mystery of yawning
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La parakinésie brachiale oscitante
Yawning: its cycle, its role
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Fetal yawning assessed by 3D and 4D sonography
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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
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15 mars 2012
J Pharmacol Exp Ther.
2007;321(2):573-582
Effects of two novel D3-selective compounds, NGB 2904 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide] and CJB 090 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide], on the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys
Martelle JL, Claytor R, Ross JT, Reboussin BA, Newman AH, Nader MA.
 
Center for the Neurobiological Investigation of Drug Abuse, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, NWinston-Salem, USA.

Chat-logomini

Abstract
The present study examined the effects of two novel dopamine D3 receptor compounds, NGB 2904 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide], an antagonist, and CJB 090 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide], a partial agonist, in two models of cocaine abuse in rhesus monkeys. To establish a dose range and time course of effects, both compounds were shown to block quinpirole-induced yawning when administered i.m. 15, 30, or 120 min before quinpirole. Next, rhesus monkeys were trained to discriminate i.m. injections of saline (0.5 ml) and cocaine (0.3 mg/kg). Neither D3 compound (0.03-3.0 mg/kg; n=3) substituted for cocaine in any monkey. When given in combination with cocaine, CJB 090 but not NGB 2904 attenuated the discriminative stimulus effects of cocaine, shifting the cocaine dose-response curve to the right. In a separate group of monkeys, responding was maintained under a second-order schedule of either food (1.0-g pellets; n=3) or cocaine (0.1 mg/kg/injection; n=4) presentation. When responding was stable, a dose of NGB 2904 (1.0-5.6 mg/kg i.v.) or CJB 090 (0.3-3.0 mg/kg i.v.) was administered for 5 consecutive days, immediately before the session. CJB 090, but not NGB 2904, decreased cocaine- and food-maintained responding. These data indicate that compounds with relatively high affinity and selectivity for the D3 receptor can attenuate the discriminative and reinforcing stimulus effects of cocaine while not producing cocaine-like effects. The present findings support the continued examination of D3 compounds as pharmacological tools for better understanding the role of this receptor subtype in cocaine addiction and as potential lead compounds for novel

Martelle SE, Nader SH, Czoty PW, John WS, Duke AN, Garg PK, Garg S, Newman AH, Nader MA. Further Characterization of Quinpirole-Elicited Yawning As a Model of Dopamine D3 Receptor Activation in Male and Female Monkeys. J Pharmacol Exp Ther. 2014 May
 
Cocaine abuse is a major problem in the United States and worldwide [National Institute on Drug Abuse (NIDA), 2004; World Health Organization, 2004]. In 2002 alone, there were an estimated 1.1 million new users of cocaine, and the 2003 National Survey on Drug Use and Health reported that 34.9 million Americans 12 years of age and older confirmed using cocaine at least once in their lifetime (Substance Abuse and Mental Health Services Administration, 2004). Despite over 30 years of research, there is no safe and effective pharmacotherapy to offer those afflicted by cocaine addiction (Mello and Negus, 1996; Carroll et al., 1999; Platt et al., 2002), although several clinical trials are currently underway (Gorelick et al., 2004; O'Brien, 2005; Vocci et al., 2005). The dopamine (DA) system is thought to play a primary role in the behavioral and reinforcing effects of cocaine (Ritz et al., 1987). Within the DA system, two superfamilies of receptors have been identified, D1- and D2-like receptors, and preclinical data suggest that both are involved in the behavioral actions of cocaine (e.g., Caine et al., 2000). The D3 receptor subtype belongs to the D2-like superfamily of receptors and coexists with D2 receptors in mesolimbic areas of the brain (Sokoloff et al., 1990). Because D3 receptors are primarily localized in limbic brain regions, compounds selectively blocking D3 receptors may be free of extrapyramidal effects (Sokoloff et al., 1990; Levant, 1997).
 
