Le bâillement, du réflexe à la pathologie
Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
 Le bâillement : un comportement universel
La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
Le bâillement, du réflexe à la pathologie
Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
 Le bâillement : un comportement universel
La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal

mystery of yawning 














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mise à jour du
16 juin 2014
J Pharmacol Exp Ther
Further Characterization of Quinpirole-Elicited Yawning As a Model of
Dopamine D3 Receptor Activation in Male and Female Monkeys
Susan E. Martelle, Susan H. Nader, Paul W. Czoty, William S. John, Angela N. Duke,
Pradeep K. Garg, Sudha Garg, Amy H. Newman and Michael A. Nader  
Departments of Physiology and Pharmacology
and Radiology, Wake Forest School of Medicine, Winston-Salem, NC
and the Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD


The dopamine (DA) D3 receptor (DRD3) has been associated with impulsivity, pathological gambling and drug addiction making it a potential target for pharmacotherapy development. Positron emission tomography (PET) studies using the DRD3-preferring radioligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin ([11C]PHNO) have shown higher binding potentials in drug abusers compared to control subjects.
Preclinical studies have examined DRD3 receptor activation using the DA agonist quinpirole and the unconditioned behavior of yawning. However, the relationship between quinpirole-elicited yawning and DRD3 receptor availability has not been determined.
In Experiment 1, 10 drug-naive male rhesus monkeys were scanned with [11C]PHNO and the ability of quinpirole (0.01-0.3 mg/kg, i.m.) to elicit yawning was examined. Significant relationships between DRD3 receptor availability and quinpirole-induced yawns were noted in several brain regions. Experiment 2 replicated earlier findings that a history of cocaine self-administration did not affect quinpirole-induced yawning and extended this to examine monkeys with a history of methamphetamine (MA) self-administration and found that monkeys with experience self-administering MA showed greater potency and significantly higher quinpirole-elicited yawning compared to controls.
Finally, quinpirole-elicited yawning was studied in drug-naive female monkeys and compared to drug-naive male. Sex differences were noted, with quinpirole being more potent and significantly eliciting more yawns in males compared to females.
Taken together these findings support the use of quinpirole-elicited yawning as a behavioral tool for examining DRD3 activation in monkeys and that both drug history and sex may influence individual sensitivity to the behavioral effects of DRD3 compounds
Martelle JL, Claytor R, Ross JT, Reboussin BA, Newman AH, Nader MA. Effects of two novel D3-selective compounds, NGB 2904 and CJB 090, on the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys. J Pharmacol Exp Ther. 2007;321(2):573-582

Psychostimulant drug use is a global problem. In 2011, the United Nations Office on Drugs and Crime estimated 14 to 21 million people worldwide used cocaine at least once in 2009, with 20% of users in the United States meeting the criteria of drug dependence (Degenhardt and Hall, 2012).
Despite the array of negative health and societal consequences, a successful pharmacotherapy for psychostimulant addiction has remained elusive (Newman et al., 2005, 2012). There is evidence that dopamine (DA) D3 receptors (DRD3), a subtype of the D2-like family of DA receptors, mediate many of the effects of psychostimulants associated with high abuse potential (Heidbreder and Newman, 2010; Heidbreder, 2012), including the role of conditioned stimuli (Achat-Mendes et al., 2010; Neisewander et al., 2004; Orio et al., 2010; Yan et al., 2013), discriminative stimulus effects (Achat-Mendes et al., 2010; Collins and Woods, 2009; Martelle et al., 2007), and cue conditioning (Le Foll et al., 2002).
