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mise à jour du 8 mai 2003
Pharmacology, Biochemistry and Behavior
2002; 74; 205-212 
Acute or chronic effects of cannabinoids on spontaneous or pharmacologically induced yawning in rats
EM Nakamura-Palacios, O Francisco, A Bueno, N. Takahashi, S Tufik
Department of Physiological Sciences, Federal University of Espirito Santo, Vitoria, Brazil


Introduction : In the past decade, the results of many studies have greatly increased the understanding of the physiology and pharmacology of cannabinoids in the central and peripheral nervous systems. For example, cannabinoid CBI and CB2 receptors and a subtype CB1A, have been characterized, cloned and the second messenger systems identified.

Anandamide, 2-arachidonyl glycerol, homo--y-linolenylethanolamide, 7,10,13,16-docosatetraenyl-ethanolamide, mead ethanolamide and palmitoylethanolamide have been proposed as endogenous ligands for cannabinoid receptors. The availability of cannabinoid antagonists selective for the CB1 receptor, SR141716A, and CB2 receptor, SR144528, has greatly facilitated studies on the physiological functions of cannabinoid systems. Additionally other antagonists such as WIN 56,098, 6-bromopravodoline (WIN 54,461), 6-iodopravadoline (AM630), LY320135, have also been synthesized and characterized.

Cannabinoids affect the actions and release of many neurotransmitters, including acetylcholine (ACh) and dopamine (DA). Recent studies have demonstrated that cannabinoids act at presynaptic CB1 receptors to inhibit ACh release in ileal myenteric plexus-longitudinal smooth muscle preparations, the hippocampus and the medialprefrontal cortex. SR 141716A antagonizes the inhibition of hippocampal ACh release produced by cannabinoid agonists, suggesting that the effects of cannabinoids on learning and memory depend on a CB1 receptor-mediated inhibition of ACh release in the hippocampus. Also, the combination of SR 141716A or delta9tetrahydrocannabinol (delta9-THC) with scopolamine produced larger disruptive effects. on a repeated-acquisition procedure in squirrel monkeys than those observed when either deltaTHC or scopolarnine was administered alone, indicating that either a CB1-receptor agonist or antagonist can alter the disruptive effects of scopolamine on leaming in squirrel monkeys.

In contrast to the inhibition of ACh release, the stimulation of CB1 receptors produces an activation of mesoprefrontal or mesolimbic dopaminergic transmission. Because these dopaminergic circuits are involved in the reinforcing effects of most drugs of abuse, the enhanced dopaminergic activity might underlie the reinforcing and abuse properties of marijuana. Additionally, the disruptive effects of cannabinoids on cognitive processes might be related to the activation of dopaminergic transmission in the prefrontal cortex.

Adversely, the synthetic cannabinoid agonist, HU 210, antagonized motor hyperactivity and stereotypical behavior elicited by cocaine and a DA receptor agonist, CQP 201 - 403. HU 210 also antagonized penile erection and stretching-yawning elicited by dopaminergic D2/D3 agonists, B-HT 920 and 7-OH-DPAT, in a manner similar to that produced by a dopaminergic D2 antagonist, ( - ) eticlopride. Additionally, an intracerebroventricular administration of an anandamide tranport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404), which causes anandamide to accumulate in the central nervous system, produced a mild and slow-developing hypokinesia and reduced the stimulation of motor behaviors elicited by the selective D2 family receptor agonist quinpirole. Therefore, it seems that cannabinoid agonists can both increase and decrease dopaminergic activity.

Yawning is a reflex, or stereotyped event exhibited by all mammals and vertebrates. It seems to be a brain stem arousal reflex with both peripheral and central loops subserving reversal of brain hypoxia or hypoxemia, probably related to an effort to keep vigilance. Its mechanisms and fonctional role are not entirely known. It seems to be centrally linked with the dopaminergic system in a D1 -D2 cooperation and the cholinergic system as the effector pathway for the dopaminergic -cholinergic linked neural mechanism.

However, many other neurotransmitters and neuropeptides, such as excitatory amino acids, serotonin, gamaaminobutyric acid, noradrenaline, nitric oxide, adrenocorticotropic hormone related peptides, oxytocin and opioid peptides, are also involved in the central control of yawning.

