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Dopamine agonist-induced yawning in rats: a dopamine D3 receptor mediated behavior Collins G et al
 
 
 
 
 
 
 
 
 
 
 
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mise à jour du 12 juin 2003
Pharmacol Biochem Behav 1992;43(4):985-91
lexique
Role of adrenergic neuronal activity in the yawning induced by tacrine and NIK-247 in rats
Kimura H, Yamada K, Nagashima M, Matsumoto S, Ishii Y, Yoshida S, Fujii K, Furukawa T
Department of phamacology, Fukuoka University, Japan

Chat-logomini

Behavioral studies have shown that physostigmine, an anticholinesterase agent, and pilocarpine, a muscarinic receptor agonist, induce yawning behavior that is abolished by scopolamine, a muscarinic receptor antagonist. The yawning induced by dopamine receptor agonists such as apomorphine and talipexole (B-HT 920) is also compIetely inhibited by scopolamine. On the basis of these results, it bas been proposed that cholinergic neuronal activity is indispensably involved in eliciting yawning behavior.

9-Amino-1,2,3,4-tetrahydroacridine (tacrine (THA)) is proposed to be a potent, centrally acting cholinesterase inhibitor. 9-Amino-2,3,5,6,7,8-hexahydro-IH-cyclopenta(b)-quinoline monohydrate HCI (NIK-247) has also been reported to exert inhibitory effects on cholinesterase. These cholinesterase inhibitors are found to improve cognitive functions at different phases of the learning and memory processes in animals and have been clinically developed as potential cognitive improvers. However, there is little documentation on yawning and acetylcholine content in animals treated with tacrine or NIK-247.

The potential functional role of adrenaline-containing neuronal systems was suggested in some of the earliest research on brain catecholamines. The earlier hypothesis that adrenaline is a neurotransmitter candidate in the brain were validated by detailed studies of the distribution of brain neurons containing phenylethanolamine N-methyltransferase (PNMT) and their close correlation with the regional distribution of enzymatic activity and adrenaline content. As inhibitors of PNMT were reported to decrease adrenaline formation without affecting dopamine and noradrenaline levels, several lines of investigation with the inhibitors subsequently suggested that brain adrenaline may be involved in cerebral cardiovascular, neuroendocrine, and behavioral regulation. Recently, we reported that administration of various beta-adrenoceptor antagonists such as pindolol, propranolol, and indenolol increased the yawning responses induced by treatment with apomorphine, talipexole, physostigmine, or pilocarpine, suggesting that alpha adrenoceptor blockade facilitates the occurrence of yawning; induced by dopaminergic and cholinergic agonists. Thus, central beta-adrenoceptors relating to central adrenergic neuronal systems might be involved in the regulation of yawning responses.

The present experiments were therefore performed to investigate whether or not tacrine and NIK-247 elicit yawning that may possibly be regulated by central adrenergic neurons via beta-adrenoceptor activities in rats. [...]

 
Discussion : Previous experiments have shown that physostigmine and pilocarpine elicit yawning and this behavior is blocked by muscarnic but not dopamine receptor antagonists. On the other hand, the yawning induced by dopamine D2 receptor agonists is antagonized by both dopamine and muscarinic receptor antagonists, implying that dopamine receptor agonist-induced yawning can result from a consequent activation of cholinergic neurons. From such findings, it has been proposed that a dopaminergic-cholinergic-linked neuronal system may participate in inducing yawning.

In the present experiment, treatment with tacrine or NIK247 evoked a yawning response to a small extent. This yawning response was markedly increased by a beta-adrenoceptor antagonist, pindolol, which did not evoke yawning; when given alone. Moreover, the yawning elicited by tacrine or NIK-247 given alone or in combination with pindolol was inhibited by scopolamine, a muscarinic receptor antagonist, but not by mecamylamine, a nicotinic receptor antagonist, and spiperone, a dopamine receptor antagonist. The present results suggest that tacrine and NIK-247 were able to elicit yawning via muscarinic receptor activation, as our previous experiments with physostigmine-induced yawning. On the other hand, the dopamine D2 receptor agonist, talipexole, also elicited yawning, which was increased by pindolol, as previously reported. Accordingly, the stimulation of muscarinic receptors is obligatory for the induction of yawning and central beta-adrenoceptor activity may regulate the occurrence of yawning induced by anticholinesterase agents and dopamine D2 receptor agonists.

