mystery of yawning
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Fetal yawning assessed by 3D and 4D sonography
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Le bâillement : de l'éthologie à la médecine clinique
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La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
 
Fetal yawning assessed by 3D and 4D sonography
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15 janvier 2012 
Psychopharmacology (Berl).
2012 ;222(1):27-36
Sensitivity to apomorphine-induced yawning and hypothermia in rats eating standard or high-fat chow
 
Baladi MG, Thomas YM, France CP.
 
Department of Pharmacology, University of Texas Health Science Center.
San Antonio, TX, USA.

Chat-logomini

Abstract
 
Feeding conditions modify sensitivity to indirect and direct acting dopamine receptor agonists as well as the development of sensitization to these drugs.
 
This study examined whether feeding condition affects acute sensitivity to apomorphine-induced yawning or changes in sensitivity that occur over repeated drug administration. Quinpirole-induced yawning was also evaluated to see whether sensitization to apomorphine confers cross-sensitization to quinpirole.
 
Drug-induced yawning was measured in different groups of male Sprague Dawley rats (n = 6/group) eating high (34.3%) fat or standard (5.7% fat) chow.
 
Five weeks of eating high-fat chow rendered otherwise drug-naïve rats more sensitive to apomorphine- (0.01-1.0 mg/kg, i.p.) and quinpirole- (0.0032-0.32 mg/kg, i.p.) induced yawning, compared with rats eating standard chow. In other rats, tested weekly with apomorphine, sensitivity to apomorphine-induced yawning increased (sensitization) similarly in rats with free access to standard or high-fat chow; conditioning to the testing environment appeared to contribute to increased yawning in both groups of rats. Food restriction decreased sensitivity to apomorphine-induced yawning across five weekly tests. Rats with free access to standard or high-fat chow and sensitized to apomorphine were cross-sensitized to quinpirole-induced yawning. The hypothermic effects of apomorphine and quinpirole were not different regardless of drug history or feeding condition.
 
Eating high-fat chow or restricting access to food alters sensitivity to direct-acting dopamine receptor agonists (apomorphine, quinpirole), although the relative contribution of drug history and dietary conditions to sensitivity changes appears to vary among agonists.
 
-Baladi MG, Newman AH, France CP. Dopamine D3 receptors mediate the discriminative stimulus effects of quinpirole in free-feeding rats. J Pharmacol Exp Ther. 2010;332(1):308-315
-Baladi MG, Newman AH, France CP. Influence of body weight and type of chow on the sensitivity of rats to the behavioral effects of the direct-acting dopamine-receptor agonist quinpirole.Psychopharmacology (Berl). 2011;217:573&endash;585
-Baladi MG, Thomas YM, France CP. Sensitivity to apomorphine-induced yawning and hypothermia in rats eating standard or high-fat chow. Psychopharmacology (Berl). 2012;222(1):27-36
-Collins GT, JM Witkin et al Dopamine agonist-induced yawning in rats: a dopamine d3 receptor mediated behavior. J Pharmacol Exp Ther 2005;314(1):310-9.
-Collins GT, Newman AH,Woods JH et al.Yawning and hypothermia in rats: effects of dopamine D3 and D2 agonists and antagonists. Psychopharmacology (Berl). 2007;193(2):159-170
-Collins GT. et al. Food restriction alters pramipexole-induced yawning, hypothermia, and locomotor activity in rats: Evidence for sensitization of dopamine D2 receptor-mediated effects. JEPT 2008;325:691-697
-Collins GT et al. Narrowing in on compulsions: dopamine receptor functions Exp Clin Psychopharmacol 2008,16(4):498-502
-Collins GT et al. Pro-erectile Effects of Dopamine D2-like Agonists are Mediated by the D3 Receptor in Rats and Mice JPEP 2009;329(1):210-217
-Collins GT, Truong YN, et al. Behavioral sensitization to cocaine in rats: evidence for temporal differences in dopamine D(3) and D (2) receptor sensitivity. Psychopharmacology (Berl). 2011;215(4):609-20
 

Introduction
 
Feeding conditions can impact sensitivity to the behavioral effects of drugs acting directly at dopamine receptors (Baladi and France 2009; Can et al. 2001; Collins et al. 2008; Sevak et al. 2008). For example, the dose-response curve for dopamine receptor agonist (e.g., quinpirole)-mduced yawning is an inverted U-shape with the ascending and descending limbs of the curve being mediated by D3 and D2 receptors, respectively (Baladi et al. 2010; Collins et al. 2005). In rats eating high-fat chow, both limbs of the dose-response curve are shifted leftward; however, antagonism of quinpirole-induced yawning is not different between rats eating high-fat or standard chow (Baladi et al. 2011), indicating that the shifts leftward in the former reflect increased sensitivity at D3 (ascending limb) and D2 (descending limb) receptors (Baladi and France 2009; Baladi et al. 2010, 2011; Collins et al. 2005). Food restriction, on the other hand, decreases sensitivity to, or in some cases eliminates, dopamine receptor agonist-induced yawning as evidenced by a flattening of the inverted U-shaped dose-response curve; this flattening is thought to reflect a selective increase in sensitivity at D2 receptors (i.e., descending limb; Coffins et al. 2008; Sevak et al. 2008).
 
