Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis

Abstract

Although anecdotal reports suggest that cannabis may be used to alleviate symptoms of depression, the psychotropic effects and abuse liability of this drug prevent its therapeutic application. The active constituent of cannabis, Delta(9)-tetrahydrocannabinol, acts by binding to brain CB, cannabinoid receptors, but an alternative approach might be to develop agents that amplify the actions of endogenous cannabinoids by blocking their deactivation. Here, we show that URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test. Moreover, URB597 increases firing activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in the nucleus locus ceruleus. These actions are prevented by the CB, antagonist rimonabant, are accompanied by increased brain anandamide levels, and are maintained upon repeated URB597 administration. Unlike direct CB, agonists, URB597 does not exert rewarding effects in the conditioned place preference test or produce generalization to the discriminative effects of Delta(9)-tetrahydrocannabinol in rats. The findings support a role for anandamide in mood regulation and point to fatty-acid amide hydrolase as a previously uncharacterized target for antidepressant drugs

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

“…Basal brain MAO-A and -B enzymatic activity is not altered in CB1 À/À mice Behavior in the FST is known to be strongly affected by monoamine neurotransmission in the brain, 41 and the endocannabinoid system has been suggested to influence monoaminergic transmission. 5,6 Therefore, we assessed potential dysregulations of monoaminergic metabolism under basal conditions in female CB1 À/À mice by measuring the enzymatic activity of two major enzymes involved in the catabolism of catecholamines and 5-HT, MAO-A and MAO-B. 42 However, no significant genotype differences could be observed in any of the brain regions analyzed, namely cortex, striatum, hippocampus and the rest of the brain (Table 1; statistics not shown).…”

“…1 They bind to presynaptically localized cannabinoid type 1 (CB1) receptors where they constrain the activity of various neurotransmitter systems, including glutamate, 2 GABA, 3 acetylcholine, 4 noradrenaline (NA) 5 and serotonin (5-HT). 5,6 The endocannabinoid system has, thus, been recognized as one of the major neuromodulatory systems of the brain that functions to maintain the homeostasis of various states including mood and emotion. 1,7 Preclinical research in rodents during the last decade has helped to elucidate the role of the endocannabinoid system in fear and anxiety.…”

“…The forced swim test (FST) represents one of the most widely used tests to detect antidepressant-like activities of drugs as well as depressionlike behavior in genetically engineered mice. 32 Drugs, which elevate the endocannabinoid tone such as the fatty acid amide hydrolase inhibitor URB597 or the endocannabinoid re-uptake inhibitor AM404, were demonstrated to exert antidepressant-like effects 6,33 in the FST in terms of reduced immobility. Surprisingly, however, also CB1 receptor antagonists such as SR141716 given in a higher dose range (3-10 mg/kg) were able to produce similar antidepressantlike effects in this test.…”

“…In addition, little is known about the neural substrates underlying the potential antidepressant-like effects of drugs interfering with endocannabinoid signaling. 5,6 In the present study, we investigated the effects of impaired CB1 receptor signaling on stress-coping behaviors in both males and females using the FST with repeated exposures. Effects of the genetic inactivation of CB1 receptors were compared to effects of the pharmacological blockade by the selective CB1 receptor antagonist SR141716.…”

Inhibition of Fatty-Acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task

“…This endogenous system has been implicated in several physiological functions including the modulation of pain (Calignano et al, 1998;Richardson et al, 1998;Walker et al, 1999), feeding (Di Marzo et al, 2001), drug dependence (Ledent et al, 1999;Lichtman et al, 2001;Gonzalez et al, 2002), excitotoxicity (Marsicano et al, 2003), anxiety (Kathuria et al, 2003), depression (Gobbi et al, 2005;Witkin et al, 2005), and cognition (Terranova et al, 1996;Marsicano et al, 2002;Varvel et al, 2005a). Of particular interest has been the discovery of fatty-acid amide hydrolase (FAAH), an integral membrane enzyme that is primarily responsible for the degradation of the endocannabinoid anandamide as well as several non-cannabinoid fatty-acid amides (FAAs; (Cravatt et al, 1996)).…”