Effects of cannabinoids on the anxiety-like response in mice.

“Several pieces of anatomical, biochemical and pharmacological evidence indicate that the endocannabinoid system via CB1 receptors is implicated in the control of emotional behavior. However, previous studies have reported unclear and contradictory results concerning the role of cannabinoids in anxiety. The aim of the present study was to examine the influence of the cannabinoid agonist WIN 55,212-2, the CB1 antagonist AM 281, the inhibitor of anandamide hydrolysis AACOCF3  and the inhibitor of anandamide transporter AM404 on the anxiety-like response in mice in the light/dark box test…

  These results support the hypothesis that the endocannabinoid system is involved in the regulation of anxiety-like behavior, and also suggest that the inhibitors of anandamide hydrolysis might be potential anxiolytic drugs.”

http://www.ncbi.nlm.nih.gov/pubmed/16702621

Anxiolytic-like effects induced by blockade of transient receptor potential vanilloid type 1 (TRPV1) channels in the medial prefrontal cortex of rats.

“The endocannabinoid anandamide, in addition to activating cannabinoid type 1 receptors (CB1), may act as an agonist at transient receptor potential vanilloid type 1 (TRPV1) channels. In the periaqueductal gray, CB1 activation inhibits, whereas TRPV1 increases, anxiety-like behavior. In the medial prefrontal cortex (mPFC), another brain region related to defensive responses, CB1 activation induces anxiolytic-like effects. However, a possible involvement of TRPV1 is still unclear.

In the present study, we tested the hypothesis that TRPV1 channel contributes to the modulation of anxiety-like behavior in the mPFC.

CONCLUSIONS:

These data suggest that TRPV1 in the ventral mPFC tonically inhibits anxiety-like behavior. TRPV1 could facilitate defensive responses opposing, therefore, the anxiolytic-like effects reported after local activation of CB1 receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/19387617

Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors.

“Anandamide and 2-arachidonoyl glycerol, referred to as endocannabinoids (eCBs), are the endogenous agonists for the cannabinoid receptor type 1 (CB1). Several pieces of evidence support a role for eCBs in the attenuation of anxiety-related behaviours, although the precise mechanism has remained uncertain…

 The fatty acid amid hydrolase (FAAH), an enzyme responsible for the degradation of eCBs, has emerged as a promising target for anxiety-related disorders, since FAAH inhibitors are able to increase the levels of anandamide and thereby induce anxiolytic-like effects…

The present work provides genetic and pharmacological evidence supporting the inhibition of FAAH as an important mechanism for the alleviation of anxiety.

 In addition, it indicates an increased activation of CB1 receptors as a mechanism underlying the effects of FAAH inhibition in two models of anxiety.”

http://www.ncbi.nlm.nih.gov/pubmed/17709120

The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition

“Converging evidence suggests that the endocannabinoid system is an important constituent of neuronal substrates involved in brain reward processes and emotional responses to stress.. It is known that the endocannabinoid system plays a modulatory role in emotional states such as anxiety and fear. Several studies utilizing rodent models of anxiety or depression showed that FAAH inhibition produced anxiolytic-like effects and anti-depressant-like effects…

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2213536/

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

“Understanding the synaptic underpinning of emotional control is essential for the development of effective strategies against neuropsychiatric conditions such as anxiety, phobias, obsessive-compulsive disorder, and depression…

The lifespan of the endocannabinoid anandamide (AEA) is regulated by the fatty acid amide hydrolase (FAAH)…

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. ..

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.”

http://molpharm.aspetjournals.org/content/78/2/260.long

Anxiolytic-like properties of the anandamide transport inhibitor AM404.

“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..

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.”

http://www.ncbi.nlm.nih.gov/pubmed/16541083

Discovery and development of endocannabinoid-hydrolyzing enzyme inhibitors.

“Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) are hydrolytic enzymes which degrade the endogenous cannabinoids (endocannabinoids) N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), respectively. Endocannabinoids are an important class of lipid messenger molecules that are produced on demand in response to elevated intracellular calcium levels. They recognize and activate the cannabinoid CB(1) and CB(2) receptors, the molecular targets for Delta(9)-tetrahydrocannabinol (Delta(9)-THC) in marijuana evoking several beneficial therapeutic effects. However, in vivo the cannabimimetic effects of AEA and 2-AG remain weak owing to their rapid inactivation by FAAH and MGL, respectively. The inactivation of FAAH and MGL by specific enzyme inhibitors increases the levels of AEA and 2-AG, respectively, producing therapeutic effects such as pain relief and depression of anxiety.”

http://www.ncbi.nlm.nih.gov/pubmed/20370710

Modulation of anxiety through blockade of anandamide hydrolysis.

