Dopamine agonist-induced yawning in rats: a dopamine D3 receptor mediated behavior
Collins G et al






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25 juillet 2002
Physiol Behav
Treatment with dexamethasone alters yawning behavior induced by cholinergic but not dopaminergic agonist
Hipolide DC, Lobo LL, De Medeiros R, Neumann B, Tufik S
department of psychobiology, Universidade de Sao Paulo, rua Botucatu, 862 Andar, SP 04034-062 Sao PAulo Bresil
Although the physiological significance of yawning is still not clear, it can be used as a model for understanding how various CNS structures interact to initiate and execute a behavior. Previous studies have established that yawning can be elicited in experimental animals by cholinomimetic drugs and by dopamine agonists. It can be also inhibited by both dopamine D2-receptor and muscarinic receptor antagonists, thereby indicating that the behavior involves dopaminergic and cholinergic activation. Findings concerning yawning behaviorafter paradoxical sleep deprivation (PSD) are particularly interesting, because there is an almost complete suppression of yawning induced by dopaminergic and cholinergic agonists. However, it is not well established whether suppression of yawning after PSD is due to absence of this sleep stage or the result of the stress-related techniques employed for PSD. Recently, we have reporied that immobilization, which is associated with the "flower-pot" PSD procedure, alters drug-induced yawning. Several neurotransmitters and neuropeptides have been documented to elicit or modulate yawning behavior, which involves the activation of dopaminergic-cholinergic linked neuronal systems.
It is generally admitted that activity of dopaminergic and cholinergic systems is altered by physical stress and/or by pharmacological agents that mimic stress response. Numerous observations suggest that glucocorticoids, the final product of activation of the hypothalamus-pituitaryadrenal axis, might be one factor capable of increasing the activity of these systems.
Because stressful manipulations have been reported to modify drug-induced yawning, the present study investigated the effects of single and repeated administration with a synthetic glucocorticoid, dexamethasone (DEXA) on yawning behavior. DEXA is primarily involved with the activation of glucocorticoid receptors (GR), and is, therefore, used to stimulate stress-related glucocorticoid actions. [...]
The present study shows that single and repeated treatments with dexamethasone (DEXA) have opposite effects on pilocarpine-induced yawning, whereas it had none on apomorphine-induced yawning.
Induction of yawning behavior appears to be dependent on a balance between dopaminergic and cholinergic systems. Although the hypothesis that yawning is elicited by dopamine inhibition and, consequently, acetylcholine activation is supported by several studies, there is a controversy about the mechanisms involved in this behavior.
There is accumulating evidence that glucocorticoids do interact with the dopaminergic system and facilitate dopamine release and increase sensitivity of dopaminergic receptors. In the present data, single and repeated DEXA treatment did not modify apomorphine-induced yawning. In contrast, previous reports showed that constant chronic stress suppresses apomorphine-induced yawning, regardless of the modality of stress. With respect to the discrepancy between the present results and the above-mentioned data, it is important to note that two types of corticosteroid receptors are distinguished in rat brain . Inoue and Koyama have found that chronic corticosterone but not DEXA treatment increases the levels of homovanillic acid (HVA) in medial prefrontal cortex. Furthermore, another possibility is that the dose of DEXA used in the present study was not sufficient to produce activation of the dopaminergic system. Previous studies have shown modification of the dopaminergic systern using doses higher than 0.25 mg/kg.
Some studies suggest a stress-specific change of dopaminergic function dependent on the brain area examined. For example, immobilization induces an increase in dopamine release and its metabolites concentration in nucleus accumbens and frontal cortex, but not in nucleus caudatum. Recently, Cabib and Puglisiallegra reported that the mesolimbic and the mesocortical dopamine systems adapt differently to repeated exposure to a stressor. Because yawning bas been associated with septal and striatal dopaminergic autoreceptors, it is possible that DEXA treatment does not modify the dopaminergic transmission in this pathway. Although Gilad observed reduction of dopamine uptake in synaptosomes from both septal and striatal regions of the brain, it is important to note that this author used another synthetic glucocorticoid.
Data of glucocorticoid effects on cholinergic transmission are scarce. Only in the last years a number of studies has focused on the importance of the cholinergie function in the neurophysiology of stress with particular reference to the septo-hippocampal cholinergie pathway, a system believed to be involved in yawning behavior. The present study shows that single administration of DEXA increased the number of yawns induced by pilocarpine. It is possible that concomitant administration of a single dose of DEXA and pilocarpine may act synergistically, potentiating the effects of the latter on yawning. However, we have demonstrated that acute immobilization, footshock, and swimming do not result in significant alteration of pilocarpine -induced yawning, although there was a clear tendency towards increase of yawning frequency in stressed animals. It is important to consider that endogenous release of corticosterone after stress (ie., immobilization) stimulates both MR and GR receptors, whereas DEXA bas high affinity for GR. There is evidence showing that short periods of stress do not alter the characteristic of the muscarinic receptor. Therefore, the mechanism that mediates the increase of yawning response after a single administration of DEXA may involve the release of acetylcholine and not changes in the sensitivity of cholinergic receptors.
Conversely, repeated treatment with DEXA resulted in a reduced number of pilocarpine-induced yawning. These finding confirm and extend our previous data that chronic immobilization suppresses cholinergic-induced yawning. Bccause repeated stress leads to habituation and adaptation processes, it is possible that repeated administration of DEXA produced a subsensitivity of postsynaptic cholinergic receptors. Consistent with this notion, it has been proposed that chronic stressful manipulations change cholinergie receptor sensitivity.
The opposite effects produced by single and repeated DEXA treatment on pilocarpine-induced yawning observed in the present study may be associated with the changes in muscarinic receptor sensitivity. Another alternative hypothesis is the balance between GR and MR receptors. The continuous stimulation of GRs will result in an adaptive reduction of GRs and an increase of MRs for maintenance of balance between those receptors.
For many years we have been evaluating the behavioral and neuropharmacological consequences of paradoxical sleep deprivation (PSD). Repeated administration of DEXA and PSD has the same effect on pilocarpine-induced yawning. It is possible that PSD effects on yawning are mediated by the stressful conditions produced by the procedure itself. The present findings show that dopaminergic and cholinergic systems differently altered by treatment with DEXA, in terms of yawning behavior.
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