Department of Pharmacology
and Toxicology, Faculty of Pharmacy, Tehran
University of Medical Sciences, Tehran,
Iran
Yawning behaviour has been suggested to bc a
physiological response associated with fatigue
and recovery from stress (Barbizet
1965). Although yawning is a strange and
still only little understood behaviour which is
displayed in many vertebrate species, it is
nonetheless a discrete and easily quantifiable
behaviour that can bc used as a model for
understanding various central nervous system
functions. Involvement of D2 dopamine receptors
in yawning behaviour has been demonstrated
(Melis &
Argiolas 1987). Apomorphine is a
non-selective D1 and D2 dopamine receptor
agonist. It is very well known that low doses of
apomorphine induce yawning effect, whereas
higher doses induce stereotyped sniffing,
licking and gnawing syndromes. The
phosphoinositide intracellular signaling
pathways, which triggers calcium release from
intracellular stores, has also been proposed to
link to D1 and D2 dopamine receptors in both
brain and peripheral tissue. It has been shown
that aminoglycoside antibiotics interact with
phosphoinositides and affect the formation of
inositol triphosphate and diacylglycerol, the
second messengers of the phosphoinositide
cascade.
There is also some evidence that
aminiglycoside antibiotics may act through
blocking calcium channels. Lithium is widely
accepted as the drug of first choice in the
treatment of manic and prophylaxis of bipolar
affective disorders. However, until now no study
has adequately explained the mechanism of the
clinical action of lithium. Lithium has also
been shown to interact with phosphoinositide
metabolism by inhibiting of inositol
monophosphatase. Our previous works have shown
that lithium can alter some behaviours induced
by dopaminergic and cholinergic agents. The
present study was carried out to clarify the
interactive effects of intracerebroventricular
administration of aminoglycoside antibiotics
with different durations of lithium pretreatment
on apomorphine-induced yawning in rats.
[...]
Discussion
We have studied the effects of lithium and
aminoglycoside antibiotics on
apomorphine-induced yawning. Subcutaneous
injection of dopamine receptor agonist
apomorphine induced yawning. The response was
decreased when increasing the dose of the drug.
Involvement of D2 dopamine receptor in yawning
behaviour is well established, however, the data
indicate that a central dopaminergic stimulation
mechanisms is involved in apomorphine-induced
yawning.
Intracerebroventricular administration of
amikacin and gentamicin as aminoglycoside
antibiotics altered the number of yawning counts
induced by apomorphine, indicating the
possible interactions of doparninergic
mechanisms with amikacin and gentamicin in the
brain. It also seems that the
intracerebroventricular injection procedure can
suppres apomorphine-induced yawning. It has been
shown that D2 dopaminergic receptor stimulation
may activate phospholipase C, which hydrolyzes
the membrane phospholipid phosphatidyl inositol
bisphosphate, which again increases inositol
triphosphate and intracellular calcium.
There is also evidence that aminoglycoside
antibiotics can alter the action of cellular
phospholipases and inhibit the formation of
inositol trisphosphate and diacylglycerol, the
second messengers of phosphoinositide cascade.
In this study the aminoglycoside antibiotics,
amikacin and gentamicin, did not show the same
effects on yawning response. Since amikacin and
gentamicin function through the same mechanism
on the phosphoinositide cascade, the possibility
that alterations in inositol trisphosphate level
by amikacin and gentamicin interact with
dopaminergic-induced yawning seems unlikely,
thus the aminoglycoside antibiotics may alter
yawning response independent of phosphoinositide
activity. In addition some studies have shown
that aminoglycoside antibiotics act as N-type
calcium channel blockers with different
affinities, thus the contradictory effects of
amikacin and gentamicin on apomorphine response
may be due to different potencies of these drugs
on neuronal calcium availibility. However,
interaction between aminoglycoside antibiotics
and phosphoinositide pathways has been
demonstrated in our previous work (Sharifzadeh
et al. 1998).
One of the major findings of the present
study is that the yawning response induced by
apomorphine was decreased in animals pretreated
with lithium for 7, 14 and 21 days. Our
previous investigations have also shown that
lithium can decrease penile erection induced by
activation of the dopaminergic system and
yawning response induced by cholonergic
activation. It has been reported that lithium
causes depletion of cytoplasmic inositol and
phosphoinositide turnover, which could interfere
with the re-synthesis of phosphatidyl inositol
bisphosphate, thus influencing the signaling
mechanisms operating through the
phosphoinositide system. Lithium has also been
shown to attenuate protein kinase C function. In
addition, lithium can inhibit the effects of a
number of adenylyl cyclase-linked receptors such
as dopamine receptors. Therefore the inhibitory
effects of lithium may be due to post-receptor
mechanism interactions, which was also reported
in our previous works. The maximum inhibitory
effect of lithium was observed after 14 days.
This result is similar to the findings of other
investigators. There is evidence that lithium
causes decrease of 32% in D2 receptor after 7
days administration and after 14 days of lithium
administration, the dopamine release from
terminals was significantly attenuated. Thus the
maximum inhibitory effect of lithium on yawning
response may be due to the decreased
dopaminergic transmission following 14 days
pretreatment. The concentrations of lithium were
decreased in serum after the l4th day. Wood et
al. (1986) described the pharmacokinetic profile
of lithium in rat, mouse and human. They found
significant inter- and intraspecies differences
in pharmacokinetic parameters. As reported,
lithium has a high volume distribution in rats
in comparison to mice and man. Therefore the
decrease of lithium concentrations after 14 days
may be related to lithium moving from serum to
tissue.
Finally, although some of our findings are
unspecific and difficult to interpret, other
different second and third messenger systems
which may be involved in the interactions among
these agents, which requires more experiments
before being clarified.
Sharifzadeh M, Abdollahi M, Dehpour AR,
Kebriaeezadeh A, Samini M, Mohammad M.
Alterations of physostigmine-induced yawning by
chronic lithium administration in rats.
Pharmacol Toxicol.1997;81(4):159-163
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