2 agonist, which
have been reported to be mediated by cholinergic
activation secondary to the inhibition of
dopamine transmission. This behavior may be
mediated by septal-striatal and hypothalamic D2
receptor activation. In the present study, we
found that yawning was induced by IP injection
of dilazep to rats. These results were examined
more closely to clarify whether the behavioral
effects of dilazep involve central cholinergic
and dopaminergic or purinergic systems.
DISCUSSION
In this study, dilazep alone induced yawning
and potentiated physostigmine yawning but did
not affect pilocarpine and bromocriptine
yawning. There was a bell-shaped dose response
curve for the effects of dilazep on yawning.
This suggests that dilazep yawning may involve
an indirect activation of cholinergic neurons,
probably by releasing acetylcholine and/or
inhibiting acetylcholinesterase. Because dilazep
yawning was not affected by (-)-sulpiride, a D2
antagonist, and by a low dose of haloperidol
that preferentially inhibits presynaptic
dopamine receptors (D2 receptors) but was
completely blocked by atropine, a muscarinic
receptor antagonist, dilazep yawning appears
unlikely to be due to cholinergic neuronal
activation secondary to the activation of
presynaptic dopamine D2 receptors.
There is some evidence that physostigmine
yawning is inhibited by SK&F38393, a D1
agonist but is potentiated by SCH23390, a D1
antagonist, whereas pilocarpine yawning is not
affected by SK&F38393, suggesting that
activation of D1 receptors may inhibit
cholinergic neurons activated by cholinesterase
inhibition, that is, endogenous acetylcholine,
but may not affect the stimulation of
cholinergic neurons to a direct acetylcholine
agonist (muscarinic M1 receptor agonist). In
this study, the effects of SK&F38393 and
SCH23390 on dilazep yawning were compatible with
those observed on physostigmine yawning.
Pretreatment with SK&F38393 markedly
inhibited dilazep yawning and physostigmine
yawning whereas SCH23390 potentiated them.
Pilocarpine yawning was unaffected by either
SK&F38393 or SCH23390. From these results,
it is suggested that dilazep as well as
physostigmine yawning may be mediated by
dopamine D1 receptor activity. The inhibitory
effects of high doses of apomorphine on dilazep
and physostigmine yawning appear to be due to
the activation of dopamine D1 receptors. D1 and
D2 dopamine receptors that exist in the striatum
stimulate and inhibit, respectively, the
formation of striatal cyclic adenosine
monophosphate. The striatum contains the highest
concentration of acetyicholine in the brain and
dopamine receptors have a regulatory role on
striatal acetylcholine.
The opposing effects of D1 and D2 receptors
on striatal cholinergic neurons have also been
shown in biochemical studies.
On the other hand, dilazep has an adenosine
action as mentioned in the introductory section.
Adenosine receptors have also been classified
into two different types, called A1 and A2
receptors on the basis of inhibitory and
stimulatory effects, respectively, of adenosine
on rat brain adenylate cyclase activity. An
adenosine A1/A2 receptor antagonist,
theophylline, inhibits physostigmine yawning. In
this study, the adenosine A1/A2 receptor
antagonist, caffeine, also inhibited dilazep as
well as physostigmine yawning. However, only
dilazep and not L-PIA or CHA (adenosine A1
receptor agonists) potentiated physostigmine
yawning. These results suggest that the
stimulatory effect of dilazep on physostigmine
yawning may not be due to an inhibition of
dopamine D, receptors via stimulation of
adenosine A1 receptors but rather may be due to
an activation of cholinergic neuron by
endogenous acetylcholine. The mode of action of
dilazep is similar to that of physostigmine,
which indirectly stimulates cholinergic
neurons.
-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
