Interactions between environmental aversiveness and the anxiolytic effects of enhanced cannabinoid signaling by FAAH inhibition in rats

Haller, József; Barna, István; Barsvári, Beáta; Pelczer, Katalin Gyimesi; Yaşar, Sevil; Panlilio, Leigh V.; Goldberg, S. R.

doi:10.1007/s00213-009-1494-7

Cited by 133 publications

(130 citation statements)

References 43 publications

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“…Furthermore, none of these drugs altered latencies to enter the dark compartment during the learning trial of the passive-avoidance procedure. The fact that we did not observe significant anxiolytic effects of URB597 like those we obtained in previous experiments using the light/dark test (Scherma et al 2008) may be due to the procedural change of allowing an adaptation trial prior to the test trial, which would minimize stress during testing (Haller et al 2009). Some of the endogenous fatty acids affected by FAAH inhibition (i.e., OEA and anandamide) also affect signaling at the TRPV1 receptor (Ahern 2003;Starowicz et al 2007;Rubino et al 2008).…”

supporting

confidence: 55%

Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors

Mazzola¹,

Medalie²,

Scherma³

et al. 2009

Learn. Mem.

116

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Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB 1 -receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for a-type peroxisome proliferatoractivated nuclear receptors, PPAR-a) when and where they are naturally released in the brain. Using a passive-avoidance task in rats, we found that memory acquisition was enhanced by the FAAH inhibitor URB597 or by the PPAR-a agonist WY14643, and these enhancements were blocked by the PPAR-a antagonist MK886. These findings demonstrate novel mechanisms for memory enhancement by activation of PPAR-a, either directly by administering a PPAR-a agonist or indirectly by administering a FAAH inhibitor.Peroxisome proliferator-activated receptor-a (PPAR-a) is a ligandactivated transcriptional factor that regulates the expression of genes involved in lipid utilization, fatty acid oxidation, and inflammation (van Raalte et al. 2004;LoVerme et al. 2006). Immunolocalization studies of PPAR-a in the adult rat brain suggest that this nuclear receptor might have specific functions in regulating expression of genes involved in cholinergic neurotransmission and learning and memory processes (Moreno et al. 2004;Cimini et al. 2005). For example, there are high concentrations of PPAR-a receptors in the hippocampus and amygdala (Moreno et al. 2004). However, the potential involvement of PPAR-a in learning and memory processes has not been systematically investigated.Endogenous ligands for PPAR-a include the lipid mediators N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA). In addition, anandamide (N-arachidonoylethanolamine), which has primarily been studied as an endogenous ligand for G-proteincoupled cannabinoid CB 1 receptors that mediate the behavioral effects of cannabis and its active constituent D 9-tetrahydrocannabinol (THC) (Devane et al. 1992;Solinas et al. 2008), has recently begun to receive attention as a potential endogenous PPAR-a ligand (O'Sullivan 2000;Mackie and Stella 2006;Sun et al. 2007). OEA has primarily been studied as a satiety factor (Rodriguez de Fonseca et al. 2001;Fu et al. 2003) and PEA as an anti-inflammatory factor (Kuehl et al. 1957;Calignano et al. 1998;Jaggar et al. 1998). OEA and PEA are structurally similar to anandamide but do not bind to or activate cannabinoid CB 1 receptors. Anandamide, OEA, and PEA are all inactivated primarily by the intracellular serine enzyme, fatty acid amide hydrolase (FAAH) (Cravatt and Lichtman 2002;Fegley et al. 2005). Consequently, selective FAAH-inhibiting drugs such as cyclohexyl carbamic acid 39-carbamoyl-3-yl ester (URB597) increase endogenous levels of anandamide, OEA, and PEA in the brain (Fegley et al. 2005;Piomelli et al. 2006).In the present experiments, the effects of FAAH inhibition on learning and memory processes and the involvement of cannabinoid CB 1 receptors and PPAR-a nuclear receptors in those effects were studied using a passive-avoidance procedure in rats. FAAH inhibition was accomplished by administering U...

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supporting

confidence: 55%

Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors

Mazzola¹,

Medalie²,

Scherma³

et al. 2009

Learn. Mem.

