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28 avril 2005
J Pharmacol Exp Ther
Dopamine Agonist-Induced Yawning in Rats: A Dopamine D3 Receptor Mediated Behavior
Collins GT, Witkin JM, Newman AH, Svensson KA, Grundt P, Cao J, Woods JH.
University of Michigan Medical School


Abstract :
A specific role for the dopamine D3 receptor in behavior has yet to be elucidated. We now report that dopamine D2/D3 agonists elicit dose-dependent yawning behavior in rats, resulting in an inverted U-shaped dose-response curve. A series of experiments was directed toward the hypothesis that the induction of yawning is a D3 receptor mediated effect, while the inhibition of the yawning observed at higher doses is due to competing D2 receptor activity.
We compared several dopaminergic agonists with a range of in vitro D3 selectivity, including; PD-128,907, PD-128,908, quinelorane, pramipexole, 7-OH-DPAT, quinpirole, bromocriptine, and apomorphine with respect to their ability to induce yawning in rats. A series of D2/D3 antagonists differing in selectivity for D3 over D2 receptors were evaluated for their ability to alter the effects of the dopamine agonists.
The antagonists L-741,626, haloperidol, nafadotride, U99194, SB-277011A, and PG01037 were used to determine effects on dose-response curves for D2/D3 agonist-induced yawning. In addition, the potential contribution of cholinergic and/or serotonergic mechanisms to the yawning response was investigated using a series of pharmacological tools including scopolamine, mianserin, and the D3-preferring antagonists; nafadotride, U99194, SB-277011A, and PG01037 to differentially modulate yawning induced by the PD-128,907, physostigmine, and TFMPP.
The results of these experiments provide convergent evidence that dopamine D2/D3 agonist-induced yawning is a D3 agonist mediated behavior, with subsequent inhibition of yawning being driven by competing D2 agonist activity. Thus, dopamine agonist-induced yawning may represent an in vivo method for selectively identifying D3 and D2 receptor-mediated activities.
 dopamine D3
Dopamine D3 receptors have received considerable interest since originally cloned. The D3 receptor shares significant sequence homology with the dopamine D2 receptor, but displays a much more restricted, limbic pattern of distribution compared to that of the D2 receptor in the rat and human brain. Based in large part on this restricted distribution and high sequence homology, it has been hypothesized that the D3 receptor may be of interest as a pharmacological target for antipsychotics and antiparkinsonian therapeutics. Additionally, the D3 receptor is thought to play a role in reinforcement pathways, as the D3 receptor is expressed in high levels within the mesolimbic dopaminergic system, and more specifically, the nucleus accumbens shell.
However, progress in defining a role for the D3 receptor has been slowed by the inability to identify behavioral effects that can be linked exclusively to a D3 mechanism. This is, at least in part, due to the lack of pharmacologically selective compounds acting at either the D3 or D2 receptors, as well as the fact that potentially selective agonists have failed to elicit obvious, direct behavioral changes. While D2/D3 agonists and antagonists have been shown to produce changes in body temperature, locomotor activity, and other behavioral measures, a role for the D3 receptor in the regulation of these effects has typically not been confirmed by studies using D3 receptor deficient mice. Recently, increases in locomotor activity by MK801 and blockade of the convulsant effects of dopamine uptake inhibitors have been proposed as in vivo models of D3 receptor activation. However, systematic replication of those findings or confirmation by other means has not been reported. The studies reported herein provide evidence supporting the contention that yawning induced by D2/D3 agonists is mediated specifically through D3 receptor activation.
The ability of dopaminergic agonists to elicit biphasic yawning resulting in an inverted Ushaped dose-response curve in rats has been a long-studied phenomenon. An early hypothesis regarding the biphasic regulation of apomorphine-induced yawning behavior attributed the induction of yawning behavior to a D2 agonist activity, while the inhibition seen at higher doses was thought to be due to a competing D1 agonist activation. The cloning of the dopamine D3 receptor and the development of agonists such as PD-128,907 and 7-OH-DPAT as well as antagonists including U99194, SB-27701A and PGD1D37 with greater degrees of in vitro selectivity for the D3 receptor have allowed greater insights into the regulation of dopaminergic agonist-induced yawning behavior to be made. Based on a series of studies examining the unconditioned behavioral effects of 7-OH-DPAT, as well as binding studies hypothesized in an extensive review that, D2/D3 agonist-induced yawning may be a D3 agonist mediated effect, while the inhibition seen at higher doses was a result of concomitant D2 agonist activation.