Sensitivity to the behavioral effects of drugs acting on dopamine systems sometimes increases over repeated tests (i.e., sensitization), and this phenomenon can occur with both direct- (e.g., apomorphine) and indirect (e.g., amphetamine)-acting dopamine receptor agonists (Kalivas and Weber 1988; Mattingly et al. 1991; Robinson and Becker 1986; Silverman 1991). Repeated treatment with drugs that directly or indirectly stimulate dopamine receptors can result in longlasting behavioral effects in humans as well (e.g., methamphetaminepsychosis; Sato et al. 1983; Strakowski et al. 1996). The development and expression of sensitization (e.g., druginduced locomotor activity) is influenced by a number of factors including the particular drug, dose, frequency of drug administration, and the context in which drug is administered (Keller et al. 2002; Pens and Zahniser 1989; Post et al. 1981; Stewart and Badiani 1993). For example, after repeated pairings, the environment in which drug is administered can itself elicit a drug-like response. Conditioning of drug effects to environmental stimuli often develops with indirect-acting dopamine receptor agonists like amphetamine and cocaine (Gold et al. 1988; Martin-Iverson and Reimer 1994) and less often with direct-acting dopamine receptor agonists like apomorphine or quinpirole (Rowlett et al. 1991; Szechtman et al. 1993; Willner et al. 1992). The conditioning of drug effects to environmental stimuli likely depends on the specific behavior being examined (Einat and Szechtman 1993), and it is unclear whether conditioning develops to drug-induced yawning.
 
Dietary conditions might impact not only acute sensitivity to drugs but also changes in sensitivity that occur over repeated drug administration (i.e., sensitization). For example, sensitization to the locomotor stimulating effects of the indirect-acting dopamine receptor agonist methamphetamine is enhanced in rats eating high-fat chow (McGuire et al. 2011). A number of studies have examined druginduced sensitization using measures of locomotion; however, the generality of those data to other behavioral effects (e.g., yawning) is largely unknown.
 
The current study extends previous results obtained with the direct-acting dopamine receptor agonist quinpirole by examining the effects of food restriction and of eating high-fat chow on a well-characterized behavioral effect (yawning) of another direct-acting dopamine receptor agonist, apomorphine, in drug-naïve rats and in rats that were tested repeatedly with apomorphine. The feeding conditions used in the current study were selected in order to maximize potential differences in drug effects between groups and were based on a previous study (Baladi et al. 2011). In the first experiment, rats with free access to either standard or high-fat chow were used to determine whether eating highfat chow for 5 or 6 weeks alters sensitivity to apomorphine- or quinpirole-induced yawning, respectively. In a second experiment, rats with free access to either standard or high-fat chow or with restricted access to standard chow were tested with apomorphine once per week for 5 weeks to examine whether sensitization develops to apomorphineinduced yawning and whether sensitization is influenced by feeding condition. It is well established that eating high-fat chow shifts the quinpirole yawning dose-response curve to the left (Baladi et al. 2011); quinpirole was examined in the current study to test whether sensitization to apomorphine-induced yawning confers cross sensitization to quinpirole-induced yawning. Apomorphine- and quinpiroleinduced hypothermia was examined to test whether another effect of these drugs was similarly changed as a consequence of repeated drug testing or eating conditions.
 
Discussion
 
This study examined the effects of food restriction and of eating high-fat chow on yawning produced by the directacting dopamine receptor agonist apomorphine in rats. These results extend previous fmdmgs with other directacting dopamine receptor agonists such as pramipexole and quinpirole (Collins et al. 2008; Sevak et al. 2008) in demonstrating that food restriction also reduces or eliminates apomorphine-induced yawning. Second, results in rats that were tested just once with drug after a period of eating high-fat or standard chow show that eating high-fat chow is sufficient to increase sensitivity to agonist-induced yawning and not to agonist-induced hypothermia. Third, once weekly apomorphine tests cause sensitization to apomorphineinduced yawning and not to apomorphine-induced hypothermia; development of sensitization is not impacted by eating high-fat chow and yawning increases significantly over repeated testing even in the absence of drug (i.e., after vehicle injection), suggesting that conditioning contributes to apparent increases in sensitivity to drug. Finally, rats that are sensitized to apomorphine-induced yawning are crosssensitized to quinpirole-induced yawning.
 