In addition, DRD3 partial agonists and antagonists have been shown to reduce self-administration of methamphetamine (MA) in a rodent model of compulsive drug intake (Orio et al., 2010). Postmortem studies indicate higher DRD3 densities in cocaine overdose victims compared to age-matched controls (Staley and Mash, 1996; Segal et al., 1997), supporting a role for this receptor subtype in drug addiction. Finally, recent brain imaging studies in humans using the positron emission tomography (PET) DRD3-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin ([11C]PHNO) revealed that DRD3 availability was higher in MA polydrug users (Boileau et al., 2012) and cocaine-dependent individuals (Payer et al., 2014) compared to age-matched controls; an outcome opposite to the decreases in D2-like receptor availability following chronic stimulant exposure (e.g., Volkow et al., 1990, 2001; Nader et al., 2006).
A behavioral assay that has been frequently used to characterize DRD3 agonists is the unconditioned behavior of drug-elicited yawning using the D3/D2 receptor agonist quinpirole in rodents (e.g., Collins et al., 2005, 2007; Baladi and France, 2009) and nonhuman primates (Martelle et al., 2007; Hamilton et al., 2010; Blaylock et al., 2011).
The quinpirole-induced yawning dose-response curve is an inverted-U shaped function of dose. Collins, Woods and colleagues concluded that the ascending limb of the quinpirole dose-response curve is mediated by DRD3, while the descending limb is primarily D2 receptor (DRD2)-mediated and coincides with an onset of hypothermia (Collins et al., 2005, 2007). Despite the differences noted in D2-like and DRD3 availability following cocaine exposure, quinpirole-elicited yawning was not different in cocaine-naïve vs. cocaine-experienced monkeys (Blaylock et al., 2011). However, while DRD3 partial agonists do not elicit yawning when administered to cocaine-naïve monkeys (Martelle et al., 2007), they do elicit yawning in monkeys with an extensive cocaine history (Blaylock et al., 2011).
This finding suggests that drug-elicited yawning may be an effective baseline on which to assess functional consequences of chronic cocaine exposure. In the present study, we utilized quinpirole-elicited yawning to examine the relationship between behavioral sensitivity and measures of DRD3 receptor availability using PET imaging with [11C]PHNO in drug-naïve male rhesus monkeys. Secondly, we extended previous findings that a cocaine history does not influence sensitivity to quinpirole-elicited yawning (Blaylock et al., 2011; Collins et al., 2011) to monkeys with an extensive MA self-administration history.
Finally, recent data investigating DA D2/D3 receptor availability in cocaine abuse (Nader et al., 2012) suggested possible sex differences in the relationship between DA receptor function and cocaine abuse. Thus, we examined the effects of quinpirole-elicited yawning in a group of drugnaïve female rhesus monkeys and compared them to drug-naïve male rhesus monkeys.
The purpose of the present study was three-fold. The first objective was to ascertain the relationship between DRD3 binding potentials and the behavioral effects of the D3-preferring agonist quinpirole in monkeys. PET imaging using the D3-preferring radioligand [11C]PHNO revealed a significant correlation between DRD3 binding potential and quinpirole-induced yawning in several regions of the brain including the caudate nucleus, putamen, globus pallidus, ventral pallidum and hippocampus.
The second objective was to test whether a history of MA self-administration differentially affected sensitivity to the unconditioned behavioral effects of quinpirole. Using a cumulative quinpirole dosing procedure, differences between MAexperienced monkeys and drug-naïve monkeys were noted, with the MA group showing greater sensitivity to quinpirole. We also replicated an earlier study (Blaylock et al., 2011) showing no differences in quinpirole-elicited yawning between drug-naïve and cocaine-experienced monkeys.
Lastly, the comparison of drug-naïve male and female monkeys revealed sex differences, with quinpirole showing greater efficacy and greater potency in eliciting yawning in males compared to females. These findings suggest that the unconditioned behavior of quinpirole-elicited yawning reflects DRD3 function in monkeys and that both sex and drug history are determinants of individual sensitivity. Receptor autoradiography studies have indicated similar DRD3 receptor distribution in nonhuman primates compared to humans (Levant, 1998; Morisette et al., 1998; Sun et al., 2012).