This hypothesis was evaluated in the present studies using a host of pharmacological tools. The abilities of a series of compounds with varying in vitro selectivities for the D3 relative to D2 receptors to elicit yawning were examined. A series of antagonists, again defined by binding in vitro selectivity for the D3 and D2 receptors, were evaluated with respect to their modification of dose-response relationships for D2/D3 agonists, with the majority of the studies using PD-128,907 as a prototype D3 agonist.
Finally, in addition to dopaminergic mechanisms, yawning can be induced by cholinergic or serotonergic compounds. While the exact mechanisms and neural pathways involved in the regulation of yawning behavior have not been fully elucidated, there is a large set of data that suggests that dopaminergic, serotonergic, and cholinergic induction of yawning occur via distinct mechanisms. In addition both dopaminergic and serotonergic pathways are thought to eventually feed onto cholinergic neurons, thus allowing for differential regulation of dopaminergic and serotonergic yawning, with a cholinergic component common in all three pathways. Therefore, some D3 antagonists that reduced PD-128,907 induced yawning were also assessed for their capacity to alter non-dopaminergicinduced yawning.
The convergent evidence from the agonist and antagonist studies support the hypothesis that dopamine agonist-induced yawning is mediated specifically through activation of D3 receptors. Therefore, yawning in rats may provide a critical model for establishing the in vivo activities of putative D3 selective ligands, a first step toward defining their role in normal and pathological physiological states. [...]
Evidence has been provided in the present paper to support the hypothesis that D2/D3 agonist-induced yawning behavior in rats is mediated by agonist activation of the dopamine D3 receptor, while the inhibition of yawning is a result of a competing agonist activation of the dopamine D2 receptor. ln agreement with the majority of previous studies, all of the D2/D3 agonists tested with exception of bromocriptine and PD-128,908, the inactive enantiomer of PD-128,907, elicited significant, dose-dependent increases in yawning behavior with inhibition seen at higher doses, resulting in the characteristic inverted U-shaped dose response curve for yawning in rats. Evidence is also provided for the selective antagonism of the induction of yawning behavior by D3 preferring antagonists, and the inhibition of yawning by D2-preferring antagonists. In addition, the current studies demonstrate that inhibition of D3 agonist-induced yawning by D3-preferring antagonists is a result of their selective antagonist activity at the D3 receptor, and not through antagonist effects at D2, serotonergic, or muscarinic cholinergic receptors.
Yawning is a D3 mediated behavior.
Several lines of evidence have been provided in support of the hypothesis that yawning is a D3 agonist mediated behavior. In general, all D3-preferring D2/D3 agonists induced significant amounts of yawning at low doses. While there were no significant differences in the effectiveness of the agonists with respect to induction of yawning behavior with the exception of apomorphine, there were differences in the potency of the D2/D3 agonists to induce yawning. The rank-order potency of the D2/D3 agonists to elicit yawning behavior was as follows; quinelorane, apomorphine, quinpirole, 7-OH-DPAT, pramipexole, and PD-128,907, while bromocriptine and PD-128,908 failed to elicit significant levels of yawning. The stereoselectivity of the yawning response with regard to PD-128,907 [and PD-128,908] is an important finding, as dopamine receptors are selective with respect to more rigid agonists. Taken together with the findings of Stahle and Ungerstedt (1984), who showed that (+)-3-PPP, but not (-)-3PPP, will elicit yawning, our current findings provide further evidence that D2/D3 agonists are inducing yawning via dopaminergic agonist mechanisms. Differences in yawning induced by bromocriptine may be a result of pharmacokinetic differences, as bromocriptine has been shown to induce significant levels of yawning in studies using a 60 minute observation period.