Dopamine receptor agonist-induced yawning has been used to study changes in dopamine systems that occur under a variety of conditions, and it is well established that the ascending and descending limbs of the agonist (e.g., quinpirole) dose-response curve are mediated by dopamine D3 and D2 receptors, respectively (Baladi et al. 2010; Collins et al. 2005). A shift downward in the apomorphine doseresponse curve in rats with restricted access to food, as shown in the current study and by others, might be due to decreased sensitivity at D3 receptors, increased sensitivity at D2 receptors, or to both decreased sensitivity at D3 and increased sensitivity at D2 receptors. However, because a D2 receptor antagonist restores agonist-induced yawning in food-restricted rats (Collins et al. 2008), the effects of food restriction are most likely due to increased D2 receptor sensitivity. Rats that were tested just once with drug after 5 or 6 weeks of eating high-fat chow were significantly more sensitive (i.e., both limbs of the dose-response curve shifted leftward) than rats eating standard chow to apomorphine-induced and quinpirole-induced yawning, respectively, indicating increased sensitivity at D3 and D2 receptors. These behavioral data parallel results from neurochemistry studies showing that food restriction decreases extracellular dopamine concentration in the nucleus accumbens (Pothos et al. 1995), increases dopamine D2 receptor binding (Thanos et al. 2008), and increases coupling between D2 receptors and G proteins (Can 2002). Moreover, rats eating high-fat chow have decreased extracellular dopamine in the nucleus accumbens (Rada et al. 2010) and increased D2 receptor binding (South and Huang 2008). Thus, feeding conditions alone (i.e., in the absence of repeated drug treatment) can significantly increase sensitivity to the behavioral and neurochemical effects of drugs.
 
Repeated, intermittent treatment can also increase sensitivity to the behavioral effects of drugs, and this phenomenon (i.e., sensitization) has been studied extensively for the locomotor stimulating effects of indirect-acting dopamine receptor agonists (e.g., cocaine). Other studies have examined sensitization to the locomotor effects of direct-acting dopamine receptor agonists like apomorphine and quinpirole (Rowlett et al. 1991; Voikar et al. 1999). Although sensitizalion develops to the locomotor effects of direct-acting dopamine receptor agonists, it is less clear whether sensitization develops to other behavioral effects of the same drugs (but see Silverman 1991) and whether eating conditions impact the development of sensitization to direct-acting agonists as it can for indirect-acting agonists (e.g., McGuire et al. 2011). In the current study, once weekly tests with apomorphine decreased the maximally effective dose of apomorphine for producing yawning, reflecting a leftward shift in the yawning doseresponse curve and providing evidence for sensitization to this effect of a direct-acting dopamine receptor agonist. The diminishing effect obtained with a dose of 0.32 mg/kg apomorphine across weekly tests with apomorphine (i.e., this was the maximally effect dose on study day 7 and almost no yawning occurred with this dose on study day 35; Fig. 2) suggests an increased sensitivity at dopamine D2 receptors (i.e., shift leftward in the descending limb of the dose-response curve).
 
Progressively across weekly tests, yawning increased after administration of even small doses of apomorphine; over the same time course, progressively more yawning was observed after the administration of vehicle. Further tests in the absence of drug indicate that environmental stimuli (i.e., cage type and injection procedure) that were repeatedly paired with drug-induced yawning came to elicit yawning in the absence of drug. Yawning in the absence of drug did not develop in food-restricted rats, perhaps because apomorphine produced very little yawning in those rats. This is consistent with the view that environmental stimuli must be paired explicitly with drug-induced effects (e.g., yawning) in order for sensitization to develop (to drugs) and possibly for conditioned increases in behavior to emerge (Einat and Szechtman 1993; Willner et al. 1992). For example, rats exposed to a running wheel following repeated quinpirole injections become sensitized to the locomotor effects of quinpirole when tested on a runway. However, rats exposed to a locked running wheel following repeated quinpirole injections do not display sensitization to the locomotor effects of quinpirole when tested on a runway (Willner et al. 1992). Thus, the absence of drug-induced sensitization and the lack of conditioned yawning in food-restricted rats might be due to the fact that apomorphine produced very little yawning in those rats. Results of the current study provide evidence that conditioning to dopamine receptor agonists extends beyond locomotor stimulating effects to yawning.
 
