Impaired action of anxiolytic drugs in mice deficient in cannabinoid CB1 receptors

Urigüen, Leyre; Pérez-Rial, Sandra; Ledent, Catherine; Palomo, Tomás; Manzanares, Jorge

doi:10.1016/j.neuropharm.2004.01.003

Cited by 196 publications

(147 citation statements)

References 25 publications

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“…KDS-4103 inhibits FAAH activity with an IC 50 value of approximately 5 nM in rat brain membranes in vitro, 0.5 nM in intact rat neurons in vitro, 3 nM in human liver microsomes in vitro, and an ID 50 value of 0.15 mg/kg following i.p. administration in the rat.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological Profile of the Selective FAAH Inhibitor KDS-4103 (URB597)

et al. 2006

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In the present article, we review the pharmacological properties of KDS-4103 (URB597), a highly potent and selective inhibitor of the enzyme fatty-acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide. In vitro, KDS-4103 inhibits FAAH activity with median inhibitory concentrations (IC 50 ) of 5 nM in rat brain membranes and 3 nM in human liver microsomes. In vivo, KDS-4103 inhibits rat brain FAAH activity after intraperitoneal (i.p.) administration with a median inhibitory dose (ID 50 ) of 0.15 mg/kg. The compound does not significantly interact with other cannabinoid-related targets, including cannabinoid receptors and anandamide transport, or with a broad panel of receptors, ion channels, transporters and enzymes. By i.p. administration to rats and mice KDS-4103 elicits significant, anxiolytic-like, antidepressant-like and analgesic effects, which are prevented by treatment with CB1 receptor antagonists. By contrast, at doses that significantly inhibit FAAH activity and substantially raise brain anandamide levels, KDS-4103 does not evoke classical cannabinoid-like effects (e.g., catalepsy, hypothermia, hyperphagia), does not cause place preference, and does not produce generalization to the discriminative effects of the active ingredient of cannabis, Ä 9 -tetrahydrocannabinol (Ä 9 -THC). These findings suggest that KDS-4103 acts by enhancing the tonic actions of anandamide on a subset of CB 1 receptors, which may Address correspondence and reprint requests to: Daniele Piomelli, PhD, Department of Pharmacology, 360 MSR II, University of California, Irvine, CA 92697-4625, USA; Tel.: +1 (949) 824-6180, Fax: +1 (949) 824-6305, E-mail: piomelli@uci.edu normally be engaged in controlling emotions and pain. KDS-4103 is orally available in rats and cynomolgus monkeys. Sub-chronic repeated dose studies (1500 mg/kg, per os) in these two species have not demonstrated systemic toxicity. Likewise, no toxicity was noted in bacterial cytotoxicity tests in vitro and in the Ames test. Furthermore, no deficits were observed in rats on the rotarod test after acute i.p. treatment with KDS-4103 at doses up to 5 mg/kg or in a functional observation battery after oral doses up to 1500 mg/kg. The results suggest that KDS-4103 will offer a novel approach with a favorable therapeutic window for the treatment of anxiety, depression and pain.

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Section: Discussionmentioning

confidence: 99%

“…When FAAH activity was assayed in membrane fractions using [ 3 H]anandamide (anandamide[ethanolamine-3 H]) as a substrate, KDS-4103 was found to inhibit rat brain activity with an IC 50 of ~5 nM (27) and human liver activity with an IC 50 Fig. 2A).…”

Section: Pharmacology Faah Inhibition In Vitromentioning

confidence: 99%

Pharmacological Profile of the Selective FAAH Inhibitor KDS-4103 (URB597)

et al. 2006

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“…In rats, for example, a single electric shock to the paw elevates anandamide levels in the midbrain (Hohmann et al, 2005), while in mice physical restraint decreases anandamide levels in the amygdala (Patel et al, 2004). Moreover, pharmacological blockade or genetic ablation of CB 1 receptors exacerbates normal reactions to acute stress, presumably by disabling an endocannabinoid modulation of these reactions (Navarro et al, 1997;Haller et al, 2004;Urigüen et al, 2004). Finally, the FAAH inhibitor URB597 enhances stress-coping behaviors in a rimonabant-sensitive manner (Kathuria et al, 2003;Gobbi et al, 2005), suggesting that anandamide interacts with a subgroup of CB 1 receptors in the brain that regulate stress responses.…”