Antagonists with a high degree of selectivity for the D3 compared to the D2 receptor selectively antagonized the induction of yawning behavior. Three of the four D3 preferring antagonists (U99194, SB-277011A, and PG01037) tested in the current studies possess the ability to dose-dependently and selectively antagonize the induction of yawning by PD-128,907, while having no effect on the inhibition of yawning observed at higher doses. As shown in figures 3G and 3D respectively, SB-27701 IA and PG01037, D3-preferring antagonists with similarly high degrees of in vitro D3 selectivity (100- and 133-fold respectively) produced almost identical effects on PD-128,907 induced yawning; significant, dose-dependent, downward/rightward shifts of the ascending limb of the yawning dose-response curve were observed, while the descending limb of the dose-response curve for PD-128,907-induced yawning was not changed. Similar effects were seen with the moderately selective (30-fold) D3-preferring antagonist U99194, however, unlike SB-27701 lA and PG01037, at relatively high-dose of 10.0 mg/kg, U99194 completely inhibited PD-128,907-induced yawning; however, it should be noted that at this dose U99194 effectively antagonized not only dopaminergic, but cholinergic and serotonergic yawning as well. Nafadotride, the least selective (3-fold) of the D3-preferring antagonists, was the only D3 antagonist to produce a non-selective antagonism of yawning behavior; shifting both the ascending and descending limbs of the dose-response curve for PD-128,907-induced yawning at the highest dose tested. This effect was similar to that observed with haloperidol, a non-selective dopamine antagonist, and suggests that at a dose of 0.32 mg/kg, nafadotride is no longer selective for the D3 receptor, but rather is active at both the D3 and D2 receptors. Taken together, these data provide strong support for the hypothesis that the induction of yawning by D21D3 agonists is mediated by an agonist activation of the D3 receptor.
Inhibition of yawning is a D2 mediated effect.
We have also provided evidence in support of the hypothesis that inhibition of D2/D3 agonist-induced yawning occuring at higher doses is mediated by an agonist activity at the D2 receptor. As shown in figure 2A and 2B, the D2-preferring antagonist L-741,626, at the first behaviorally active dose (1.0 mg/kg), selectively antagonized the inhibitory effects of high doses of PD-128,907 and quinelorane, resulting in a rightward shift in the descending limbs while having virtually no effect on the ascending limbs of the doseresponse curves for both PD-128,907- and quinelorane-induced yawning. In addition L741,626 produced a rightward shift in the maximal effective dose of P0-128,907 and quinelorane, resulting in an increased effectiveness for both agonists. These data not only suggest that L-741,626, at a dose of 1.0 mg/kg, is an effective D2 antagonist in vivo, but that it is also devoid of D3 antagonist activity.
Further support for the differential regulation of yawning behavior by the D3 and D2 receptors was provided by the effects of the non-selective DA antagonist haloperidol. As D3- and D2-preferring antagonists selectively antagonize the ascending and descending limbs of the dose-response curve for D2/D3 agonist-induced yawning respectively, it would be expected that antagonists with mixed D2/D3 actions, such as haloperidod, would shift both the ascending and descending limbs of yawning dose-response curves at their initial active doses. Indeed, at the first behaviorally active dose (0.032 mg/kg), haloperidol produced rightward shifts in both the ascending and descending limbs of the dose-response curves for both PD-128,907- and quinelorane-induced yawning. This not only suggests that the effects of D3- and D2-prefemng antagonists are a result of selective antagonist activity, but that non-selective D2/D3 antagonists produce effects distinct from those of other dopaminergic antagonists on D3 agonist induced yawning.
However, it should be noted that in addition to possessing high affinities for the D3 and D2 receptors, halopendol also has significant affinities for the D1, D4, and D5 receptors. It is, however, unlikely that activity at these receptors is influencing PD-128,907-induced yawning behavior as the D1/D5-selective antagonist, SCH 23390, and the D4-selective antagonist, L-745,870, at behaviorally active doses did not alter yawning elicited by either low (0.032-0.1 mg/kg) or high (0.32 mg/kg) doses of PD-128,907. This provides further evidence that D2/D3 agonist-induced yawning behavior is under the direct control of the D3 (induction) and D2 (inhibition) receptors, but not the D1, D4, or D5 receptors. However, the possibility remains that other dopaminergic receptors may modulate D3 agonist-induced yawning elicited by other D2/D3 agonists, as several of the agonists tested, such as apomorphine, quinelorane, and quinpirole, possess significant affinities for the Dl, D4, and D5 receptors (apomorphine), or 04 receptor (quinelorane and quinpirole) in addition to the D3 and D2 receptors.
Dopaminergic, serotonergic, and cholinergic regulation of yawning.
