mystery of yawning
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Yawning: its cycle, its role
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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
Le bâillement foetal
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mise à jour du
20 mai 2011
Psychopharmacol (Berlin)
2011;217:573-585
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
Baladi MG, Newman AH, France CP.
 
Department of Pharmacology, University of Texas
Health Science Center San Antonio USA

Chat-logomini

Abstract
Amount and type of food can alter dopamine systems and sensitivity to drugs acting on those systems.
 
This study examined whether changes in body weight, food type, or both body weight and food type contribute to these effects. Rats had free or restricted access (increasing, decreasing, or maintaining body weight) to standard (5.7% fat) or high-fat (34.3%) chow.
 
In rats gaining weight with restricted or free access to high-fat chow, both limbs of the quinpirole yawning dose-response curve (0.0032-0.32 mg/kg) shifted leftward compared with rats eating standard chow. Restricting access to standard or high-fat chow (maintaining or decreasing body weight) decreased or eliminated quinpirole-induced yawning; within 1 week of resuming free feeding, sensitivity to quinpirole was restored, although the descending limb of the dose-response curve was shifted leftward in rats eating high-fat chow. These are not likely pharmacokinetic differences because quinpirole-induced hypothermia was not different among groups. PG01037 and L-741,626 antagonized the ascending and descending limbs of the quinpirole dose-response curve in rats eating high-fat chow, indicating D3 and D2 receptor mediation, respectively. Rats eating high-fat chow also developed insulin resistance.
 
These results show that amount and type of chow alter sensitivity to a direct-acting dopamine-receptor agonist with the impact of each factor depending on whether body weight increases, decreases, or is maintained. These data demonstrate that feeding conditions, perhaps related to insulin and insulin sensitivity, profoundly impact the actions of drugs acting on dopamine systems.
 
-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
-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

Discussion
 
Dopamine systems are altered in various diseases, and they are the target of many drugs that are used clinically as well as drugs of abuse. Dopamine systems also mediate, at least in part, the reinforcing effects of many drugs and of food. Moreover, it is clear that feeding conditions impact the activity of dopamine systems in brain as well as the effects of drugs acting on those systems. Because feeding conditions (i.e., amount and type of food) can vary markedly within and among individuals, it is possible that variations in food intake and nutritional status contribute to the development of psychopathologies (e.g., vulnerability to drug abuse) and impact the response of individuals to drugs. This study examined the impact of how much rats eat (increasing, decreasing, or maintaining body weight) and the type of chow they eat (standard or high fat) on the behavioral effects of the direct-acting dopamine-receptor agonist quinpirole. While the type of chow appeared to be the predominant factor in determining quinpirole effects under some conditions, under other conditions, body weight appeared to be the predominant factor.
 
It is well established that restricting access to food significantly alters brain neurochemistry and the behavioral effects of drugs. It is also clear that allowing animals to eat certain foods (e.g., high fat) can affect brain neurochemistry and the behavioral effects of drugs. In this study, quinpirole-induced yawning varied significantly across eating conditions and across different periods of time. For example, after 21 (free-feeding) or 28 (restricted) days of eating high-fat chow while gaining body weight (Experiment 1), the descending limb of the quinpirole dose&endash;response curve was shifted leftward, reflecting increased sensitivity at dopamine D2 receptors. In contrast, the descending limb of the quinpirole dose&endash;response curve was shifted leftward after just 7 or 14 days in rats eating high-fat chow and losing (Experiment 2) or maintaining (Experiment 3) body weight, respectively. Thus, although qualitatively similar effects were observed across conditions (shift left in the descending limb of the dose&endash;response curve), those effects occurred at different times among groups. Moreover, increased sensitivity to quinpirole-induced yawning was correlated with the emergence of insensitivity to insulin-induced hypoglycemia (Experiment 5). Upon resumption or continuation of free-feeding, the descending limb of the quinpirole dose&endash;response curve remained shifted leftward in all rats eating high-fat chow. In contrast, when rats that previously had restricted access to standard chow were allowed free access to standard chow, their sensitivity to quinpirole returned and was not different from rats that had only free access to standard chow throughout the study (compare Group 1 to Groups 4 and 6, Panel E), indicating the reversibility of food restriction (standard chow)-induced changes in sensitivity to quinpirole.
 
