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ABSTRACT: There is growing evidence for an implication of the CB1 receptor subtype of the endocannabinoid system in the regulation of eating and fat deposition. To further define the physiological role of these receptors in the control of energy balance, we characterized the phenotype of CB1 receptor knockout (CB1(-/-)) mice maintained on an obesity-prone regimen or on a standard chow.
CB1(-/-) male mice were compared to wild-type animals (CB1(+/+) male mice) in two feeding paradigms: (1) with a standard laboratory regimen (3.5 kcal/g, 14.5% of energy as fat) and (2) on a free-choice paradigm consisting of offering both the standard laboratory chow and a high-fat diet (HFD) (4.9 kcal/g, 49% of energy as fat).
When maintained on the standard diet, CB1(-/-) mice are lean. At the age of 20 weeks, their body weight and adiposity are, respectively, 24 and 60% lower than that of CB1(+/+) mice. They are slightly hypophagic, but when expressed as percent of body weight, their relative energy intake is similar to that of the wild-type animals. Furthermore, inactivation of CB1 receptors reduces plasma insulin and leptin levels, and enhances the response to intracerebroventricular leptin injection. The free-choice paradigm shows that the preference for a high-fat highly palatable chow is slightly delayed in onset but maintained in CB1(-/-) mice. However, loading CB1(-/-) mice with this obesity-prone diet does not result in development of obesity. Knockout mice do not display hyperphagia or reduction of their relative energy intake in contrast to CB1(+/+) mice, and their feeding efficiency remains low. These data suggest an improved energetic metabolism with the high-fat regimen. Furthermore, the insulin resistance normally occurring in HFD-fed mice is not present in CB1(-/-) mice.
These results provide evidence that the stimulation of CB1 receptors is a key component in the development of diet-induced obesity, and that these receptors and their endogenous ligands are implicated not only in feeding control but also in peripheral metabolic regulations. The lack of effect of SR141716, a selective CB1 receptor antagonist, in CB1(-/-) mice further supports this hypothesis, as this compound was previously shown to display potent anti-obesity properties in diet-induced obese C57BL/6 mice.
International Journal of Obesity 05/2004; 28(4):640-8. · 4.69 Impact Factor
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E Bignon,
R Alonso, M Arnone,
R Boigegrain,
R Brodin,
C Gueudet,
M Héaulme,
P Keane,
M Landi,
J C Molimard,
D Olliero,
M Poncelet,
E Seban,
J Simiand,
P Soubrié,
M Pascal,
J P Maffrand,
G Le Fur
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ABSTRACT: SR146131 is a potent and selective agonist at cholecystokinin subtype 1 (CCK1) receptors in vitro. The present study evaluates the activity of the compound in vivo. SR146131 completely inhibited gastric and gallbladder emptying in mice (ED50 of 66 and 2.7 micrograms/kg p.o., respectively). SR146131 dose dependently reduced food intake in fasted rats (from 0.1 mg/kg p.o.), in nonfasted rats in which food intake had been highly stimulated by the administration of neuropeptide Y (1-36) (from 0.3 mg/kg p.o.), in fasted gerbils (from 0.1 mg/kg p.o.), and in marmosets maintained on a restricted diet (from 3 mg/kg p.o.). SR146131 (10 mg/kg p.o.) also increased the number of Fos-positive cells in the hypothalamic paraventricular nucleus of rats. Locomotor activity of mice was reduced by orally administered SR146131 (from 0.3 mg/kg p.o.). When administered intrastriatally, SR146131 elicited contralateral turning behavior in mice. Furthermore, orally administered SR146131 (0.3-10 mg/kg), also reduced the levels of cerebellar cyclic GMP. Finally, SR146131 (0.1 microgram/kg to 1 mg/kg, p.o.) significantly and dose dependently antagonized fluphenazine-induced mouth movements in rats. The CCK1 antagonist SR27897B prevented all the effects of SR146131. Conversely, SR146131 was unable to elicit any agonist or antagonist effects in a model of CCK2 receptor stimulation in vivo. SR146131 is a very potent and selective nonpeptide CCK1 agonist in vivo. SR146131 is more potent than any other CCK1 agonists reported to date. Because pharmacodynamic studies suggest that SR146131 should have a high absolute bioavailability, it may be a promising drug for the treatment of eating and motor disorders in humans.
Journal of Pharmacology and Experimental Therapeutics 06/1999; 289(2):752-61. · 3.83 Impact Factor
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ABSTRACT: SR 141716, a selective central CB1 cannabinoid receptor antagonist, markedly and selectively reduces sucrose feeding and drinking as well as neuropeptide Y-induced sucrose drinking in rats. SR 141716 also decreases ethanol consumption in C57BL/6 mice. In contrast, blockade of CB1 receptors only marginally affects regular chow intake or water drinking. The active doses of SR 141716 (0.3-3 mg/kg) are in the range known to antagonize the characteristic effects induced by cannabinoid receptor agonists. These results suggest for the first time that endogenous cannabinoid systems may modulate the appetitive value of sucrose and ethanol, perhaps by affecting the activity of brain reward systems.