That sensitization develops to apomorphine-induced yawning in the current study, but not to quinpirole-induced yawning in a previous study (Baladi et al. 2011), might be due to the relative selectivity of these compounds for dopamine receptor subtypes. Apomorphine has similar affinities for dopamine D3, D2, and Dl receptors (Andersen et al. 1985; Sokoloff et al. 1990) while quinpirole is more than 113-fold selective for D3 receptors over D2 receptors (Sokoloff et al. 1990) with negligible affinity for Dl receptors. The neurobiological mechanisms underlying sensitization remain unclear, and there is debate regarding the involvement of specific dopamine receptor subtypes in the development of sensitization (Mattingly et al. 1991; Voikar et al. 1999). In addition, non-dopaminergic systems (e.g., serotonin, glutamate) might also play a role in sensitization (Kuczenski and Segal 1989; Schenk et al. 1993; Voikar et al. 1999; Wolf and Jeziorski 1993). Nevertheless, several reports suggest that stimulation of Dl receptors is critical for the development of sensitization to both direct and indirect-acting dopamine receptor agonists (Braun and Chase 1988; Criswell et al. 1989; Henry and White 1991; Mattingly et al. 1991; Stewart and Vezina 1989). Thus, sensitization to yawning induced by apomorphine, but not quinpirole, might be due to the relatively high affinity of apomorphine and relatively low affinity of quinpirole for dopamine Dl receptors.
 
Rats eating standard chow and sensitized to apomorphineinduced yawning were cross-sensitized to quinpirole-induced yawning. That is, both limbs (ascending D3 -receptor mediated and descending D2 receptor-mediated) of the quinpirole yawning dose-response curve were shifted to the left in rats eating standard chow and tested once weekly with apomorphine, compared with rats eating standard chow that were tested only once with apomorphine (Fig 5, upper panel, circles; Table 1). However, in rats eating high-fat chow, cross sensitization from apomorphine to quinpirole was only evident in the descending limb (D2 receptor-mediated) of the quinpirole dose-response curve. That is, the descending limb of the quinpirole dose-response curve was shifted leftward in rats eating high-fat chow and tested weekly with apomorphine as compared with rats eating high-fat chow and tested just once with apomorphine (Fig. 5, upper panel, squares; Table 1). Thus, rats eating high-fat or standard chow show similar, but not identical, cross sensitization from apomorphine to quinpirole. The extent to which the ascending limb (D3 receptormediated) of the quinpirole dose-response curve can be shifted leftward, either by dietary or pharmacological manipulation, remains to be determined; however, it is clear that the same receptors (D3 and D2) mediate quinpirole-induced yawning in rats eating standard or high-fat chow (Baladi et al. 2011).
 
Both of the direct-acting dopamine receptor agonists produced hypothermia in all rats. Moreover, the hypothermic effects of apomorphine and quinpirole were similar among groups of rats with different drug and diet histories. Direct-acting dopamine receptor agonist-induced hypothermia is thought to be mediated predominantly by D2 receptors because those effects are antagonized by D2, and not D3, receptor antagonists (Baladi et al. 2010; Chaperon et al. 2003; Collins et al. 2007). Because neither repeated drug treatment nor eating high-fat chow alter the hypothermic effects of apomorphine or quinpirole, drug- and diet-induced changes in yawning produced by these drugs are likely due to pharmacodynamic and not pharmacokinetic mechanisms. A similar dissociation between hypothermia and other effects has been reported for another dopamine receptor agonist in cocaine-sensitized rats (Collins et al. 2011) and for cannabinoid receptor agonists in rats eating high-fat chow (Wiley et al. 2011). Differential effects of feeding condition on dopamine agonist-induced yawning and hypothermia might reflect different populations of dopamine receptors mediating these effects [the paraventricular nucleus of the hypothalamus mediating yawning (Argiolas and Melis 1998) and the anterior hypothalamus/preoptic area mediating hypothermia (Lin et al. 1982)] and/or other compensatory mechanisms regulating body temperature.
 
In summary, this study extends previous results regarding the effects of food restriction and eating high-fat chow on sensitivity to dopamine receptor agonist-induced yawning (Baladi et al. 2011; Collins et al. 2008; Sevak et al. 2008). Food restriction decreased and eventually eliminated apomorphine-induced yawning. Eating high-fat chow for 5 weeks, in the absence of any other treatment, was sufficient to increase the sensitivity of rats to apomorphineinduced yawning. On the other hand, repeated weekly testing with apomorphine increased the sensitivity of all rats to apomorphine-induced yawning regardless of the type of chow they ate, a finding that is in contrast to what is observed after repeated testing with quinpirole (i.e., shift left in the dose-response curve for animals eating high-fat chow and not for those eating standard chow). Overall, these results are similar but not identical to the increased sensitivity that develops to quinpirole-induced yawning in rats eating high-fat chow and tested weekly with quinpirole. These results also provide some of the first evidence showing conditioning to drug-induced yawning, an effect that might mask diet-induced differences in the development of sensitization to apomorphine-induced yawning. Although many factors can impact sensitivity to the behavioral effects of drugs (Dafiiy and Yang 2006), together with a growing body of literature, these results clearly support the view that eating conditions modify the behavioral effects of drugs acting on dopamine systems in a manner that might be relevant to understanding individual differences in response to recreational as well as therapeutic drug use (Carroll et al. 1981; Goodwin et al. 1987).