In rats eating high-fat chow and gaining weight, the shift leftward in the ascending limb of the dose&endash;response curve was evident after 14 days and persisted until the end of the study. A similar shift leftward in the ascending limb (D3) of the dose&endash;response curve was evident after 14 days in rats eating high-fat chow and maintaining body weight, although that shift was no longer evident 7 days later, presumably because of an even greater increase in sensitivity at D2 receptors that masked any expression of yawning. In the same rats (i.e., eating high-fat chow with body weight maintained, Group 7), normal sensitivity to quinpirole was apparent after just 7 days of free access to high-fat chow (Day 42, panel D, Fig. 3). With continued free access to high-fat chow and with further body weight gain, the ascending limb of the quinpirole dose&endash;response curve shifted leftward and was not different from what was observed in rats that had free access to high-fat chow throughout the study (compare Groups 2 and 7). In rats losing weight, eating high-fat chow also appeared to delay, but not prevent, the elimination of quinpirole-induced yawning, perhaps reflecting increased sensitivity at D3 receptors that eventually was overcome by a greater increase at D2 receptors. Collectively, two major trends are apparent from these data: (1) eating high-fat food increases sensitivity to D3 (leftward shift in the ascending limb) and D2 (leftward shift in the descending limb) receptor-mediated effects of quinpirole; and (2) regardless of chow type, food restriction (so that body weight does not increase) increases sensitivity to D2 receptor-mediated effects of quinpirole and, eventually, suppresses quinpirole-induced yawning.
 
Sensitivity to the behavioral effects of drugs acting on dopamine systems sometimes increases after repeated intermittent drug administration (i.e., sensitization) and feeding conditions can impact those increases in sensitivity. For example, eating high-fat chow accelerates the rate at which sensitivity increases to the locomotor-stimulating effects of the indirect-acting dopamine-receptor agonist methamphetamine in rats.
 
Although sensitization can also develop to the locomotorstimulating effects of quinpirole, there was no evidence in the current study for sensitization to quinpirole-induced yawning. The quinpirole-yawning dose&endash;response curve in rats with free access to standard chow was very consistent across many weeks of once per week quinpirole testing. It also appears unlikely that feeding conditions (e.g., eating high-fat chow) selectively enhance the development of sensitization to quinpirole since rats that eat high-fat chow and are tested just once with quinpirole show the same changes in sensitivity that were observed in the current study in rats that were tested weekly with quinpirole. Feeding conditions (e.g., food restriction) that significantly altered the descending limb of the quinpirole yawning dose&endash;response curve (mediated by D2 receptors) had no effect on quinpirole-induced hypothermia, which also is thought to be mediated by D2 receptors. That quinpirole-induced hypothermia did not vary across feeding conditions suggests that changes in quinpirole-induced yawning were not due to pharmacokinetic factors and, possibly, that the receptors mediating the hypothermic effects of quinpirole are not the same receptors mediating yawning (i.e., D2 and D1). Both yawning and hypothermia are thought to be centrally mediated, although different populations of dopamine receptors might mediate these effects (the anterior hypothalamus/preoptic area for quinpirole-induced hypothermia and the paraventricular nucleus of the hypothalamus for quinpirole-induced yawning.
 
Moreover, other (non-dopamine) mechanisms might also contribute to the regulation of body temperature in a manner that attenuates nutrition-related changes in dopamine-receptor sensitivity that might otherwise be expected to impact body temperature.
 
While the current study examined changes in a behavioral effect (i.e., yawning) that is thought to be mediated by dopamine receptors in the paraventricular nucleus of the hypothalamus, it is likely that dopamine receptors in some other brain regions are also impacted by feeding conditions. For example, food restriction increases sensitivity to the locomotor-stimulating effects of direct-acting dopamine-receptor agonists, including quinpirole, possibly indicating changes in receptor sensitivity in the mesolimbic dopamine pathway .
 
