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Fetal yawning assessed by 3D and 4D sonography
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mise à jour du
1 septembre 2015
European Journal of Pharmacology
2015;764:529-536
Drinking sucrose or saccharin enhances sensitivity
of rats to quinpirole-induced yawning
Katherine M. Serafine, Todd A. Bentley, Dylan J. Kilborn,
Wouter Koek, Charles P. France
Department of Pharmacology, University of Texas Health Science Center at San Antonio. USA  

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ABSTRACT
Diet can impact sensitivity of rats to some of the behavioral effects of drugs acting on dopamine systems. The current study tested whether continuous access to sucrose is necessary to increase yawning induced by the dopamine receptor agonist quinpirole, or if intermittent access is sufficient. These studies also tested whether sensitivity to quinpirole-induced yawning increases in rats drinking the non-caloric sweetener saccharin. Dose-response curves (0.0032-0.32 mg/kg) for quinpirole-induced yawning were determined once weekly in rats with free access to standard chow and either continuous access to water, 10% sucrose solution, or 0.1% saccharin solution, or intermittent access to sucrose or saccharin (i.e., 2 days per week with access to water on other days). Cumulative doses of quinpirole increased then decreased yawning, resulting in an inverted U-shaped dose-response curve. Continuous or intermittent access to sucrose enhanced sensitivity to quinpirole-induced yawning. Continuous, but not intermittent, access to saccharin also enhanced sensitivity to quinpirole-induced yawning. In all groups, pretreatment with the selective D3 receptor antagonist PG01037 shifted the ascending limb of the quinpirole dose-response curve to the right, while pretreatment with the selective D2 receptor antagonist L-741,626 shifted the descending limb to the right. These results suggest that even intermittent consumption of diets con-taining highly palatable substances (e.g. sucrose) alters sensitivity to drugs acting on dopamine systems in a manner that could be important in vulnerability to abuse drugs.
 
Résumé
Le régime alimentaire peut avoir un impact sur la sensibilité manifestée par des rats à certains des effets comportementaux induits par des médicaments agissant sur le système dopaminergique.
 
La présente étude a testé si un accès continu au saccharose est capable d'augmenter les bâillements induits par l'agoniste des récepteurs de la dopamine, le quinpirole, ou si l'accès intermittent est suffisant.
 
Ces études ont également vérifié si la sensibilité aux bâillements augmente chez les rats buvant l'édulcorant non-calorique, la saccharine au bâillements induits par le quinpirole.
 
Les résultats suggèrent que la consommation, même intermittente d'alimentaire contenant des substances sucrés hautement agréables au goût (par exemple, le saccharose) modifie la sensibilité aux médicaments qui agissent sur les systèmes dopaminergiques d'une manière qui pourrait être important face à la vulnérabilité à l'abus de drogues.
 
1. Introduction
Diet (e.g., type and amount of food consumed) can impact sensitivity to drugs acting on dopamine systems (Avena and Hoebel, 2003; Collins et al., 2008; Gosnell, 2005; Baladi et al., 2012a, 2011a; Puhl et al., 2011). For example, rats eating a high fat chow or drinking a 10% sucrose solution are more sensitive than rats eating standard chow and drinking water to the behavioral effects of direct- (i.e., quinpirole; Baladi et al., 2011a, b) and in-direct-acting (i.e., cocaine; Baladi et al., 2012b) dopamine receptor agonists. Although consumption of foods high in fat or sugar contributes to the development of obesity, sensitivity changes to the behavioral effects of drugs acting on dopamine systems even in the absence of weight gain (Baladi et al., 2011a, b); specifically, consuming a high fat or high sugar diet can markedly affect drug sensitivity in the absence of accelerated body weight gain.
 
