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1 mars 2009
Pharmacol Toxicol
Alterations of physostigmine-induced yawning
by chronic lithium administration in rats
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.
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.