The mechanism(s) mediating changes in the behavioral effects of quinpirole across eating conditions are not known and might include changes in dopamine content or turnover, receptor number, or function. It is well established that different feeding conditions (amount and type of food) can significantly modify circulating concentrations of hormones such as insulin, leptin, and ghrelin that are known to have effects on dopamine systems. These hormones can activate specific receptors on dopamine neurons and either inhibit (insulin and leptin) or stimulate (ghrelin) dopamine signaling. Food restriction decreases while eating high-fat chow increases circulating insulin. Moreover, plasma concentrations of insulin and leptin are increased similarly in rats with free or restricted (body weight matched to rats with free access to high-fat chow) access to high-fat chow, consistent with the similar behavioral effects observed in the current study between rats with free or restricted access to high-fat chow (Experiment 1). Whether hormonal changes contribute to altered behavioral effects of drugs acting on dopamine systems is yet to be determined, although a growing body of literature obtained in diabetic animals and in animals eating different amounts and types of chow strongly implicates insulin and leptin as playing major roles in drug effects that are mediated by dopamine systems (e.g., reinforcing effects). For example, in the current study, eating high-fat chow changed the behavioral effects of quinpirole and, in parallel, induced insulin resistance, supporting the view that insulinsignaling pathways play a role in diet-induced changes in drug response.
 
Finally, these data indicate that response to drugs (therapeutic and recreational) might be profoundly impacted by eating conditions, including body weight and type of food and that changes in drug sensitivity might be long lasting. Thus, modest weight loss or weight gain might contribute to individual differences in response to drugs. Moreover, the type of food eaten might impact brain neurochemistry resulting in an altered response to drugs. While the current obesity epidemic (more than one third of adults in the USA were obese in 2007&endash;2008) is a pressing public health problem that is relevant to the current study, data in rats indicate that being overweight per se might not be the most important factor affecting response to drugs.
 
Rather, it appears to be the consumption of fat and, perhaps, resulting hormonal changes that markedly alter dopamine systems. Understanding the relationship between feeding conditions and drug response could facilitate our understanding of individual differences in response to therapeutic drugs and in vulnerability to drug abuse.

mise à jour du
8 avril 2012
J Pharmacol Exp Ther.
2010;332(1):308-315
Dopamine D3 receptors mediate the discriminative stimulus effects of quinpirole in free-feeding rats
Baladi MG, Newman AH, France CP.
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, Texas. USA.
Chat-logomini
Abstract

The discriminative stimulus effects of dopamine (DA) D3/D2 receptor agonists are thought to be mediated by D2 receptors. To maintain responding, access to food is often restricted, which can alter neurochemical and behavioral effects of drugs acting on DA systems. This study established stimulus control with quinpirole in free-feeding rats and tested the ability of agonists to mimic and antagonists to attenuate the effects of quinpirole. The same antagonists were studied for their ability to attenuate quinpirole-induced yawning and hypothermia. DA receptor agonists apomorphine and lisuride, but not amphetamine and morphine, occasioned responding on the quinpirole lever. The discriminative stimulus effects of quinpirole were attenuated by the D3 receptor-selective antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl (PG01037) and the nonselective D3/D2 receptor antagonist raclopride, but not by the D2 receptor-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl-1H-indole (L-741,626); the potencies of PG01037 and raclopride to antagonize this effect of quinpirole paralleled their potencies to antagonize the ascending limb of the quinpirole yawning dose-response curve (thought to be mediated by D3 receptors). L-741,626 selectively antagonized the descending limb of the quinpirole yawning dose-response curve, and both L-741,626 and raclopride, but not PG01037, antagonized the hypothermic effects of quinpirole (thought to be mediated by D2 receptors). Food restriction (10 g/day/7 days) significantly decreased quinpirole-induced yawning without affecting the quinpirole discrimination. Many discrimination studies on DA receptor agonists use food-restricted rats; together with those studies, the current experiment using free-feeding rats suggests that feeding conditions affecting the behavioral effects of direct-acting DA receptor agonists might also have an impact on the effects of indirect-acting agonists such as cocaine and amphetamine.

....................