Psychopharmacologia 08/1997; 132(1):104-6. · 4.08 Impact Factor
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ABSTRACT: The effect of SR 59026A, a new selective 5-HT(1A) receptor agonist, was evaluated on sexual behaviour of male rats in different experimental conditions. SR 59026A (1-10mg/kg p.o.) stimulated the copulatory behaviour of sexually experienced rats, as evidenced by a decrease in the number of pre-ejaculatory mounts and intromissions and a shortening of the ejaculation latency. SR 59026A also facilitated the sexual behaviour of naive male rats characterized by a low level of sexual performance: over the same dose range, the percentage of naive males that copulated was significantly increased and the ejaculation latency reduced. In experiments designed to evaluate the onset of sexual satiation, SR 59026A (1 and 3mg/kg) increased significantly the number of ejaculations and delayed the time of sexual satiation. Finally, in agreement with studies on other 5-HT(1A) receptor agonists, SR 59026A did not modify the occurrence of spontaneous erections in isolated male rats. Therefore, the present study shows that SR 59026A improves the sexual performance of male rats in a number of different experimental models, and the compound may prove to be of interest for the treatment of certain states of human male sexual dysfunction.
Behavioural pharmacology 05/1995; 6(3):276-282. · 2.85 Impact Factor
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ABSTRACT: Evaluated the effect of SR 59026A on sexual behavior of male rats in different experimental conditions. SR 59026A (1–20 mg/kg po) stimulated the copulatory behavior of sexually experienced Ss, as evidenced by a decrease in the number of pre-ejaculatory mounts and intromissions and a shortening of the ejaculation latency. SR 59026A in the same dose range increased the percentage of naive Ss that copulated and reduced ejaculation latency. In tests designed to evaluate the onset of sexual satiation, SR 59026A (1 and 3 mg/kg) increased significantly the number of ejaculations and delayed the time of sexual satiation. In agreement with studies on other 5-HT
1A receptor agonists, SR 59026A did not modify the occurrence of spontaneous erections in isolated male Ss. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Behavioural Pharmacology 03/1995; · 2.72 Impact Factor
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ABSTRACT: The activity of SR 27897, a potent and selective CCK-A vs CCK-B receptor antagonist (Ki = 0.2 nM on guinea-pig pancreas vs 2000 nM on rat brain) was studied on behavioural, electrophysiological and biochemical effects induced by peripheral or central injection of CCK-8S. For comparative purposes, devazepide, a reference CCK-A receptor antagonist, was investigated in these same models. CCK-induced hypophagia and CCK-induced hypolocomotion in rats, two behavioural changes associated with the stimulation of peripheral CCK-A receptors, were dose-dependently antagonized by SR 27897 (ED50 = 0.003 and 0.002 mg/kg i.p., respectively) and devazepide (ED50 = 0.02 and 0.1 mg/kg i.p., respectively). CCK-induced decrease of cerebellar cGMP levels in mice was also reduced by SR 27897 (ED50 = 0.013 mg/kg) and by devazepide (0.084 mg/kg). The CCK-induced turning behaviour after intrastriatal injection in mice, and the potentiation of the rate suppressant activity of apomorphine on rat DA neurons, were blocked by higher doses of SR 27897 and devazepide, consistent with the probable central origin of these effects. The respective ED50s were 0.2 mg/kg i.p. for SR 27897 and 4.9 mg/kg i.p. for devazepide in the former model, while the respective minimal effective doses were 1.25 and 5 mg/kg i.p. in the latter test. In most tests the i.p./p.o. ratio for SR 27897 was near unity, suggesting a high oral bioavailability of the compound. Taken together, these findings support the notion that SR 27897 behaves as a potent CCK-A antagonist able to cross the blood brain barrier.
Archiv für Experimentelle Pathologie und Pharmakologie 08/1993; 348(1):102-7. · 2.65 Impact Factor
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ABSTRACT: Using [3H]ethylketocyclazocine after suppression of mu, delta and sigma binding by 100 nM DAGO + 100 nM DADLE + 10 microM phencyclidine we showed the existence of a subclass of kappa sites insensitive to dynorphins 1-9 and 1-17, and alpha and beta neoendorphins, but sensitive to the non-peptidic opiates. The dynorphin-sensitive site probably corresponds to the "standard" kappa site while the importance of the dynorphin-resistant site remains to be established.
Life Sciences 02/1983; 33 Suppl 1:179-82. · 2.53 Impact Factor