Rats drinking sucrose are more sensitive than rats drinking water to the behavioral effects of quinpirole (Baladi et al., 2011b). Like many other direct-acting dopamine receptor agonists, quin-pirole dose-dependently increases then decreases yawning in rats (Collins et al., 2008; Baladi and France, 2010) resulting in an in-verted U-shaped dose-response curve. Experiments using selec-tive dopamine receptor antagonists have revealed that the as-cending limb (initiation of yawning) is mediated by dopamine D3 receptors, while the descending limb (inhibition of yawning) is mediated by dopamine D2 receptors (Collins et al., 2008; Baladi et al., 2011a; though see Depoortere et al. (2009), Sanna et al. (2011, 2012)). The D3 receptor-mediated ascending limb of the quinpirole dose-response curve is shifted to the left in rats drinking sucrose (Baladi et al., 2011b). When consumption of highly preferred substances (fat or sugar) is restricted or access is intermittent, animals often increase consumption which is ac-companied by an enhanced sensitivity to drugs acting indirectly on dopamine systems (Avena and Hoebel, 2003; Gosnell, 2005; Puhl et al., 2011). However, intermittency of access varied mark-edly across these studies and it is not known whether intermittent access to sucrose enhances sensitivity of rats to the behavioral effects of the direct-acting dopamine receptor agonist quinpirole. While the mechanism(s) underlying these changes in sensi-tivity is not known, consumption of a diet high in sucrose or fat also causes metabolic changes (e.g., insulin resistance) that could impact drug sensitivity. Changes in insulin signaling can impact dopamine neurotransmission (Daws et al., 2011); however, non-caloric sweeteners such as saccharin are also highly preferred (compared with water) by rats (Carroll et al., 2007, 2008) but do not cause insulin resistance. Animals that show the greatest pre-ference for sweeteners often are also more sensitive to drugs acting on dopamine systems (Carroll et al., 2008). The current study examined the effects of continuous or intermittent access to sucrose or saccharin solutions on sensitivity of rats to quinpirole-induced yawning.
 
4. Discussion
It is well established that sensitivity to the behavioral effects of quinpirole is enhanced in rats drinking sucrose (Baladi et al„ 2011b); however, it was not known whether continuous access is necessary, or if intermittent access to sucrose is sufficient to cause such changes. Moreover, sucrose is high in calories and it is not known whether consumption of non-caloric sweet solutions might also change the sensitivity of rats to the behavioral effects of quinpirole. This study examined the effects of continuous and in-termittent access to sucrose or saccharin on sensitivity of rats to quinpirole-induced yawning. Rats with continuous access to a 10% sucrose solution were more sensitive than rats drinking water to quinpirole-induced yawning. Moreover, rats drinking a 10% su-crose solution only two days per week (i.e., intermittent access) also were more sensitive than rats drinking water to quinpirole-induced yawning, although to a lesser extent than those with continuous access to sucrose (i.e., significant leftward shift of the ascending limb only on week 8). Rats with continuous access to saccharin, but not rats with intermittent access to saccharin, were more sensitive than rats drinking water to quinpirole-induced yawning (similar shifts in ascending and descend limbs to those seen with intermittent sucrose group). These results are consistent with a previous report showing that consuming sucrose enhances sensitivity of rats to quinpirole-induced yawning (Baladi et al„ 2011b) and they extend those results by revealing that inter-mittent access to sucrose is sufficient to significantly enhance sensitivity to quinpirole-induced yawning. These results further demonstrate that the non-caloric sweetener saccharin enhances sensitivity of rats to quinpirole, suggesting that highly palatable taste in the absence of calories is sufficient to change sensitivity to direct-acting dopamine receptor agonists such as quinpirole.
 