Yawning induced by DA receptor agonists yields an inverted U-shaped dose-response curve, and it is thought that the ascending limb of this curve (induction of yawning) is mediated by actions at D3 receptors and the descending limb (inhibition of yawning) is mediated by actions at D2 receptors (Collins et al., 2005). The same antagonists that were compared for their ability to antagonize the discriminative stimulus effects of quinpirole also were compared for their ability to antagonize quinpiroleinduced yawning. The D3 receptor-selective antagonist PG01037 attenuated the ascending limb of the quinpirole dose-response curve in a dose-related manner without affecting the descending limb. In contrast, a dose of the D2 receptor-selective antagonist L-741,626 (1.0 mg/kg) that attenuated the descending limb of the quinpirole doseresponse curve had no effect on the ascending limb. The nonselective D3/D2 receptor antagonist raclopride dose dependently attenuated both limbs of the dose-response curve for quinpirole-induced yawning. The ability of these antagonists to attenuate the discriminate stimulus effects of quinpirole in free-feeding rats parallels their ability to attenuate the ascending and, presumably, D3 receptormediated limb of the dose-response curve for quinpiroleinduced yawning. In particular, the potencies of PG01037 and raclopride, but not of L-741,626, to antagonize the discriminative stimulus effects of quinpirole parallel their relative potencies in attenuating the ascending limb of the yawning dose-response curve (Table 1), further supporting the view that the discriminative stimulus effects of quinpirole in free-feeding rats are mediated predominantly, if not exclusively, by D3 receptors.

Based on the effects of various DA receptor agonists administered alone and in combination with different DA receptor antagonists, it is thought that the hypothermic effects of D3/D2 receptor agonists (e.g., including quinpirole) are mediated by D2 receptors (Nunes et al., 1991; Chaperon et al., 2003; Collins et al., 2007). Consistent with that view, quinpirole-induced hypothermia was attenuated by the D2 receptor-selective antagonist L-741,626 and the nonselective D3/D2 receptor antagonist raclopride but not by the D3 receptor- selective antagonist PG01037.

Food restriction markedly decreases sensitivity of rats to quinpirole-induced yawning (Sevak et al., 2008; Baladi and France, 2009); interpretations of that observation might include decreased sensitivity of D3 receptors to agonists, increased sensitivity of D2 receptors to agonists, or both decreased sensitivity of D3 and increased sensitivity of D2 receptors. However, results of behavioral as well as molecular studies indicate that the effect of food restriction is to increase sensitivity of D2 receptors (Carr et al., 2003; Collins et al., 2008; Thanos et al., 2008). If the discriminative stimulus effects of DA receptor agonists in freefeeding rats are mediated by D2 receptors, then it might be expected that food restriction would increase sensitivity to those effects, as reflected by a leftward shift in the doseresponse curve. However, food restriction (10 g/day for 7 days) that markedly decreased sensitivity to quinpiroleinduced yawning had no effect on the discriminative stimulus effects of quinpirole in the same group of rats, supporting the hypothesis that D2 receptors are not involved in the discriminative stimulus effects of quinpirole in freefeeding rats. Food restriction in the current study reduced body weight to approximately 90% of free-feeding weight, somewhat less than body weight loss reported in other studies using food restriction and studying dopamine drugs (e.g., 80&endash;85%; Weathersby and Appel, 1986; Carr et al., 2003; Collins et al., 2008; Koffarnus et al., 2009). Together with the current antagonism studies, these data support the view that D3 receptors mediate the discriminative stimulus effects of quinpirole in free-feeding rats and that sensitivity of D3 receptors to agonists is not markedly affected by food restriction. Future studies might include establishing a discrimination with a highly selective D2 receptor agonist in free-feeding rats (i.e., acute food restriction might shift the dose-response curve leftward) or with a highly selective D3 receptor agonist in food-restricted rats (i.e., D3 and not D2 receptor antagonists should block the training stimulus). Moreover, it is not clear whether the reinforcer used to maintain responding (i.e., shock) influences the contribution of different DA receptors in the discriminative stimulus effects of agonists. In summary, although D2 receptors are thought to mediate the discriminative stimulus effects of quinpirole in food-restricted rats, D3 receptors seem to mediate the discriminative stimulus effects of quinpirole in free-feeding rats. Thus, feeding conditions can affect the contribution of D3 and D2 receptors to the discriminative stimulus effects of quinpirole. Several mechanisms are thought to underlie the effects of food restriction on DA receptors, including increased DA receptor number and signaling and reduced plasma levels of hormones such as insulin and leptin that can directly affect DA systems. Understanding the link between feeding condition and DA neurotransmission might be critical for understanding the comorbidity of eating disorders and drug abuse and also has implications for understanding how feeding condition might affect the behavioral effects of other drugs acting on DA systems, including drugs of abuse such as cocaine and amphetamine.