Sharifzadeh M, Abdollahi M, Dehpour AR,
Kebriaeezadeh A, Samini M, Mohammad M
Department of Toxicology
& Pharmacology, Faculty of Pharmacy, Tehran
University of Medical Sciences,
Iran.
The effect of chronic lithium pretreatment
on physostigmine-induced yawning was
investigated in male rats. Intraperitoneal
administration of physostigmine to rats induced
yawning in a biphasic manner. However the
maximum response was obtained by 0.2 mg/kg of
the drug. Intracerebroventricular
administrations of a putative M1 and M2
muscarinic receptor antagonists, pirenzepine and
methoctramine decreased physostigmine-induced
yawning. Intraperitoneal administration of a
non-selective muscarinic receptor antagonist,
atropine, also decreased the
physostigmine-induced yawning significantly.
Chronic lithium pretreatment (30 days) reduced
yawning induced by physostigmine. The inhibitory
effect of pirenzepine, methoctramine and
atropine on physostigmine-induced yawning
increased in rats pretreated with chronic
lithium. These findings indicate that yawning is
induced by a central cholinergic mechanism and
that chronic pretreatment of lithium may
interact with the cholinergic-induced
behaviour.
Yawning behaviour has been suggested to be a
physiological response associated with fatigue
and recovery from stress (Barbizet 1985).
Although yawning is a curious and still little
understood behaviour which is displayed in many
vertebrate species, it is nonetheless a discrete
and easily quantifiable behaviour that can be
used as a model for the understanding of various
central nervous system functions.
It has been reported that cholinomimetics
cause yawning in rats (Ushijima et al. 1984;
Yamada & Fucukawa 1980 & 1981). A
central cholinergic mechanism with muscarinic
receptors underly yawning in rats (Urba-Holmgren
et al. 1977). In fact, muscarinic receptors have
been designated as either M1 or M2 depending on
whether they have high or low affinity for
pirenzepine (Hammer & Giachetti 1982).
Lithium is an effective drug in the
treatment of manicdepressive illness. Although
the specific biochemical mechanisms responsible
for the therapeutic efficacy of lithium are
unknown, a variety of physiological processes
are affected by this drug (Wood & Goodwin
1987). Lithium has been shown to reduce
phosphoinositide metabolism by inhibiting
inositol monophosphatase (Berridge et al. 1982;
Nahorzki et al. 1991) thereby partially
inactivating those receptors that utilize
phosphoinositide as part of their transducing
mechanism such as M1-muscarinic receptors
(Berridge et al. 1982). Although the
interpretation of lithium effects on brain
adenylate cyclase has been questioned, some
reports have shown that lithium inhibits the
effects of a number of adenylyl cyclase-linked
receptors (Ebstein et al. 1980). Ît has
been reported that chronic treatment of rats
with lithium chloride decreases the muscarinic
receptor-linked response (Kendall & Nahorski
1987).
The present study was carried out to examine
the effect of chronic lithium administration on
yawning induced by physostigmine with serum
lithium concentrations were 0.26±0.01
mmol/l.
Discussion
In the present work the effects of chronic
administration of lithium on yawning induced by
the cholinesterase inhibitor, physostigmine, was
studied in rats. Intraperitoneal injection of
physostigmine induced yawning. The response was
decreased when increasing the doses of the drug.
However the data indicate that a central
cholinergic stimulation mechanism is involved in
physostigmine-induced yawning. This is in
agreement with our previous observation that
activation of cholinergic mechanisms can induce
yawning (Zarrindast et al. 1995), which has also
been shown by Urba-Holmgren et al. (1977);
Yamada & Furukawa (1980 & 1981);
Ushijima et al. (1984); and Gower (1987).
Intracerebroventricular injection of pirenzepine
(Hammer et al. 1980; Hammer & Giachetti
1982; Doods et al. 1987), reduced the number of
yawning responses induced by physostigmine,
indicated that M1-muscarinic receptors are
involved in the yawning syndrome and agrees with
data presented by the other researcher (Gower
1987). The present results also show that
methoctramine (Massi et al. 1989; Feuerstein et
al. 1992), when administered centrally,
decreased the behaviour induced by
physostigmine, and also that M2 muscarinic
receptors are involved in yawning episodes.
Pretreatment of animals by intraperitoneal
administration of atropine decreased the
response induced by intraperitoneal injection of
physostigmine. This result is in agreement with
our previously work that intracerebroventricular
administration of atropine reduced the number of
physostigmine-induced yawning (Zarrindast et al.