Furthermore, autoradiographic studies have demonstrated higher densities of D3 receptors in cocaine overdose victims compared with noncocaine-abusing controls (Staley and Mash, 1996). Taken together, these studies support a hypothesis that D3 receptors may be an important therapeutic target in cocaine abuse. Pharmacological tools provide evidence for a possible role of D3 receptors in the discriminative and reinforcing effects of cocaine (e.g., Caine and Koob, 1993). Pretreatments with the D2/D3 agonists quinpirole or 7-hydroxy-N,N-di-n-propyl-2- aminotetralin produced dose-dependent decreases in cocaine self-administration in rats (Caine and Koob, 1993). More recently, the D3-selective partial agonist BP 897 has been shown to decrease cocaine seeking by rats self-administering cocaine under a second-order schedule (Pilla et al., 1999). Unlike the full agonists, BP 897 does not maintain selfadministration in rats or monkeys (Pilla et al., 1999; Beardsley et al., 2001) or mimic the discriminative stimulus effects of cocaine or methamphetamine in monkeys (Beardsley et al., 2001). One goal of the present study was to examine, in rhesus monkeys, another D3 partial agonist, CJB 090, in cocaine discrimination and cocaine self-administration studies.
 
D2-like receptor antagonists block discriminative and reinforcing effects of cocaine in rodents and monkeys (e.g., Kleven et al., 1990; Caine et al., 2000). Advances in medicinal chemistry have resulted in development of D3-selective antagonists (Newman et al., 2005). In a rodent model of relapse, the D3 antagonists SB-277011-A and NGB 2904 inhibited cocaine-induced drug seeking (Gilbert et al., 2005; Gal and Gyertyan, 2006). Also in rodents, SB-277011-A decreased cocaine self-administration under several conditions (Vorel et al., 2002; Di Ciano et al., 2003; Xi et al., 2005, 2006). A second goal of the present study was to assess the ability of another D3-selective antagonist, NGB 2904, to alter the discriminative and reinforcing effects of cocaine in rhesus monkeys.
 
The D3 antagonist NGB 2904 binds with approximately 56-fold selectivity at the human D3 receptor (hD3) compared with the human D2L receptor (hD2L), whereas the D3 partial agonist CJB 090 has approximately 50-fold selectivity at the hD3 compared with the hD2L receptor (Grundt et al., 2005). Both NGB 2904 and CJB 090 are twice as selective for hD3 receptors as is quinpirole, which has 23-fold selectivity for D3 over D2 receptors in HEK 293 cells (R. Luedtke, unpublished data). Because neither drug had been evaluated in nonhuman primates, the first experiment examined their ability to block quinpirole-induced yawning, suggested by behavioral experiments in rodents to be D3 receptor mediated (Collins et al., 2005). The second experiment examined the ability of each compound to substitute for cocaine and to shift the cocaine dose-response curve in monkeys trained to discriminate cocaine. As a positive control, we also evaluated the nonselective D2/D3 antagonist haloperidol in these same monkeys. The third experiment assessed the ability of NGB 2904 and CJB 090 to alter cocaine- and food-reinforced responding using a second-order schedule that has been shown to be sensitive to D3 partial agonist effects (Pilla et al., 1999).
 
Discussion
 
The effects of two novel DA D3-selective compounds were evaluated in several nonhuman primate models. Both the D3-selective partial agonist CJB 090 and the D3-selective antagonist NGB 2904 dose-dependently reversed quinpiroleinduced yawning. Neither compound substituted for cocaine in drug discrimination studies. CJB 090 blocked the discriminative stimulus effects of cocaine and decreased cocaine- and food-maintained responding. In contrast, NGB 2904 produced equivocal effects on cocaine discrimination and did not affect rates of cocaine- or food-maintained responding at doses that reversed quinpirole-induced yawning. Neither drug produced D2-like side effects, such as catalepsy or stereotypy, at doses that affected cocaine discrimination and self-administration. The current findings further support the continued development of compounds with high affinity at D3 receptors as potential treatment agents for cocaine abuse. There is growing interest in the use of D3 compounds in preclinical models of cocaine abuse (see Newman et al., 2005). Partial agonists may provide a unique versatility as a potential pharmacotherapeutic treatment because the efficacy of the compounds should vary with levels of extracellular DA competing for the receptor (Pulvirenti and Koob, 1994; Childress and O'Brien, 2000; Platt et al., 2002; Negus, 2006). In contrast, an antagonist would be expected to decrease cocaine seeking and decrease the positive subjective effects of cocaine, irrespective of levels of extracellular DA (Platt et al., 2002). Because CJB 090 and NGB 2904 had not previously been tested in monkeys, we first assessed the effects of both drugs on an unconditioned behavior believed to be mediated by D3 receptors based on studies in rodents (see Collins et al., 2005).
 