The studies reviewed above demonstrate that cannabinoids can alter transmission mediated by both dopaminergic and cholinergic pathways, both of which are involved in the yawning response. Because cannabinoids are known to alter responses mediated by these neurotransmitter systems, the current study was carried out to examine the effects of acute and chronic treatments with cannabinoid agonists on the spontaneous yawning response as well as that produced by a cholinergic and dopaminergic agonists in rats. [...]

Discussion :

The dose-dependent yawning induced by cholinergic and dopaminergic agonists was consistent with several studies. One could argue that what we are callig as yawning might actually be what is described as conditional gaping in rats as a manifestation of the vomiting response, relating our results to an antiemetic effect of cannabinoids. However, gaping behavior is characterized by a rapid opening and closing of the mouth usually accompanied by chin rubbing, reflecting an aversive response or a rejection taste reactivity response, in contrast to yawning, a slower and wide opening of the mouth, sometimes accompanied by stretching behavior, a pattern of response observed in our study. Additionally, the experimental observation of a conditional rejection reactions in rats usually needs a flavor, which will induce this response through oral infusion, to be previously paired to an emetic drug such as lithium chloride, a procedure that was not used in our study. Finally, there are very few reports in the literature referring to cholinergic agonists inducing gaping, or apomorphine inducing gaping and this one in large doses, far beyond the dose range employed in our study.

According to Yamada and Furukawa (1980) and Ushijima et al. (1984a), yawning induced by pilocarpine is produced centrally, as shown by the observation that yawning induced directly by a cholinergic agonist such as pilocarpine or indirectly by a cholinesterase inhibitor such as physostigmine can be blocked by muscarinic antagonists that penetrate the central nervous system (e.g., scopolamine) but not by those acting only peripherally (e.g., methylscopolamine).

Low doses of apomorphine act preferentially at D2 presynaptic receptors to cause a reduction in DA release. Considering the inhibitory modulation of DA on ACh release, the reduced release of DA could result in a greater release of ACh, and thereby increase yawning. Centrally acting muscarinic antagonists abolish yawning induced by dopaminergic and cholinergic agonists, whereas dopaminergic antagonists only abolish apomorphineinduced yawning. These observations strongly suggest that the yawning induced by low doses of a dopaminergic agonist is due to an increase in central cholinergic transmission.

In the present study, acutely administered delta8-THC or delta-9THC decreased yawning induced by pilocarpine in a dosedependent manner and completely blocked yawning induced by apomorphine. It is likely that these actions involve a cannabinoid modulation of central dopaminergic and/or cholinergic systems, a dopaminergic-cholinergic linked neural mechanism or actions of the cannabinoids at another site distal to that of pilocarpine.

The inhibitory effects of these cannabinoids on pilocarpine-induced yawning cannot be readily explained by the known ability of cannabinoid agonists to inhibit ACh release or a competitive interaction between the cannabinoid and pilocarpine for occupancy of muscarinic receptors. The cannabinoid agonists produced a dose-dependent inhibition of the actions of pilocarpine that could not be overcome by increasing doses of pilocarpine. This form of antagonisrn is analogous to that seen with the inhibition of indirectly acting agonistsand suggests that the cannabinoids are acting at a site distal to the actions of pilocarpine.

Yawning induced by low doses of apomorphine was much more sensitive to antagonism by both d8-THC and d9-THC than that produced by pilocarpine. Similar to what was observed for pilocarpine, increasing doses of apomorphine did not overcome the inhibition produced by d8-THC. Apomorphine at 40µg/kg and pilocarpine at 2 mg/kg produced similar increases in yawning. The lowest dose of d9-THC, 0.5 mg/kg, completely abolished the response to apomorphine. In contrast, this dose only produced about a 30% decrease in the yawning produced by pilocarpine. The inhibitory effects of the cannabinoid agonists on the actions of apomorphine appear to be due to an antagonism rather than an enhancement of dopaminergic transmission.

Behavioral effects of apomorphine are biphasic, low doses induce yawning and sedation, probably by presynaptic D2 autoreceptors activation, whereas higher doses induce stereotypy and hyperactivity, probably by postsynaptic D1 activation. These behaviors are mutually exclusive in that yawning decreases with increasing doses of apomorphine.

Several studies have shown that cannabinoid agonists can either increase dopaminergic activity or produce a dopaminergic antagonistic-like effect. The antagonistic-like actions of cannabinoid agonists might best explain our results since the apomorphine-induced yawning was the most affected by cannabinoid agonists and no sign of stereotypy or hyperactivity was observed in animals treated with the combination of cannabinoids with apomorphine.

