mystery of yawning
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La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
 
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
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21 octobre 2012
 
Neuroscience Letters
2012; 531:91-95
 The modulatory role of M2 muscarinic receptor on apomorphine-induced yawning and genital grooming
 
Gamberini MT, Bolognesi ML, Nasello AG.
 
Department of Physiological Sciences of the Santa Casa de São Paulo - Faculty of Medical Sciences, Brazil.

Chat-logomini

 
Abstract
 
The interaction between dopaminergic and cholinergic pathways in the induction of behavioral responses has been previously established. In the brain, M2 receptors are found predominantly in presynaptic cholinergic neurons as autoreceptors, and in dopaminergic neurons as heteroceptors, suggesting a control role of acetylcholine and dopamine release, respectively.
 
Our aim was to investigate the role of M2 receptors on the yawning and genital grooming of rats induced by apomorphine, a dopaminergic receptor agonist, focusing on the interaction between cholinergic and dopaminergic pathways. Initially, the effect of atropine, a non-selective muscarinic antagonist, on yawning and genital grooming induced by apomorphine (100?g/kg s.c.) was analyzed. Atropine doses of 0.5, 1 and 2mg/kg i.p. were administered to Wistar rats 30min before induction of the behavioral responses by apomorphine.
 
Number of yawns and time spent genital grooming were quantified over a 60min period. Apomorphine-induced yawning was increased by low dose (0.5mg/kg i.p.) but not by high doses (1 and 2mg/kg, i.p.) of atropine. Genital grooming was antagonized by 2mg/kg i.p. of atropine and showed no changes at the other doses tested. Tripitramine, a selective M2 cholinergic antagonist, was used as a tool for distinguishing between M2 and all other muscarinic receptor subtypes in yawning and genital grooming. Tripitramine doses of 0.01, 0.02 and 0.04?mol/kg i.p. were administered to Wistar rats 30min before apomorphine (100?g/kg s.c.). Number of yawns and time spent genital grooming were also quantified over a 60min period. Tripitramine 0.01?mol/kg increased all parameters. Higher doses, which possibly block all subtypes of muscarinic receptor, did not modify the response of apomorphine, suggesting a non-selective effect of tripitramine at these doses.
 
Given that low doses of tripitramine increased the behavioral responses induced by apomorphine and that the main distribution of the M2 receptor is presynaptic, we raised the hypothesis that tripitramine may alter cholinergic and/or dopaminergic transmission in brain areas responsible for induction of yawning and genital grooming in rats, possibly by control of acetylcholine and/or dopamine release.
 
In addition, the present study showed the involvement of M2 cholinergic receptors in the complex mechanisms of functional interactions between dopaminergic and cholinergic systems involved in the control of yawning and genital grooming.
 Gamberini MT, Bolognesi ML, Nasello AG. The modulatory role of M2 muscarinic receptor on apomorphine-induced yawning and genital grooming. Neuroscience Letters 2012; 531:91-95
-Gamberini MT, Gamberini MC, Nasello AG. Involvement of dopaminergic and cholinergic pathways in the induction of yawning and genital grooming by the aqueous extract of Saccharum officinarum L. (sugarcane) in rats. Neuroscience Letters 2015;584:270-275
-Naselo A, Tieppo C, Felicio L Apomorphine induced yawning in the rat : influence of fasting and time of day Physiology & Behavior 1995;57(5):967-971
-Nasello AG et al Modulation by sudden darkness of apomorphine-induced behavioral responses Physiology & Behavior 2003;78:521-525
1. Introduction
 
Dopaminergic and cholinergic transmissions are involved in 29 motor and cognitive physiological processes. Imbalances between 30 these transmissions are found in some disorders, such as Parkin- 31 son's disease, Huntington's disease and schizophrenia [19]. The 32 pharmacological strategies used for the treatment of these diseases 33 are based on restoring the dopamine (DA)/acetylcholine (ACh) balance in the CNS.
 
In rats, the interrelationship between dopaminergic and cholinergic transmission can be explored through behavioral tools such as yawning and genital grooming. The involvement of the dopaminergic system in the induction of yawning and genital grooming becomes evident by the administration of small doses of apomorphine, a direct DA receptor agonist, with marked affinity for DA D2-like (D2/D3/D4) receptors.
 
Results of microinjection studies suggest that the induction of yawning by D2-like agonists may be mediated by their action in the striatum or septum. Also, the action of acetylcholine in the control of yawning and genital grooming has been well characterized by cholinergic agonists and antagonists that induce or abolish these behaviors, respectively.
 
A large body of evidence suggests a central role of cholinergic neurons as a site of action for the induction of cholinergic yawning and genital grooming, as well as a common mediator of these responses induced by a variety of pharmacological mechanisms. In the striatum, a high density of dopaminergic and cholinergic terminals exists and these neurotransmitters have potent interactions at multiple levels such as presynaptic regulation of neurotransmitters and postsynaptic effects in target cells, including cholinergic neurons.
 
Another central nucleus capable of initiate yawning and genital grooming is the paraventricular nucleus (PVN). One described mechanism by which dopamine agonist induces yawning is the activation of D2 receptors. This elevates nitric oxide synthase activity in the cell bodies of paraventricular oxytocinergic neurons projecting to extra-hypothalamic brain areas, increasing oxytocin release.
 