Extending earlier results in rats, the D2/D3 agonist quinpirole was shown to significantly induce yawning in monkeys in a dose-dependent fashion. Examining several D2/D3 compounds on quinpirole-induced yawning, Collins et al. (2005) concluded that the ascending limb of the quinpirole dose-response curve was mediated via D3 receptors, whereas the descending limb was mediated via D2 receptors. At the peak of the quinpirole dose-response curve, D3- but not D2-selective antagonists significantly reduced quinpirole-induced yawning (Collins et al., 2005). In the present study, when tested in combination with the dose of quinpirole that induced maximal yawning, both CJB 090 and NGB 2904 dose-dependently attenuated yawning; both compounds had similar potency, supporting the hypothesis that these drugs are acting as dopamine D3 receptor antagonists in vivo. Further investigation of the pharmacological basis of quinpirole-induced yawning in monkeys, as observed in rodents (Collins et al., 2005), will require additional testing and is beyond the scope of the present report. Nevertheless, in addition to confirming in vivo activity in monkeys, these results provide important time course data related to the drug discrimination and self-administration studies. In vitro studies demonstrated that CJB 090 was 50-fold selective for D3 receptors over D2 receptors in human D3 and D2 receptor transfected cell lines (Grundt et al., 2005). There seems to be some species differences because CJB 090 is nearly 100-fold selective for D3 receptors over D2 receptors in rat-transfected cell lines (Newman et al., 2003). Functional in vitro assays of agonist-induced mitogenesis established that CJB 090 induced only up to a 29.7% increase in mitogenesis, suggesting that CJB 090 functioned as a D3-selective partial agonist (Newman et al., 2003).
 
However, CJB 090 did not show a behavioral profile that was indicative of a D3 agonist because it neither elicited significant yawning when administered alone nor substituted for cocaine in drug discrimination. This is similar to what has been reported with BP 897, a purported D3 partial agonist, which does not have cocaine-like discriminative stimulus effects or maintain selfadministration in rats and monkeys (Beardsley et al., 2001). Taken together, these findings suggest that identification of partial agonists using in vitro functional assays may not predict agonist-like activity in vivo. However, when evaluated in combination with cocaine, CJB 090 was able to attenuate the discriminative-stimulus effects of cocaine, resulting in rightward shifts in the cocaine dose-response curve. Attenuation of the cocaine cue by CJB 090 was surmountable by increasing doses of cocaine. When tested in monkeys selfadministering cocaine under a second-order schedule, CJB 090 also decreased cocaine-maintained responding. Doses of CJB 090 that decreased cocaine self-administration also decreased responding maintained by food, suggesting nonselective reductions in cocaine reinforcement (but see Nader et al., 2002).
 