In the present study, the highest uptake and binding potentials were in the caudate nucleus, putamen and ventral striatum. Previous studies in humans have found a similar pattern of distribution of PHNO binding, with highest binding potentials in the putamen, globus pallidus and substantia nigra (Searle et al., 2010; Boileau et al., 2012, 2013; Gallezot et al., 2014). Tziortzi and colleagues (2011) utilized the DRD3 antagonist GSK598809 to better determine the contribution of DRD3 and DRD2 to the PHNO signal in various brain regions.
These investigators found that 100% of PHNO signal in the substantia nigra and hypothalamus and the majority of the signal in the ventral pallidum and globus pallidus were DRD3 mediated. In contrast, only 20% of the signal in the ventral striatum was attributed to DRD3 whereas 100% of the signal in the caudate nucleus was a result of DRD2 binding (Tziortzi et al., 2011).
Since the ascending limb of the quinpirole-elicited yawning dose-response curve is thought to be DRD3 mediated (Collins et al., 2005, 2007), the results of the mixed model which showed approximately 5 greater yawns for every 1-unit increase in binding potential in the globus pallidus, supports this conclusion.
Furthermore, in the present study, yawning was negatively correlated with binding in the caudate nucleus and putamen, consistent with predominant DRD2-mediated signal associated with [11C]PHNO binding potential and pharmacological studies suggesting that the descending limb of the quinpirole-elicited yawning dose-response curve is DRD2 mediated (Collins et al., 2005, 2007). Recent PET studies of chronic cocaine (Payer et al., 2014) and poly-drug MA (Boileau et al., 2012) users reported that both drugs were associated with elevated levels of DRD3 availability in the substantia nigra. Furthermore, the use of cocaine and MA has previously been shown to be associated with decreased D2-like receptor availability (Volkow et al., 1990, 2001; Nader et al., 2006; Payer et al., 2014).
In the present study, quinpirole-elicited yawning was used to assess group differences in DRD3 activity in monkeys with a cocaine or MA history and drug-naïve male monkeys. In drug-naïve monkeys, the quinpirole dose-response curve was an inverted U-shaped function of dose, as has been reported previously in monkeys (Martelle et al., 2007; Hamilton et al., 2010; Blaylock et al., 2011). Similarly, quinpirole-elicited yawning was not different between drug-naïve and cocaine-exposed monkeys (Blaylock et al., 2011), although there was substantial individual-subject variability in the quinpirole dose-response curves. The reasons for these individual differences are not yet determined, but may be due to differences in cocaine intake.
Consistent with the present findings, a recent study found substantial individual subject differences in the reinforcing effects of DRD3 agonists, quinpirole, pramipexole, and ropinirole (Koffarnus et al., 2012), which may be due to differences in cocaine selfadministration histories.
Additional studies are needed to better understand how different cocaine exposures affect DRD3 compounds. In contrast to the lack of differences between drug-naïve and cocaine-exposed monkeys, MA-exposed monkeys were more sensitive to the behavioral effects of quinpirole compared to control monkeys. Changes in sensitivity on the ascending limb of the quinpirole dose-response curve have been hypothesized to be due to upregulation of DRD3 and/or downregulation of DRD2 (Collins et al., 2011); PET and receptor autoradiography studies support this mechanism following long-term MA exposure (Kuczenski et al., 2009; Boileau et al., 2012).
It also remains possible that changes in DA transporter (DAT) and subsequent changes in extracellular DA may interact with quinpirole's effects at DRD3 and DRD2. Consistent with this hypothesis is that MA exposure has been shown to decrease DAT (Chu et al., 2008; Groman et al., 2013) while chronic cocaine exposure has been reported to increase DAT density (Letchworth et al., 2001). Irrespective of the mechanisms, the present findings suggest that despite both stimulants resulting in increases in [11C]PHNO binding (Boileau et al., 2012; Payer et al., 2014), the behavioral effects of DRD3 compounds may be different in subjects with a MA history compared to a cocaine history.
