anandamide and Anxiety-Disorders

Recent years have yielded significant advances in our understanding of microglia, the immune cells of the central nervous system (CNS). Microglia are key players in CNS development, immune surveillance, and the maintenance of proper neuronal function throughout life. In the healthy brain, homeostatic microglia have a unique molecular signature. In neurological diseases, microglia become activated and adopt distinct transcriptomic signatures, including disease-associated microglia (DAM) implicated in neurodegenerative disorders. Homeostatic microglia synthesise the endogenous cannabinoids 2-arachidonoylglycerol and anandamide and express the cannabinoid receptors CB1 and CB2 at constitutively low levels. Upon activation, microglia significantly increase their synthesis of endocannabinoids and upregulate their expression of CB2 receptors, which promote a protective microglial phenotype by enhancing their production of neuroprotective factors and reducing their production of pro-inflammatory factors. Here, we summarise the effects of the microglial cannabinoid system in the CNS demyelinating disease multiple sclerosis, the neurodegenerative diseases Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, chronic inflammatory and neuropathic pain, and psychiatric disorders including depression, anxiety and schizophrenia. We discuss the therapeutic potential of cannabinoids in regulating microglial activity and highlight the need to further investigate their specific microglia-dependent immunomodulatory effects.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Anxiety Disorders; Arachidonic Acids; Chronic Pain; Depressive Disorder; Endocannabinoids; Glycerides; Humans; Mental Disorders; Microglia; Multiple Sclerosis; Neuralgia; Neurodegenerative Diseases; Parkinson Disease; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Schizophrenia

A long-standing literature linking endocannabinoids (ECBs) to stress, fear, and anxiety has led to growing interest in developing novel anxiolytics targeting the ECB system. Following rapid on-demand biosynthesis and degradation upon neuronal activation, the ECB N-arachidonoylethanolamide (anandamide, AEA) is actively degraded by the serine hydrolase enzyme, fatty acid amide hydrolase (FAAH). Exposure to stress rapidly mobilizes FAAH to deplete the signaling pool of AEA and increase neuronal excitability in a key anxiety-mediating region--the basolateral amygdala (BLA). Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior. Additionally, inhibition of FAAH facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing AEA-CB1 (cannabinoid type 1) receptor signaling and synaptic plasticity in the BLA. These preclinical findings propose restoring deficient BLA AEA levels by pharmacologically inhibiting FAAH as a mechanism to therapeutically mitigate the effects of traumatic stress.

Topics: Amidohydrolases; Amygdala; Animals; Anxiety Disorders; Arachidonic Acids; Endocannabinoids; Enzyme Inhibitors; Humans; Polyunsaturated Alkamides; Stress, Physiological; Stress, Psychological

Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ(9)-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca(2+)) increase, etc.), on CBD behavioural effects.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety Disorders; Arachidonic Acids; Cannabidiol; Clinical Trials as Topic; Depression; Dose-Response Relationship, Drug; Endocannabinoids; Humans; Neurogenesis; Phytotherapy; Polyunsaturated Alkamides; Psychotic Disorders; Receptor, Cannabinoid, CB1; Receptor, Serotonin, 5-HT1A; Synaptic Transmission; TRPV Cation Channels

Anxiety disorders are the most prevalent mental health disorder worldwide, with a lifetime prevalence of 5-7 % of the human population. Although the etiology of anxiety disorders is incompletely understood, one aspect of host health that affects anxiety disorders is the gut-brain axis. Adolescence is a key developmental window in which stress and anxiety disorders are a major health concern. We used adolescent female mice in a gastrointestinal (GI) colonization model to demonstrate that the commensal fungus Candida albicans affects host health via the gut-brain axis. In mice, bacterial members of the gut microbiota can influence the host gut-brain axis, affecting anxiety-like behavior and the hypothalamus-pituitary-adrenal (HPA) axis which produces the stress hormone corticosterone (CORT). Here we showed that mice colonized with C. albicans demonstrated increased anxiety-like behavior and increased basal production of CORT as well as dysregulation of CORT production following acute stress. The HPA axis and anxiety-like behavior are negatively regulated by the endocannabinoid N-arachidonoylethanolamide (AEA). We demonstrated that C. albicans-colonized mice exhibited changes in the endocannabinoidome. Further, increasing AEA levels using the well-characterized fatty acid amide hydrolase (FAAH) inhibitor URB597 was sufficient to reverse both neuroendocrine phenotypes in C. albicans-colonized mice. Thus, a commensal fungus that is a common colonizer of humans had widespread effects on the physiology of its host. To our knowledge, this is the first report of microbial manipulation of the endocannabinoid (eCB) system that resulted in neuroendocrine changes contributing to anxiety-like behavior.

Topics: Animals; Anxiety; Anxiety Disorders; Arachidonic Acids; Brain; Candida albicans; Corticosterone; Endocannabinoids; Female; Gastrointestinal Microbiome; Hypothalamo-Hypophyseal System; Mice; Mice, Inbred C57BL; Models, Animal; Neurosecretory Systems; Pituitary-Adrenal System; Polyunsaturated Alkamides; Signal Transduction; Stress, Psychological

Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors.

Topics: Acute Disease; Amides; Amidohydrolases; Animals; Anti-Anxiety Agents; Anxiety Disorders; Arachidonic Acids; Cannabinoid Receptor Agonists; Carbamates; Chronic Disease; Dioxanes; Endocannabinoids; Enzyme Inhibitors; Ethanolamines; Female; Gene Expression; Male; Mice; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; Rats, Sprague-Dawley; Receptors, Cannabinoid; Stress, Psychological

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(-1), intraperitoneal (i.p.)) exerted dose-dependent 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(-1), 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.

Topics: Animals; Animals, Newborn; Anti-Anxiety Agents; Anxiety Disorders; Anxiety, Separation; Arachidonic Acids; Behavior, Animal; Brain; Cannabinoid Receptor Modulators; Carrier Proteins; Disease Models, Animal; Endocannabinoids; Male; Maze Learning; Neural Inhibition; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Cannabinoid, CB1; Reflex, Startle; Rimonabant