Likewise, BP 897 has been shown to reduce cue-induced reinstatement in rats, to attenuate the discriminative stimulus effects of cocaine in mice, and to decrease cocaine seeking in rats responding under a second-order schedule (Pilla et al., 1999; Beardsley et al., 2001; Cervo et al., 2003; Gilbert et al., 2005). Taken together, these data suggest that in the presence of high dopaminergic tone, i.e., after cocaine administration, DA D3 receptors play a modulatory role in the production of cocaine-induced interoceptive cues and in the positive reinforcing effects of cocaine. NGB 2904 has been classified as an antagonist at DA D3 receptors with high binding affinity (1.4 nM) at the hD3 receptor and 150-fold selectivity for primate D3 receptors over primate D2L receptors (Yuan et al., 1998). As was noted with CJB 090, species variation has been observed with NGB 2904. For example, NGB 2904 showed 830-fold selectivity for D3 over D2 receptors in cloned rat DA receptors and only 56-fold selectivity in cloned human DA receptors (Newman et al., 2003; Grundt et al., 2005). Irrespective of these binding affinities, NGB 2904 selectively and potently inhibited D3 receptors as demonstrated by antagonism of quinpirole-stimulated mitogenesis (Yuan et al., 1998), and it decreased quinpirole-induced yawning in monkeys (present study). In addition, NGB 2904 injections did not maintain self-administration in monkeys (J. L. Martelle, J. T. Ross, and M. Nader, unpublished data) and did not substitute for cocaine in drug discrimination, further suggesting a lack of agonist action.
 
In the present study, NGB 2904 had equivocal effects on cocaine discrimination and was inactive in decreasing cocaine- maintained responding under a second-order schedule. Doses that were effective in blocking quinpirole-induced yawning did not affect cocaine self-administration in rhesus monkeys. In an earlier study using the moderately selective D3 antagonist PNU 99194-A, which has an approximate 100- fold lower affinity at D3 receptors compared with NGB 2904, decreases in cocaine- and food-maintained responding were observed (Claytor et al., 2006). The fact that we did not observe significant effects on cocaine self-administration following NGB 2904 administration under conditions in which PNU 99194-A did affect responding suggests that NGB 2904, despite its higher affinity and selectivity for D3 receptors, may not be an effective pharmacotherapy for cocaine abuse. However, it should be pointed out that D3 receptor antagonists have shown promise in rodent models of cocaine abuse (Ashby et al., 2003; Di Ciano et al., 2003; Gilbert et al., 2005; Xi et al., 2005, 2006). Previous experiments have demonstrated that higher doses of NGB 2904 produce diminished D3 antagonist-like effects compared with intermediate doses (Gilbert et al., 2005). This finding could be related to the high lipophilicity of NGB 2904 leading to low bioavailability, poor pharmacokinetics, and significantly lower absolute levels in the brain after i.v. administration compared with another D3-selective antagonist, SB-277011-A (Reavill et al., 2000), under the same conditions (Newman et al., 2005). Another possibility for the equivocal effects of NGB 2904 on cocaine discrimination, but not CJB 090, may be related to the affinity of each compound at D2 receptors (Ki 112 versus 24 nM for NGB 2904 and CJB 090, respectively; Grundt et al., 2005). However, there was no evidence of catalepsy induced by any dose of CJB 090 or NGB 2904, which suggests that D2 receptors are not likely involved in the behaviors observed in this study. Nevertheless, the precise contribution of D2 and D3 receptors in the behavioral effects of NGB 2904, CJB 090 and other "D3-selective" compounds will require additional studies with highly selective D2 and D3 agonists, which are not currently available.
 
The present study aimed to examine: 1) the effects of a potent and selective D3 antagonist (NGB 2904) and partial agonist (CJB 090) on the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys and 2) whether or not a D3 partial agonist, as determined by quinpirole-stimulated mitogenesis in Chinese hamster ovary cells, would show any agonist activity in vivo. In summary, we found that the D3 partial agonist CJB 090, but not the D3 antagonist NGB 2904, was able to block the discriminative stimulus effects of cocaine and to decrease cocaine self-administration. There was no evidence that CJB 090 produced DA agonist effects in vivo. It remains possible that the behavioral effects observed with CJB 090 were due to D2 receptor antagonism, although blockade of the behavioral effects of cocaine occurred at doses that did not induce catalepsy. These findings support the continued examination of compounds acting at D3 receptors as pharmacological tools for further understanding the mechanistic underpinnings of cocaine addiction and as potential leads for therapeutic agents.