This antagonistic-like action of cannabinoid agonists may involve D2 dopamine receptor mediation. Beltramo et al. (2000) recently showed that both, anandamide transport inhibitor AM404 and anandamide by itself counteract two characteristic responses mediated by activation of D2 family receptors, that is, yawning induced by apomorphine in a dose equivalent to the highest one employed in our study (80 µg/kg sc) and quinpirole-induced stimulation of motor behaviors. Because the stimulation of motor behavior elicited by systemic administration of the D2-like agonist quinpirole was increased by SR 141716A, Giufftida et al. (1999) suggested that the endocannabinoid system may modulate D2 dopamine-induced activation of psychomotor activity acting as an inhibitory feedback mechanism to this behavior.

Neurotransmitter or neuromodulator systems other than cholinergic or dopaminergic also have to be considered. According to Argiolas and Melis (1998), activation of the paraventricular nucleus of the hypothalamus by DA, excitatory aminoacids and oxytocin facilitates yawning by releasing oxytocin at extrahypothalamic areas such as the hippocampus, the pons and/or the medulla oblongata that play a key role in the expression of this behavioral event. The yawning induced by these neurotransmitters or neuropeptides was only antagonized by opioid peptides.

There were no changes in the ability of pilocarpine or apomorphine to induce yawning at 24 h or 7 days after cessation of the chronic administration of d8-THC. Previous studies on yawning have shown that rodents treated chronically with haloperidol, a dopaininergic antagonist, exhibited a central hyposensitivity to apomorphine and physostigmine, both of which act via the release of ACh, but not with pilocarpine, a directly acting agonist. On the other hand, after chronic treatinent with muscarinic antagonists such as atropine or scopolamine there was a supersensitivity to physostigmine and pilocarpine, but not to apomorphine. Our results suggest that, unlike their effects on other behaviors, chronic treatment with a cannabinoid agonist does not alter the sensitivity of systems modulating yawning.

Recent studies have shown that the repeated administration of cannabinoid agonists might or might not change the acute effects of some drugs. For example, Ferrari et al. (1999) found that a short-term treatment (7 days) with a cannabinoid agonist, HU 210, did not modify cocaineinduced effects, although it increased locomotor activity and stimulated escape attempts produced by a D1/D2 agonist, CQP 201-403. A chronic administration of d9-THC (3 weeks) did not change the effects of amphetamine or heroin in low-responder rats, but it significantly increased the locomotor effects of these drugs in high-responder rats.

Nevertheless, a salient finding of the present study was that animals treated with d8-THC for 30 days showed higher spontaneous yawning 7 days after drug discontinuation compared to animals treated with saline. The latency for this effect of chronic cannabinoid treatment is much less than that observed by Lamarque et al. (2001). In their study, the increased locomotor responses to heroin only occurred in high-responder rats with a latency of 41 days after cessation of treatinent for heroin-treated rats. The basis for this différence in latency of presumed withdrawal signs is not known.

The lack of any changes in the sensitivity to pilocarpine or apomorphine after cessation of treatment suggests that the increased spontaneous yawning observed in our study could be due to changes in noncholinergic, nondopaminergic neurotransmitter or neuromodulator systems involved in yawning, such as opioid peptides. Endogenous opioid peptides seem to exert an inhibitory control on the yawning response at the paraventricular level. The repeated administration of cannabinoid agonists produced a time-related increase in proenkephalin gene expression and mu-opioid receptor'activation of G-proteins in the paraventricular nucleus, as well as in other structures such as spinal cord, caudate-putamen, nucleus accumbens, ventromedial nucleus of hypothalamus, and pituitary. It is proposed that the increase in spontaneous yawning observed after cessation of cannabinoid treatment might be related to the loss of an increased tone at mu-opioid receptors. Yawning is one of the nine signs in the diagnostic criteria for opioid withdrawal (DSM-IV-TR, 1994). The possible involvement of an opioid system in spontaneous yawning following cannabinoid withdrawal merits farther investigation.

In summary, acute administration of d8-THC or d9-THC significantly reduced yawning induced by cholinergic or dopaminergic agonists. Chronic exposure to the cannabinoid agonist did not change yawning induced by cholinergic or dopaminergic agonists 24 h or 7 days after drug discontinuation. However, an increased spontaneous yawning was observed 7 days after cannabinoid withdrawal. This sign might provide a good behavioral instrument for carrying out studies on cannabinoid withdrawal and/or dependence.

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