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mise à jour du
20 octobre 2002
Behav Brain Res
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Two inbred rat sublines that differ in spontaneous yawning behavior also differ in their responses to cholinergic and dopaminergic drugs
Urba-Holmgren R, Santos A, Holmgren B, Eguibar JR
Departamento de Ciencias Fisiolôgicas , Puebla, Mexico
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren


Introduction : Yawning is a behavioral pattern that has gained increasing recognition in this last quarter of the twentieth century. The easiness with which this motor act may be induced, or modulated in frequency by different pharmacological agents in laboratory animals, particularly among rodents, has brought to focus a complex set of neurotransmitters and hormonal mechanisms underlying yawning behavior.

It has been suggested that regulation of yawning is partly the result of an interaction between dopaminergic and cholinergic influences on the central yawning pattern generator. The fine details and localization of these interactions in the central nervous system have not been entirely worked out. Some authors believe that dopaminergic induction of yawning results from activation of low threshold postsynaptic receptors exciting yawning, while others suggest it is due to D2 autoreceptors restraining the dopaminergic inhibitory influences on yawing, thus disinhibiting cholinergic yawn-excitatory pathways. There is practically general agreement in that muscarinic cholinergic antagonists counteract yawning, whatever the pharmacological tool used to induce it (ACTH physostigmine or pilocarpine, apomorphine or other dopamine agonists). These results suggest that the cholinergic link in yawning regulation is downstream in relation to the dopaminergic one.

In a previous paper in this same journal we reported the development of two inbred sublines of Sprague-Dawley rats which differ significantly in spontaneous mean yawning frequency (MYF): one of them yawns at a low frequency (LY); the other at a higher rate (HY). The prescrit report is an attempt to identify the neural substrates of this genetic difference in spontaneous yawning frequency between HY and LY Sprague-Dawley rats, by comparing their sensitivities to well known dopaminergic and cholinergic yawn-inducing drugs. [...]

Discussion : The results reported above show that two sublines of Sprague-Dawley rats which differ in their spontaneous yawning frequencies also differ in their responses to drugs with well known yawn-inducer activities.

It is known that the concentrations and turnover rates of several neurotransmitters, the activities of their synthesizing or degradative enzymes and their receptor densities in the brain show genetic variations . Durkin et al. have suggested that some changes in regional neurotransmitter activities in the brain might be due to primary differences in their underlying genetic mechanisms, whereas other might be secondary to imbalances in neurotransmitter interactions. Strain differences in behavioral expression or in sensitivity to drugs may be one major consequence of these changes.

Elicitation of yawning is mainly the result of an interaction, somewhere in the brain, between inhibitory dopaminergic and excitatory cholinergic influences on the built-in motor program for yawning. Yawning induced by low doses of apomorphine or other DA agonists has most generally been interpreted as the result of their selective action on low-threshold DA autoreceptors regulating impulse discharge, synthesis and release of the neurotransmitter . Other authors have postulated that this effect could be due to postsynaptic excitatory DA2, receptors . On the other hand, higher doses of DA agonists decrease yawning by acting on high threshold postsynaptic DA yawn-inhibitory receptors.

In our previous paper we had advanced the idea that HY rats may have an increase in cholinergic tone, understood as a direct and general effect, intrinsic te, the cholinergic system as a whole, or as an indirect and more particular phenomenon, consecutive to a decrease in tonic DA inhibitory activity, and therefore restricted only to cholinergic pathways subject to dopaminergic restraining control. In the case of a primary difference affecting the cholinergie system as a whole, different sensitivities to cholinergic drugs, with no changes or smaller ones in the response to doparninergic drugs, may be present when comparing HY and LY rats. The alternative hypothesis, that the, primary genetic influences modifying yawning behavior in these two sublines are exerted on dopaminergic pathways may lead to differences in sensitivity both to doparninergic drugs and secondarily to cholinergic drugs.

The results obtained with APO and (- )3PPP, point to the latter alternative. Both drugs have been demonstrated to act on dopamine receptors and have been used to study the role of DA pathways on yawning and other behavioral patterns. In HY rats the yawning dose-response curves traced with these dopaminergic agents are shifted to the left in relation to those in LY animals, indicating higher DA sensitivity in the former group. This suggests that the primary genetic difference between HY and LY rats is a decrease in the synthesis and/or release of dopamine in the former subline when compared with the latter. If this interpretation were correct, postsynaptic cholinergic neurones, partially disinhibited, would increase their activity, releasing more ACh and thus increasing MYF. The chronic increase in ACh might lead, as a secondary effect, to a diminution in sensitivity of muscarinic cholinoceptive receptors related to the yawning central pattern generator. We have tested this possibility by the use of pilocarpine, a well known muscarinic agonist and yawn-inducer .

We expected a diminution in pilocarpine-induced yawning in HY rats but our above described results do not agree with this prediction: no différences in pilocarpine-induced yawning responses are evident between HY and LY rats . The high turnover of ACh-esterase in the CNS could explain that although more ACh may be released in HY rats the steady average concentration of the neurotransmitter in synaptic space would not increase enough to determine changes in postsynaptic receptors sensitivity. At this point it seems interesting to comment that Overstreet has recently shown differences in muscarinic responses between Flinders-sensitive (FSL) and Flinders-resistant (FRL) lines of rats, differences that do not necessarily correlate with changes in receptors. Nevertheless other results reported here show significant differences between the two sublines (HY and LY) in regard to physostigmine-induced yawning. Higher doses of this drug (a competitive inhibitor of AChE) are needed to induce yawning in HY rats. It is a well known fact that competitive enzyme inhibitors are less effective when their natural enzyme substrate is increased. The lower yawn-inducing effect of physostigmine in HY rats could be understood as due to a higher basal concentration of ACh as compared with LY animals.

In summary, the whole set of our results with yawn-inducing dopaminergic and cholinergic drugs suggest that the primary genetic différence between the HY and LY Sprague-Dawley sublines seems to affect the activity of dopaminergic inhibitory pathways that normally restrain yawning frequency.