Subsequently, oxytocin activates cholinergic neurotransmission in the hippocampus and reticular formation of the brainstem. Microinjections of oxytocin into the medial preoptic area were also shown to induce grooming. All five muscarinic receptor subtypes (M1&endash;M5) are expressed in the CNS. In situ hybridization and immunohistochemical studies have shown that M1 and M4 are present predominantly in efferent neurons as heteroreceptors, but also in cholinergic neurons as autoreceptors. M2 is expressed predominantly in striatal interneurons as a presynaptic autoreceptor in cholinergic neurons, and as a heteroreceptor in dopaminergic neurons. The suppression of striatal acetylcholine release by M2/M4 autoreceptors, together with the effects of M2/M4 action on dopamine transmission, lend support to the hypothesis of modulation of cholinergic pathways on dopaminergic transmission in striatum.
 
Considering the close relationship between dopaminergic and cholinergic transmission in yawning and genital grooming, the aim of this study was to explore a possible cholinergic modulation of dopaminergic neurotransmission using a selective antagonist of muscarinic M2 receptor subtype, tripitramine.
 
Discussion
 
Dopamine (DA) and acetylcholine (ACh) have potent interactions in different areas of the CNS at multiple levels, including presynaptic regulation of neurotransmitter release and postsy-naptic effects in target cells. To explore potential cholinergic modulation of the dopaminergic neurotransmission involved in yawning and genital grooming, we conducted this study analyzing the behavioral responses of rats to the antagonists of muscarinic receptor subtypes.
 
Our data suggests that cholinergic receptors are involved in the modulation of the yawning and genital grooming induced by apomorphine. The results showed that low doses of atropine (0.5 mg/kg) increased the total number of yawns induced by apomorphine in rats.
 
Although the functional interactions between cholinergic and dopaminergic systems are complex, it has been hypothesized that acetylcholine release by M2/M4 autoreceptors, together with the effects of M2/M4 action on dopamine transmission, modulates dopaminergic transmission. Since atropine shows selectivity at M2 receptors in rats: M4 > M5 > M1 > M2 > M3, the potentiation in yawning induced by the lower dose of atropine may be explained by a possible antagonist effect on M2 receptors, blocking the negative feedback of acetylcholine release and/or suppressing inhibition of dopamine release.
 
We have also considered the possible antagonistic effect on other cholinergic receptors of atropine, as a possible explanation for the blocking of genital grooming by higher doses of atropine (2 mg/kg). These results led to the hypothesis that different doses of atropine antagonize the muscarinic receptor subtypes differently.
 
The M2 cholinergic receptors have been characterized in a variety of areas of the CNS, including areas associated to yawning and genital grooming. Hindbrain, brainstem, and midbrain regions, such as the cerebellum (75% muscarinic receptor density, mrd), pons/medulla (70% mrd), and thalamus/hypothalamus (43% mrd) are enriched with M2 receptors.
 
In contrast, forebrain regions contain markedly lower percentages of M2 receptors, with the cortex expressing 20%, hippocampus 19% and olfactory tubercle 20%, of total receptor density. M2 muscarinic autoreceptors are predominant in the striatum, but the presence of postsynaptic receptors has also been described in the dorsal striatum of rat.
 
Tripitramine displays a unique binding profile for muscarinic receptor subtypes: M2 > M4 M1 > M3, distinguishing between M2 and all other muscarinic receptor subtypes. Therefore, we used tripitramine as a tool for exploring the specific involvement of M2 cholinergic receptor in yawning and genital grooming induced by the dopaminergic agonist, apomorphine. Low doses of tripitramine (0.01 mol/kg) were able to potentiate the behavioral response induced by apomorphine, increasing the number of total yawns and total time spent genital grooming in rats compared to control animals.
 
The same effects were not obtained when tripitramine doses were increased. We speculated that tripitramine, at high doses, loses its specificity for M2 cholinergic receptors, whereas it may also antagonize M1 cholinergic receptor, essential for these behavioral responses. Given that low doses of tripitramine, a selective M2 cholinergic receptor antagonist, increased the behavioral responses induced by apomorphine and that the main distribution of M2 receptor is presynaptic, it was suggested that the presynaptic cholinergic control of acetylcholine and/or dopamine release in brain areas could be involved in the potentiation of yawning and genital grooming.
 
It was previously shown that M2 antagonists can facilitate memory storage by potentiating cholinergic tone. This potentiation may have inhibited dopaminergic bursts with resultant enhanced yawning and genital grooming.
 
In psychosis, schizophrenia, pounding, Tourette's syndrome and hyperkinesias in general, antidopaminergic drugs were used chronically and some patients displayed various side-effects.
 
Accordingly, the treatment of choice for these complications constitutes cholinergic drugs. Furthermore, typical and atypical antipsychotic drugs were shown to increase the extracellular release of acetylcholine in the striatum.
 
Thus, it can be speculated that the therapeutic effect of antipsychotic drugs may be partly mediated via a stimulation (or disinhibition) of striatal acetylcholine release, which in turn helps normalize the functional interaction between acetylcholine&endash;dopamine systems particularly in the ventral striatum thereby restoring a more optimal balance in the activity of these systems. Hence, cholinergic drug-based treatments are still used but more specific effects on the dopaminergic system through M2 antagonism could be investigated to simultaneously enhance cholinergic transmission and block dopaminergic transmission.
 
-Naselo AG, Tieppo C, Felicio L Apomorphine induced yawning in the rat: influence of fasting and time of day Physiology & Behavior 1995;57(5):967-971
-Nasello AG et al Modulation by sudden darkness of apomorphine-induced behavioral responses Physiology & Behavior 2003;78:521-525