anandamide and Autism-Spectrum-Disorder

The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG). The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation. The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer's disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist.

Topics: Alzheimer Disease; Animals; Arachidonic Acids; Autism Spectrum Disorder; Bone Diseases; Cannabinoid Receptor Agonists; Cardiovascular Diseases; Drug Discovery; Endocannabinoids; Fragile X Syndrome; Humans; Molecular Targeted Therapy; Multiple Sclerosis; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid

Autism spectrum disorder (ASD) has a multifactorial etiology. Major efforts are underway to understand the neurobiological bases of ASD and to develop efficacious treatment strategies. Recently, the use of cannabinoid compounds in children with neurodevelopmental disorders including ASD has received increasing attention. Beyond anecdotal reports of efficacy, however, there is limited current evidence supporting such an intervention and the clinical studies currently available have intrinsic limitations that make the interpretation of the findings challenging. Furthermore, as the mechanisms underlying the beneficial effects of cannabinoid compounds in neurodevelopmental disorders are still largely unknown, the use of drugs targeting the endocannabinoid system remains controversial. Here, we studied the role of endocannabinoid neurotransmission in the autistic-like traits displayed by the recently validated Fmr1-

Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Cannabinoids; Endocannabinoids; Fragile X Mental Retardation Protein; Models, Genetic; Phenotype; Polyunsaturated Alkamides; Rats; Receptor, Cannabinoid, CB1

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by social interaction impairment, stereotypical/repetitive behaviors and emotional deregulation. The endocannabinoid (eCB) system plays a crucial role in modulating the behavioral traits that are typically core symptoms of ASD. The major molecular mechanisms underlying eCB-dependent long-term depression (eCB-LTD) are mediated by group 1 metabotropic glutamate receptor (mGluR)-induced removal of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Recently, modulation of anandamide (AEA), one of the main endocannabinoids in the brain, has been reported to alter social behaviors in genetic models of ASD. On this basis, we investigated the effects of treatment and the synaptic mechanism underlying AEA-mediated signaling in prenatal exposure to valproic acid (VPA) in rats. We found that the social deficits, repetitive behaviors and abnormal emotion-related behaviors in VPA-exposed offspring were improved after treatment with an inhibitor of AEA degrading enzyme, URB597. Using an integrative approach combing electrophysiological and cellular mechanisms, the results showed that the impaired eCB-LTD, abnormal mGluR-mediated LTD (mGluR-LTD) and decreased removal of AMPAR subunits GluA1 and GluA2 were reversed by URB597 in the prefrontal cortex (PFC) of VPA-exposed offspring. Taken together, these results provide the first evidence that rescue of the ASD-like phenotype by URB597 is mediated by enhancing the mechanism of removal of AMPAR subunits GluA1/2 underlying AEA signaling in the PFC in a VPA-induced model of ASD.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Autism Spectrum Disorder; Benzamides; Carbamates; Disease Models, Animal; Endocannabinoids; Enzyme Inhibitors; Female; Long-Term Synaptic Depression; Neuronal Plasticity; Polyunsaturated Alkamides; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Protein Transport; Rats; Receptors, AMPA; Receptors, Metabotropic Glutamate; Social Behavior; Valproic Acid

The theory of a fetal origin of adult diseases links many pathological conditions to very early life events and is known as a "developmental programming" phenomenon. The mechanisms of this phenomenon are not quite understood and have been explained by inflammation, stress, etc. In particular the epidemic of obesity, with more than 64% of women being overweight or obese, has been associated with conditions in later life such as mental disorders, diabetes, asthma, and irritable bowel syndrome. Interestingly, these diseases were classified a decade ago as Clinical Syndrome of Endocannabinoid Deficiency (CECD), which was first described by Russo in 2004. Cannabinoids have been used for the treatment of chronic pain for millenniums and act through the mechanism of "kick-starting" the components of the endogenous cannabinoid system (ECS). ECS is a pharmacological target for the treatment of obesity, inflammation, cardiovascular and neuronal damage, and pain. We hypothesize that the deteriorating effect of maternal obesity on offspring health is explained by the mechanism of Fetal Syndrome of Endocannabinoid Deficiency (FSECD), which accompanies maternal obesity. Here we provide support for this hypothesis.

Topics: Adult; Animals; Arachidonic Acids; Asthma; Autism Spectrum Disorder; Cannabinoids; Endocannabinoids; Female; Fetal Nutrition Disorders; Glycerides; Humans; Insulin Resistance; Irritable Bowel Syndrome; Models, Theoretical; Obesity; Phenotype; Polyunsaturated Alkamides; Pregnancy; Pregnancy Complications; Syndrome; Young Adult

Marijuana exerts profound effects on human social behavior, but the neural substrates underlying such effects are unknown. Here we report that social contact increases, whereas isolation decreases, the mobilization of the endogenous marijuana-like neurotransmitter, anandamide, in the mouse nucleus accumbens (NAc), a brain structure that regulates motivated behavior. Pharmacological and genetic experiments show that anandamide mobilization and consequent activation of CB1 cannabinoid receptors are necessary and sufficient to express the rewarding properties of social interactions, assessed using a socially conditioned place preference test. We further show that oxytocin, a neuropeptide that reinforces parental and social bonding, drives anandamide mobilization in the NAc. Pharmacological blockade of oxytocin receptors stops this response, whereas chemogenetic, site-selective activation of oxytocin neurons in the paraventricular nucleus of the hypothalamus stimulates it. Genetic or pharmacological interruption of anandamide degradation offsets the effects of oxytocin receptor blockade on both social place preference and cFos expression in the NAc. The results indicate that anandamide-mediated signaling at CB1 receptors, driven by oxytocin, controls social reward. Deficits in this signaling mechanism may contribute to social impairment in autism spectrum disorders and might offer an avenue to treat these conditions.

Topics: Analysis of Variance; Animals; Arachidonic Acids; Autism Spectrum Disorder; Benzamides; Benzodiazepines; Camphanes; Carbamates; Clozapine; Cocaine; Endocannabinoids; Immunohistochemistry; Infusions, Intraventricular; Lipids; Male; Mice; Mice, Inbred C57BL; Nucleus Accumbens; Oxytocin; Piperazines; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Reward; Signal Transduction; Social Behavior