There is accumulating evidence of sex differences in cocaine abuse (O'Brien and Anthony, 2005), including greater vulnerability in initiating drug use, progressing to dependence faster, and more adverse physical, mental, and social consequences of abuse in women compared to men (Zilberman et al., 2003; Greenfield et al., 2010). Several animal models using female subjects have supported these observations (e.g., Lynch and Carroll, 2002; Mello et al., 2007; Mello, 2010; Nader et al., 2012).
As it relates to DRD3 function, sex differences have not been reported. In the present study, we found significant differences between male and female monkeys at lower quinpirole doses, with females being less sensitive to the behavioral effects of quinpirole. It is possible that the entire quinpirole dose-response curve for females is shifted to the right of males and that if higher doses of quinpirole were tested, even greater sex differences would have been observed. However, it is important to note that quinpirole-induced hypothermia was not different in drug-naïve females and males suggesting that baseline DRD2 availability is not different.
PET data using DRD2-like radiotracers in monkeys have confirmed no significant differences between male and female monkeys (Hamilton et al., 2010). Although DRD2-availability may not be different at baseline, our data suggest that sex differences in pharmacodynamics may be influencing the behavioral results. Consistent with this hypothesis, an investigation of healthy human subjects reported that drug-elicited DA release in the ventral striatum, caudate nucleus and putamen was greater in male subjects compared to females (Munro et al., 2012).
Additionally, a recent study showed that female smokers have significantly higher D2-like receptor availability than male smokers (Brown et al., 2012), further supporting the growing evidence of gender differences in dopaminergic system dynamics (Becker, 1999; Dreher et al., 2007; Festa et al., 2010; Hedges et al., 2010). On the other hand, the quinpiroleelicited yawning dose-response curve has been shown to be malleable to changes in food content and body weight (Baladi and France, 2009). Although males and females in this study ate the same high-protein diet, the heaviest female weighed less than the lightest male.
Whether changes in diet would similarly affect the quinpirole dose-response curve in males and females remains to be investigated. There is evidence supporting the use of DRD3 antagonists and partial agonists for the treatment of cocaine and MA abuse as well as accompanying symptoms such as cognitive dysfunction (Newman et al., 2012; Mugnaini et al., 2013; Nakajima et al., 2013). Considering female rhesus monkeys in the current study were less sensitive to the behavioral effects of quinpirole, it is likely that drug potency will be a critical variable in future studies investigating DRD3 compounds as a treatment option.
As there are known gender differences in drug pharmacokinetics and pharmacodynamics (see Gandhi et al., 2004 for review), and also that the fields of Neuroscience and Pharmacology publish predominately male subject-based studies (Beery and Zucker, 2011), the present findings support the consideration of sex differences as a critical variable in the development of treatment strategies for drug abuse (Zilberman et al., 2003; see Becker and Hu, 2008). Finally, this and other studies (Bouileou et al., 2013; Payer et al., 2014) have associated DRD3 availability and a history of psychostimulant abuse but have yet to establish the nature of this relationship. Future studies will need to focus on whether high or low DRD3 availability is a risk factor in psychostimulant abuse or a result of exposure to the drug. There are some limitations to the present study.
The relationship between [11C]PHNO binding potential and quinpirole-elicited yawning is not consistent with DRD3 and DRD2 signal in every brain region examined. For example, monkeys experienced fewer yawns with increasing DRD3 binding potential in the ventral pallidum. This relationship is not consistent with the high DRD3 signal reported in that brain region (Tziortzi et al., 2011), suggesting possible alternative mechanism.
Past studies have implicated specific brain areas in dopamine agonistelicited yawning including the nigrostriatal pathway, hypothalamus, and the paraventricular nucleus (Dourish et al., 1985; Melis et al., 1987), thus it is expected that yawning does not necessarily have to correlate with DRD3 and DRD2 signal in every brain region. Furthermore, yawning is not limited to dopaminergic modulation and several other neurotransmitters and neurohormones are involved (Argiolas and Melis, 1998) creating a complex neural circuit (Sanna et al., 2012) that requires additional testing.