1995).
The major finding of the present study is
the yawning response induced by physostigmine
was decreased in animals pretreated with chronic
lithium. Our previous investigations have also
shown that chronic lithium can decrease penile
erection induced by activation of dopaminergic
system (Dehpour et al. 1995 ; Sharifzadeh et al.
1996).
It has been shown that M1-muscarinic
receptor stimulation may activate phospholipase
C via G protein which hydrolyzes the membrane
phospholipid, phosphatidyl inositol bisphosphate
(PIP2) which increases inositol trisphosphate
(1P3) and intracellular Ca2 (Lefkwitz et al.
1992). There is also evidence that activation of
M2 receptors is accomplished by inhibition of
adenylyl cyclase and opening of potassium
channels( Berridge et al. 1982; Harden et al.
1985; Lefkwitz et al. 1992).
It has been reported that lithium treatment
reduces the level of inositol in the brain via
the inhibition of inositol-1phosphatase
(Hallcher & Sherman 1980) and that this
could interfere with the resynthesis of PIP2 and
thus influence the signaling mechanisms
operating through the phosphoinositide system.
Lithium has also been shown to inhibit the
effect of a number of adenylyl cyclase-linked
receptors (Ebstein et al. 1980). It can affect
the polyphosphoinositide cycles and adenylyl
cyclase system, therefore the inhibitory effects
of chronic lithium may be due to postreceptor
mechanism interactions. Moreover there are many
reports that chronic treatment of animals with
lithium chloride decreases receptor-mediated
inositol phospholipid hydrolysis in the cerebral
cortex with major effects on the muscarinic
receptor-linked response (Kendall & Nahorski
1987).
It has also been found that lithium produced
an inhibition of the inositol triphosphate (1P3)
response to muscarinic agonist in the rat cortex
(Avissar et al. 1988). The accumulating data on
the regulatory role played by G proteins in
phosphatidyl inositol metabolism (Avissar et al.
1988), suggest that this additional lithium site
might also be located on G proteins (Avissar et
al. 1988). Therefore the inhibitory effects of
lithium on M1-receptor may be due to inhibition
of the phosphatidyl inositol system via its
interaction with G proteins.
The increased guanine nucleotide binding
following agonist stimulation is a important
characteristic of G proteins which in turn leads
to their activation. The modulation by guapine
nucleotides of agonist binding to muscarinic
receptors is well described and has been proven
to be mediated through G proteins (Avissar et
al. 1988). There is evidence that increase in
GTP binding capacity induced by the muscarinic
receptor agonists was abolished by lithium
(Avissar et al. 1988). Since the M2-muscarinic
receptor is known to be coupled to G proteins
(Avissar et al. 1988), and lithium abolishes the
effect of muscarinic receptor agonist on GTP
binding, thus lithium inhibition of
physostigmine effect may be related to its
interaction with G proteins. In addition Coffey
et al. (1984) also suggested that lithium may
stabilize cholinergic receptor sensitivity,
which is another possibility for inhibitory
effects of chronic lithium on
physostigmine-induced yawning.
It is well-known that lithium facilitates
the seizures induced by muscarinic agonists.
Some experiments provide direct biochemical
evidence that short-term treatment with lithium
increases release of endogenous
neurotransmitters such as serotonin and
acetyicholine but this effect has not been
report with long-term lithium administration
(Sharp et al. 1991; Dehpour et al. 1992) . Thus
the facilitatory effects of lithium on the
seizures induced by muscarinic agonists may be
due to short-term administration of lithium.
Also Vizi et al. (1972) reported that lithium
decreases acetylcholine synthesis in rat brain
cortex which is in agreement with our
results.
Both pirenzepine and methoctramine
potentiated the inhibitory effect of lithium on
yawning induced by physostigmine. The blockade
of M1 receptors by pirenzepine and inhibition of
phosphoinositides cycle by lithium are other
possibilities for synergistic effect of lithium
and pirenzepine. The synergistic effect of
lithium and M2-muscarinic receptor antagonist,
methoctramine, on yawning in this study may be
related to more inhibition of adenylyl cyclase
system. Blockade of M1 and M2 muscarinic
receptors by atropine induces more inhibitory
effect on yawning response in animals pretreated
with chronic lithium.
In conclusion, the results of the present
study indicate that lithium exerts an inhibitory
effect on physostigmineinduced yawning by
interfering with muscarinic receptor mechanisms.
More experiments are required to clarify the
site(s) of action and biochemical interactions
of chronic lithium and physostigmine-induced
yawning.