The findings of the current study confirm, and extend those of earlier studies, and demonstrate that while scopolamine will dosedependently antagonize yawning induced by cholinergic, serotonergic, and dopaminergic agonists, serotonergic and dopaminergic antagonists are able to selectively antagonize yawning elicited by their respective agonists. More specifically, nafadotride, SB-27701 lA, and PG01037, D3-preferring antagonists with a wide range (3-133 fold) of selectivities for the D3 receptor over the D2 receptor in vitro, were able to selectively antagonize PD-128,907-induced yawning, while having no effect on yawning elicited by either physostigmine or TFMPP . This suggests that SB-27701 lA and PG01037 are not only selective for the D3 over the D2 receptor, but that they are also selective for the D3 receptor over certain serotonergic and cholinergic receptors at doses up to 56.0 mg/kg. Similarly, while nafadotnde demonstrated little or no preference for the D3 compared to the D2 receptor in vivo, no serotonergic or tholinergic antagonist activity was detected at doses up to 1.0 mg/kg. However, in contrast to the effects of the other D3-preferring antagonists, U99194, at a dose of 10.0 mg/kg, significantly antagonized yawning elicited by PD-128,907, TFMPP and physostigmine, suggesting that at higher doses, it is no longer selective for dopaminergic receptors. While U99194 is unique in this regard within this group of D3-preferring antagonists, clozapine, an antagonist with significant affinities for dopaminergic, serotonergic and cholinergic receptors has also been shown to antagonize both dopaminergic and cholinergic yawning, suggesting that antagonism of physostigmine-induced yawning may be a reliable measure of anti-cholinergic activity. Further evidence of an in vivo anti-muscarinic activity of U99194 has been demonstrated by Gaudie and colleagues (2001) who showed in discrimination studies that U99194 generalized to a scopolamine cue, suggesting that U99194 may possess anti-cholinergic activity at higher doses. Although it has been suggested that U99194 functions as a D3 selective antagonist in vivo at doses ranging from 13.0 to 400 mg/kg based on its inability to increase plasma prolactin, to induce catalepsy, and to inhibit the induction of hypothermia by PD-128,907, the results of the current study suggest that while U99194 may be selective for the D3 compared to the D2, a significant anti-cholinergic effect is apparent at 10.0 mg/kg. Thus the current studies support the hypothesis that dopaminergic, serotonergic and cholinergic agonists induce yawning via distinct mechanisms, and furthermore that yawning induced by D2/D3 agonists is a result of agonist activation of D3 receptors, and not serotonergic or cholinergic receptors.
To summarize the results of the studies reported herein, evidence has been provided in support of the hypothesis that the induction of yawning by D2/D3 agonists is mediated through an agonist activity at the D3 receptor, while the subsequent inhibition of yawning seen at higher doses is a result of an increasing D2 agonist activity. Based on these findings several conclusions can be drawn: First, the ascending limb of the doseresponse curves corresponds to doses that are selectively activating D3 receptors over D2 receptors, while the descending limb corresponds to those activating both the D3 and D2 receptors. Additionally, determinations of in vivo D3 potency and effectiveness may be possible, based on the onset and maximal amount of yawning elicited. Furthermore, inhibition of yawning may provide useful information regarding in vivo D2 potency, and lastly, the shape of the dose-response curves may allow for determinations of in vivo D3 selectivity of D3-preferring D2/D3 agonists to be made. The results of the current set of studies have demonstrated that D3 selective antagonism will only shift the ascending limb of the yawning dose-response curve, that D2 selective antagonism will only shift the descending limb of the yawning dose-response curve, while non-selective D2/D3 antagonism will shift both the ascending and descending limbs of the dose-response curve for D2/D3 agonist-induced yawning behavior in rats. In conclusion, as the current studies have provided evidence that the induction of yawning behavior by D2/D3 agonists is mediated by the D3 receptor, yawning may be an important pharmacological effect that can be used in the characterization, classification, and discovery of in vivo D3 agonist and antagonist actions. Thus, it may be possible to relate other behavioral effects of D2/D3 agonists and antagonists to their ability to modulate yawning. Whether the potency and selectivity measures of these compounds can be utilized across behavioral measures will need to be explored in the future.
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Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren
Distribution of dopamine D3 receptor expressing neurons in the human forebrain:
comparison with D2 receptor expressing neurons
Gurevich EV, Joyce JN.
Neuropsychopharmacology 1999;20(1):60-80
Based on studies in the rat, Sokoloff et al. have made the valuable suggestion that the D3 receptor is a particularly important target for antipsychotics in the mesolimbic DA system. These study in the human demonstrates that the distribution of D3 receptors and D3 mRNA-bearing neurons is consistent with relative segregation of the D3 subtype to the limbic striatum as well as it primary and secondary targets and many sources of its afferents.