116

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“…The antianxiety properties of intraperitoneal URB597 have been tested in experimental conditions not including social defeat stress (Kathuria et al, 2003;Patel and Hillard, 2006;Moreira et al, 2008;Scherma et al, 2008;Haller et al, 2009;Micale et al, 2009). Thus, mice were injected with a single intraperitoneal dose of URB597 or of vehicle at the end of the social defeat stress protocol, and the effects on both OFT and EPM were evaluated 24 h later.…”

Section: Resultsmentioning

confidence: 99%

“…Enhancement of AEA signaling through FAAH inhibition has emerged recently as an interesting novel route in the treatment of mood disorders (Kathuria et al, 2003;Gobbi et al, 2005;Patel and Hillard, 2006;Bortolato et al, 2007;Hill et al, 2007;Naidu et al, 2007;Cippitelli et al, 2008;Moreira et al, 2008;Rubino et al, 2008;Scherma et al, 2008;Haller et al, 2009;Micale et al, 2009). The mechanism by which FAAH inhibition results in ameliorated emotional control is largely undetermined, although magnification of AEA signaling at cannabinoid CB1 receptors (CB1Rs) has been implicated based on the fact that blockade of these receptors prevents the anxiolytic properties of both pharmacological and genetic inactivation of FAAH (Moreira et al, 2008;Haller et al, 2009;Micale et al, 2009). CB1Rs are particularly abundant in the striatum, a subcortical brain area recognized to play an important role in anxietyrelated behaviors (Rogan et al, 2005;Favilla et al, 2008), and are involved in the AEA-elevating effects of mood enhancing doses of (3Ј-(aminocarbonyl)[1,1Ј-biphenyl]-3-yl)-cyclohexylcarbamate (URB597), a potent and selective FAAH inhibitor (Bortolato et al, 2007).…”

mentioning

confidence: 99%

Preservation of Striatal Cannabinoid CB1 Receptor Function Correlates with the Antianxiety Effects of Fatty Acid Amide Hydrolase Inhibition

et al. 2010

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The endocannabinoid anandamide (AEA) plays a crucial role in emotional control, and inhibition of its degradation by the fatty acid amide hydrolase (FAAH) has a potent antianxiety effect. The mechanism by which the magnification of AEA activity reduces anxiety is still largely undetermined. By using FAAH mutant mice and both intraperitoneal and intracerebroventricular administration of the FAAH inhibitor (3Ј-(aminocarbonyl)[1,1Ј-biphenyl]-3-yl)-cyclohexylcarbamate (URB597), we found that enhanced AEA signaling reversed, via central cannabinoid CB1 receptors (CB1Rs), the anxious phenotype of mice exposed to social defeat stress. This behavioral effect was associated with preserved activity of CB1Rs regulating GABA transmission in the striatum, whereas these receptors were dramatically down-regulated by stress in control animals. The hypothalamic-pituitaryadrenal (HPA) axis was not involved in the antistress effects of FAAH inhibition, although the HPA axis is a biological target of endogenous AEA. We also provided some physiological indications that striatal CB1Rs regulating GABA synapses are not the receptor targets of FAAH inhibition, which rather resulted in the stimulation of striatal CB1Rs regulating glutamate transmission. Collectively, our findings suggest that preservation of cannabinoid CB1 receptor function within the striatum is a possible synaptic correlate of the antianxiety effects of FAAH inhibition.The lifespan of the endocannabinoid anandamide (AEA) is regulated by the fatty acid amide hydrolase (FAAH), which cleaves and increases tissue levels of AEA (Kathuria et al., 2003;McKinney and Cravatt, 2005;. Enhancement of AEA signaling through FAAH inhibition has emerged recently as an interesting novel route in the treatment of mood disorders (Kathuria et al.,

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“…CBD acts as a TRPV1 agonist at high concentrations, potentially by interfering with AEA inactivation [48]. In addition to dose-dependent activation of TRPV1 channels, the anxiogenic versus anxiolytic balance of CB 1 R agonists also depends on dynamic factors, including environmental stressors [33,49].…”

Section: The Endocannabinoid Systemmentioning

confidence: 99%

Cannabidiol as a Potential Treatment for Anxiety Disorders

et al. 2015

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Cannabidiol (CBD), a Cannabis sativa constituent, is a pharmacologically broad-spectrum drug that in recent years has drawn increasing interest as a treatment for a range of neuropsychiatric disorders. The purpose of the current review is to determine CBD's potential as a treatment for anxiety-related disorders, by assessing evidence from preclinical, human experimental, clinical, and epidemiological studies. We found that existing preclinical evidence strongly supports CBD as a treatment for generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder when administered acutely; however, few studies have investigated chronic CBD dosing. Likewise, evidence from human studies supports an anxiolytic role of CBD, but is currently limited to acute dosing, also with few studies in clinical populations. Overall, current evidence indicates CBD has considerable potential as a treatment for multiple anxiety disorders, with need for further study of chronic and therapeutic effects in relevant clinical populations.

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Interactions between environmental aversiveness and the anxiolytic effects of enhanced cannabinoid signaling by FAAH inhibition in rats

Cited by 133 publications

References 43 publications

Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors

Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors

Preservation of Striatal Cannabinoid CB1 Receptor Function Correlates with the Antianxiety Effects of Fatty Acid Amide Hydrolase Inhibition

Cannabidiol as a Potential Treatment for Anxiety Disorders

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