mise à jour du
8 mai 2003
Pharmacology & Toxicology 2000;87:84-88  
Effects of different periods of lithium pretreatment and aminoglycoside antibiotics
on apomorphine-induced yawning in rats
M Sharifzadeh, EK Firooz, M Abdollahi
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. [...]


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.

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