There were significant differences among some groups with regard to the enhanced sensitivity to quinpirole-induced yawning. For example, only in rats with continuous access to sucrose were both the ascending (D3 receptor mediated) and the descending (D2 receptor mediated; see Depoortere et al. (2009); Sanna et al. (2011, 2012)) limbs of the quinpirole dose-response curve shifted left-ward (Figs. 3 and 4) in week 8. In contrast, only the ascending limb of the quinpirole yawning dose-response curve was shifted left-ward in rats with intermittent access to sucrose (week 8). This difference regarding shifting one limb but not the other might be related to previous studies showing that the duration of access to a highly palatable diet determines the magnitude of effect on do-pamine neurotransmission and on sensitivity to drugs acting on dopamine systems (Avena and Hoebel, 2003; Avena et ah, 2008; Puhl et ah, 2011; Spangler et ah, 2004). By week 9, both the as-cending and descending limbs of the quinpirole dose-response curve were significantly shifted to the left both in rats with in-termittent access to sucrose and in rats with continuous access to saccharin. Previous studies have shown that feeding conditions can differentially impact the two limbs of the quinpirole yawning dose-response curve (similarly to what has been demonstrated with food restriction; Collins et ah, 2008). However, by week 9, a leftward shift in both limbs of the dose-response curve was re-vealed in rats with intermittent access to sucrose, suggesting that a longer duration of access causes a greater shift in the dose-response curve. Although differences in sensitivity have been re-ported using a shorter duration of access to sucrose (Baladi et ah, 2011b), in that study only the ascending limb of the quinpirole dose-response curve was shifted to the left. A final quinpirole dose-response curve generated in week 16 did not reveal any further change in sensitivity to quinpirole in any group, suggesting a potential ceiling effect with regard to the impact of sucrose or saccharin on sensitivity to the behavioral effects of quinpirole. It is not known if other concentrations of sucrose or saccharin might have resulted in different consumption or further impacted sen-sitivity to quinpirole.
 
Insulin resistance can develop in rats drinking sucrose or eating a high fat chow (Baladi et ah, 2011a) and insulin signaling has been shown to regulate dopamine neurotransmission (Daws et ah, 2011). However, it is not clear whether insulin resistance is ne-cessary to change sensitivity to the behavioral effects of drugs acting on dopamine systems, since rats with restricted access to high fat chow (such that their body weights are not increased relative to control rats eating standard chow) are more sensitive to quinpirole (Baladi et al. unpublished observation), but do not de-velop insulin resistance (see Serafine et al. (2014) for an example in female rats). Similarly, in the present experiment rats drinking saccharin were more sensitive than rats drinking water to quin-pirole-induced yawning, further suggesting that diet-induced en-hancement in sensitivity to drugs acting on dopamine systems can occur in the absence of insulin resistance. That the hypothermic effects of quinpirole were not significantly altered by the feeding conditions used in this study is consistent with previous reports using highly palatable diets (e.g., high fat chow or sucrose; Baladi et al., 2011a, b). These results are also consistent with other reports demonstrating that D2 receptor antagonists attenuate dopamine agonist-induced hypothermia in rats (Chaperon et al., 2003; Col-lins et al., 2007; see Millan et al. (2000, 2008) for examples of D3 receptor antagonists modulating agonist-induced hypothermia in a different outbred rat strain) as well as in mice (Boulay et al., 1999a, b).
 
Intake of highly palatable foods often escalates when access is limited (Avena and Hoebel, 2003; Puhl et al., 2011). In the present study, food and fluid intake changed systematically between days when rats in the intermittent access groups drank water and days when they drank either sucrose or saccharin (Table 1); however, body weight gain was similar between rats with intermittent ac-cess and those with continuous access. Moreover, there was no evidence of escalated intake; in fact, rats with intermittent access to sucrose drank similar amounts across days throughout the duration of the experiment (data not shown). It is possible that a different schedule of intermittent access, similar to what was used by others (e.g., Avena and Hoebel, 2003; Puhl et al., 2011), might have escalated intake, changed patterns of consumption, or changed in sensitivity to quinpirole differently or to a greater extent. The results of the present study add to the growing body of literature showing that changing feeding conditions, content or access conditions, can dramatically impact dopamine systems and sensitivity to drugs acting on those systems. Non-caloric sweet-eners are often used in place of caloric sweeteners to reduce the risk of negative health consequences (i.e., diabetes, obesity) asso-ciated with sweeteners like sucrose. The results of the present study demonstrate that consuming non-caloric sweeteners might significantly impact dopamine systems. Many drugs, including those used clinically and those used recreationally, target dopa-mine systems; although consuming non-caloric sweeteners might reduce the risk of some adverse health consequences (e.g., obesity and diabetes), consuming saccharin or other non-caloric sweet-eners could also change sensitivity to drugs in a manner that alters therapeutic effectiveness of drugs or vulnerability to abuse drugs. Given a continuing escalation in the consumption of foods high in fat and sugar across much of the world (e.g., U.S. Department of Agriculture, U.S. Department of Health and Human Services, 2010), it is becoming increasingly important to understand the impact of these dietary conditions on sensitivity to drugs.