A previous experiment showed that the dopamine D1/ D2 receptor agonist, apomorphine, induced yawning that was enhanced by pindolol, propranolol, indenolol, and alprenolol, which block central beta-adrenoceptors, but not by the peripheral beta-adrenoceptor antagonists, carteolol and atenolol, suggesting that yawning is enhanced by central beta-adrenoceptor blockade but not by peripheral blockade. Pindolol is also known to have serotonin (5-HT) receptor blocking actions in addition to beta-adrenoceptor antagonistic properties. However, the yawning induced by talipexole was increased by pretreatment with pindolol but was unaffected by either metergoline, a potent antagonist of 5-HT, and 5-HT2 receptors, or ketanserin, a specific antagonist of 5-HT2 recepters. Moreover, we found that various beta-adrenoceptor antagonists, which have no 5-HT receptor antagonistic properties, also increased the yawning induced by dopamine receptor agonists. Accordingly, the 5-HT receptor antagonistic property of pindolol may not be related te the observed enhancement of yawning responses by the drug.

Dopamine receptor agonists, locally applied into the striatum, elicited yawning behavior, and those administered systemically were ineffective in evoking yawning after bilateral lesions of the striatum. by 6-hydroxydoparnine. Therefore, the striatum, is proposed te be one of the important sites in the rat brain areas involved in evoking yawning behavior. In contrast with these reports, microinjection of dopamine receptor agonists into the paraventricular nucleus (PVN) of the hypothalamus induced yawning behavior in rats and electrolytic lesion of the hypothalamic PVN prevented the drug induced yawning responses, suggesting that the PVN is also the brain area where dopamine receptor agonists act for inducing yawning. However, a role of cholinergic neuron activity in the PVN for evoking yawning is still unknown. On the other hand, high beta-adrenoceptor density was found in the rat striatum . AccordingIy, in this experiment acetylcholine content of the striatum was measured after treatment with cholinesterase inhibitors. The systemic administration of tacrine or NIK-247 increased acetylcholine content of the striatum, and this was accompanied by a modest yawning response. These results seem to be compatible with recent findings that intraperitoneal injection of tacrine increased acetylcholine content in the striatum, cortex, and hippocampus in rats. However, although pindolol increased the yawning responses induced by tacrine or NIK-247 and the beta-adrenoceptor antagonist did not alter basal acetylcholine content and failed to enhance the increase of acetylcholine content in the striatum induced by the two cholinesterase inhibitors. Our previous experiments have also shown that pretreatment with pindolol or propranolol increased the yawning responses induced by the direct muscarinic receptor agonist, pilocarpine, suggesting that beta-adrenoceptor antagonists may not affect the synthesis and/or release of acetylcholine in the brain areas involved in eliciting yawning behavior. Furthermore, various beta-adrenoceptor antagonists, including pindolol, did not change the activity of acetylcholinesterase in the brain. Taken together, it may be assumed that central beta-adrenoceptors do not regulate the activities of striatal cholinergic neurons.

According to expectation, in the present experiment, the tacrine-induced yawning responses were increased notably by LY-78335 and UK- 1 187A. These drugs are reported to block adrenaline synthesis without change of dopamine and noradrenaline levels in the brain via the inhibition of noradrenaline N-methyltransferase. However, the dose-response curve of yawning to PNMT inhibitors in combination with tacrine was bell shaped. Similarly, the combined treatment with pindolol and tacrine was shown te have bell-shaped responses of yawning. Although the real reason for showing a bell-shaped dose-response curve is obscure at present, it is a possibility that a high dose of PNMT inhibitors or the beta-adrenoceptor antagonist with the anticholinesterase agent produces changes of the other neuronal activities that inhibit the occurrence of yawning. Furthermore, pretreatment with LY78335 or UK-1187A facilitated talipexole-induced yawning. Therefore, PNMT inhibitors as well as 0-adrenoceptor blockers seem to enhance yawning responses via the inhibition of central adrenergic neuronal activity.

The results suggest that the beta-adrenoceptor blockade and inhibition of central adrenaline synthesis facilitate the occurrence of yawning induced by tacrine, NIK-247, or talipexole and that the central adrenergic neuronal systems may participate in the regulation of yawning evoked by cholinergic and dopaminergic agonists. However, further work is warranted to clarify a neuronal circuit between a dopaminergic-cholinergic-linked neuronal system and an adrenergic neuronal system involved in yawning behavior.

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