“The psychoactive constituent of cannabis, Delta(9)-tetrahydrocannabinol, produces in humans subjective responses mediated by CB1 cannabinoid receptors, indicating that endogenous cannabinoids may contribute to the control of emotion. But the variable effects of Delta(9)-tetrahydrocannabinol obscure the interpretation of these results and limit the therapeutic potential of direct cannabinoid agonists. An alternative approach may be to develop drugs that amplify the effects of endogenous cannabinoids by preventing their inactivation. Here we describe a class of potent, selective and systemically active inhibitors of fatty acid amide hydrolase, the enzyme responsible for the degradation of the endogenous cannabinoid anandamide. Like clinically used anti-anxiety drugs, in rats the inhibitors exhibit benzodiazepine-like properties in the elevated zero-maze test and suppress isolation-induced vocalizations. These effects are accompanied by augmented brain levels of anandamide and are prevented by CB1 receptor blockade.

 Our results indicate that anandamide participates in the modulation of emotional states and point to fatty acid amide hydrolase inhibition as an innovative approach to anti-anxiety therapy.”

http://www.ncbi.nlm.nih.gov/pubmed/12461523

Endocannabinoids mediate anxiolytic-like effect of acetaminophen via CB1 receptors.

“Acetaminophen (Paracetamol), a most commonly used antipyretic/analgesic agent, is metabolized to AM404 (N-arachidonoylphenolamine) that inhibits uptake and degradation of anandamide which is reported to mediate the analgesic action of acetaminophen via CB1 receptor. AM404 and anandamide are also reported to produce anxiolytic-like behavior. In view of the implication of endocannabinoids in the effect of acetaminophen, we contemplated that acetaminophen may have anxiolytic-like effect. Therefore, this possibility was tested by observing the effects of various doses of acetaminophen in mice on anxiety-related indices of Vogel conflict test and social interaction test. The results from both the tests indicated that acetaminophen (50, 100, or 200 mg/kg, i.p.) or anandamide (10 or 20 microg/mouse, i.c.v.) dose dependently elicited anxiolytic-like effect, that was comparable to diazepam (2 mg/kg, i.p.). Moreover, co-administration of sub-effective dose of acetaminophen (25 mg/kg, i.p.) and anandamide (5 microg/mouse, i.c.v) produced similar anxiolytic effect. Further, pre-treatment with AM251 (a CB1 receptor antagonist; 1 mg/kg, i.p.) antagonized the effects of acetaminophen and anandamide with no per se effect at 1 mg/kg dose, while anxiogenic effect was evident at a higher dose (5 mg/kg, i.p.). None of the treatment/s was found to induce any antinociceptive or locomotor impairment effects. In conclusion, the findings suggested that acetaminophen (50, 100, or 200 mg/kg, i.p.) exhibited dose dependent anxiolytic effect in mice and probably involved endocannabinoid-mediated mechanism in its effect.”

http://www.ncbi.nlm.nih.gov/pubmed/19580839

Endocannabinoid system and stress and anxiety responses.

“Cannabinoid agonists induce complex and often contradictory effects on anxiety in humans and experimental animals. The data from animal tests provide evidence of dose-dependent bidirectional modulation of anxiety by the cannabinoid system and the importance of environmental context. The mechanisms mediating the effects of cannabinoids on anxiety-related responses appear to involve CB1 and non-CB1 cannabinoid receptors. In addition, the CRH, GABA(A), cholecystokinin, opioid and serotonergic systems have also been implicated. Brain regions such as the amygdala, hippocampus and cortex, directly involved in the regulation of emotional behavior, contain high densities of CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic-like and depressive-like phenotypes in several tests, as well as profound alterations in their adrenocortical activity. Pharmacological blockade of CB1 receptors induces anxiety in rats, and inhibition of anandamide metabolism produces anxiolytic-like effects.

Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states and may constitute a novel pharmacological target for anti-anxiety therapy.”

http://www.ncbi.nlm.nih.gov/pubmed/15927244