Section: Discussionmentioning

confidence: 99%

Anxiolytic-Like Properties of the Anandamide Transport Inhibitor AM404

Bortolato

Campolongo

Mangieri

et al. 2006

Neuropsychopharmacol

210

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The endocannabinoids anandamide and 2-arachidonoyglycerol (2-AG) may contribute to the regulation of mood and emotion. In this study, we investigated the impact of the endocannabinoid transport inhibitor AM404 on three rat models of anxiety: elevated plus maze, defensive withdrawal and separation-induced ultrasonic vocalizations. AM404 (1-5 mg kg À1 , intraperitoneal (i.p.)) exerted dosedependent anxiolytic-like effects in the three models. These behavioral effects were associated with increased levels of anandamide, but not 2-AG, in the prefrontal cortex and were prevented by the CB 1 cannabinoid antagonist rimonabant (SR141716A), suggesting that they were dependent on anandamide-mediated activation of CB 1 cannabinoid receptors. We also evaluated whether AM404 might influence motivation (in the conditioned place preference (CPP) test), sensory reactivity (acoustic startle reflex) and sensorimotor gating (prepulse inhibition (PPI) of the startle reflex). In the CPP test, AM404 (1.25-10 mg kg À1 , i.p.) elicited rewarding effects in rats housed under enriched conditions, but not in rats kept in standard cages. Moreover, AM404 did not alter reactivity to sensory stimuli or cause overt perceptual distortion, as suggested by its lack of effect on startle or PPI of startle. These results support a role of anandamide in the regulation of emotion and point to the anandamide transport system as a potential target for anxiolytic drugs.

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“…Sensitivity of FST behavior to desipramine treatment is slightly altered in CB1 À/À mice The effects of anxiolytic drugs have been shown to be impaired in CB1 À/À mice, 39 and only little is known about the interaction of the endocannabinoid system with antidepressants. 40 To examine if the genetic knockout of CB1 leads to a different reaction or sensitivity to antidepressants in the FST, female CB1 þ / þ and CB1 À/À mice were treated with the NA reuptake inhibitor desipramine (Figure 4).…”

Section: Effects Of Sr141716 On Fst Behavior Are Specific For Cb1 Recmentioning

confidence: 99%

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice

et al. 2007

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Dysregulation of the endocannabinoid system is known to interfere with emotional processing of stressful events. Here, we studied the role of cannabinoid receptor type 1 (CB1) signaling in stress-coping behaviors using the forced swim test (FST) with repeated exposures. We compared effects of genetic inactivation with pharmacological blockade of CB1 receptors both in male and female mice. In addition, we investigated potential interactions of the endocannabinoid system with monoaminergic and neurotrophin systems of the brain. Naive CB1 receptor-deficient mice (CB1 À/À ) showed increased passive stress-coping behaviors as compared to wild-type littermates (CB1 þ / þ ) in the FST, independent of sex. These findings were partially reproduced in C57BL/6N animals and fully reproduced in female CB1 þ / þ mice by pharmacological blockade of CB1 receptors with the CB1 receptor antagonist SR141716. The specificity of SR141716 was confirmed in female CB1 À/À mice, where it failed to affect behavioral performance. Sensitivity to the antidepressants desipramine and paroxetine was preserved, but slightly altered in female CB1 À/À mice. There were no genotype differences between CB1 þ / þ and CB1 À/À mice in monoamine oxidase A and B activities under basal conditions, nor in monoamine content of hippocampal tissue after FST exposure. mRNA expression of vesicular glutamate transporter type 1 was unaffected in CB1 À/À mice, but mRNA expression of brain-derived neurotrophic factor (BDNF) was reduced in the hippocampus. Our results suggest that impaired CB1 receptor function promotes passive stress-coping behavior, which, at least in part, might relate to alterations in BDNF function.

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Impaired action of anxiolytic drugs in mice deficient in cannabinoid CB1 receptors

Cited by 196 publications

References 25 publications

Pharmacological Profile of the Selective FAAH Inhibitor KDS-4103 (URB597)

Pharmacological Profile of the Selective FAAH Inhibitor KDS-4103 (URB597)

Anxiolytic-Like Properties of the Anandamide Transport Inhibitor AM404

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice

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