The Endocannabinoid System and Autism Spectrum Disorders: Insights from Animal Models.

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“Autism spectrum disorder (ASD) defines a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction with restricted or repetitive motor movements, frequently associated with general cognitive deficits. Although it is among the most severe chronic childhood disorders in terms of prevalence, morbidity, and impact to the society, no effective treatment for ASD is yet available, possibly because its neurobiological basis is not clearly understood hence specific drugs have not yet been developed. The endocannabinoid (EC) system represents a major neuromodulatory system involved in the regulation of emotional responses, behavioral reactivity to context, and social interaction. Furthermore, the EC system is also affected in conditions often present in subsets of patients diagnosed with ASD, such as seizures, anxiety, intellectual disabilities, and sleep pattern disturbances. Despite the indirect evidence suggestive of an involvement of the EC system in ASD, only a few studies have specifically addressed the role of the EC system in the context of ASD. This review describes the available data on the investigation of the presence of alterations of the EC system as well as the effects of its pharmacological manipulations in animal models of ASD-like behaviors.”

https://www.ncbi.nlm.nih.gov/pubmed/28880200

http://www.mdpi.com/1422-0067/18/9/1916

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Role of Endocannabinoids on Neuroinflammation in Autism Spectrum Disorder Prevention

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Autism Spectrum Disorder (ASD) disease has become a mounting socio-economical alarm around the world. Neuroinflammtion had been shown in postmortem brain specimens from ASD patients.

The Endocannabinoids System (ES) consists of a family of locally produced, short-lived, endogenous, phospholipid-derived agonists (endocannabinoids) that control energy balance and body composition. The growing number of medical benefits of ES, such as their ability to regulate processes like neuroinflammation, neurogenesis and memory, raise the question of their potential role as a preventive treatment of ASD.

The complex nature of ASD advocates a multimodal drug approach that could protect from the various processes underlying neurodegeneration and thus, at minimum, delay the pathological process. The expected benefit from a chronic treatment aimed at stimulating the endocannabinoid system is a delayed progression of ASD: i.e., reduced inflammation, sustained potential for neurogenesis, and delayed memory impairment. Such results could lead to new therapeutic strategies that target the inflammation and the decline in neurogenesis associated ASD.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535348/

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Endocannabinod Signal Dysregulation in Autism Spectrum Disorders: A Correlation Link between Inflammatory State and Neuro-Immune Alterations.

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“Several studies highlight a key involvement of endocannabinoid (EC) system in autism pathophysiology. The EC system is a complex network of lipid signaling pathways comprised of arachidonic acid-derived compounds (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), their G-protein-coupled receptors (cannabinoid receptors CB1 and CB2) and the associated enzymes. In addition to autism, the EC system is also involved in several other psychiatric disorders (i.e., anxiety, major depression, bipolar disorder and schizophrenia). This system is a key regulator of metabolic and cellular pathways involved in autism, such as food intake, energy metabolism and immune system control. Early studies in autism animal models have demonstrated alterations in the brain’s EC system. Autism is also characterized by immune system dysregulation. This alteration includes differential monocyte and macrophage responses, and abnormal cytokine and T cell levels. EC system dysfunction in a monocyte and macrophagic cellular model of autism has been demonstrated by showing that the mRNA and protein for CB2 receptor and EC enzymes were significantly dysregulated, further indicating the involvement of the EC system in autism-associated immunological disruptions. Taken together, these new findings offer a novel perspective in autism research and indicate that the EC system could represent a novel target option for autism pharmacotherapy.”  https://www.ncbi.nlm.nih.gov/pubmed/28671614

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Cannabis ‘mimics love hormone in the brain’, study finds – marking new research possibilities for autism

Cannabis behaves like the human 'love hormone'

“Cannabis has a reputation for inducing feelings of peace and love – and now scientists claim they have found the reason why.

A new study reveals the illegal drug acts much in the same way as chemicals produced by the natural ‘love hormone’ oxytocin, which is known to boost emotional feelings and bonding towards romantic partners, between mothers and babies and friends.

The research, conducted on mice, found that higher levels of oxytocin led to the release of anandamide – which behaves very similarly in the brain to the psychoactive ingredient in cannabis, THC.

Both chemicals attach to the same brain cell receptors, producing a similar ‘high’.

As part of the study, the researchers found that blocking anandamide reduced the pro-social effects of oxytocin – while a drug which preserved anandamide in the mice’s brains seemed to make them happier around other mice than other, untreated, animals.

Scientists say the results could highlight new paths for research in the treatment of autism, for which symptoms often include difficulty socialising.

It is very difficult to directly deliver oxytocin to the brain, however.

Dr Daniele Piomelli, of the Italian Institute of Technology in Genoa, Italy, said another strategy could be to intervene further down the oxytocin-anandamide pathway.

Our findings open the exciting possibility that drugs that block the degradation of anandamide, which are currently being tested for various anxiety disorders, could give a boost to the brain’s own oxytocin and help people with autism socialise more.

– DR DANIELE PIOMELLI, RESEARCHER

The findings were published in the journal Proceedings of the National Academy of Sciences.”

http://www.itv.com/news/2015-10-27/cannabis-mimics-love-hormone-in-the-brain-study-finds/

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Enhancement of Anandamide-Mediated Endocannabinoid Signaling Corrects Autism-Related Social Impairment

Mary Ann Liebert, Inc. publishers

We recently uncovered a signaling mechanism by which the endocannabinoid anandamide mediates the action of oxytocin, a neuropeptide that is crucial for social behavior, to control social reward. Oxytocin signaling has been implicated in autism spectrum disorder (ASD), and social reward is a key aspect of social functioning that is thought to be disrupted in ASD. Therefore, as a proof of principle for the core component of ASD—social impairment—we tested an endocannabinoid-enhancing compound on two widely studied mouse models of ASD, the BTBR and fmr1−/− (model of Fragile X Syndrome).

Remarkably, we found that FAAH blockade completely reversed the social impairment in both mouse models. CB1 receptor blockade prevented the prosocial action of FAAH inhibition in BTBR mice.

The results suggest that increasing anandamide activity at CB1 receptors improves ASD-related social impairment and identify FAAH as a novel therapeutic target for ASD.

In conclusion, the present study provides new insights into the role of endocannabinoid signaling in social behavior and validates FAAH as a novel therapeutic target for the social impairment of ASD.”
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Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome

“Fragile X syndrome, the most commonly known genetic cause of autism, is due to loss of the fragile X mental retardation protein, which regulates signal transduction at metabotropic glutamate receptor-5 in the brain.

The results identify the endocannabinoid signalosome as a molecular substrate for fragile X syndrome, which might be targeted by therapy.”  http://www.nature.com/articles/ncomms2045

“Cannabis-like chemical combats chief genetic cause of autism” http://www.belfasttelegraph.co.uk/news/health/cannabislike-chemical-combats-chief-genetic-cause-of-autism-28867862.html#ixzz2DRLsbjJO

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Targeting anandamide metabolism rescues core and associated autistic-like symptoms in rats prenatally exposed to valproic acid.

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“Autism spectrum disorders (ASD) are characterized by altered sociability, compromised communication and stereotyped/repetitive behaviors, for which no specific treatments are currently available. Prenatal exposure to valproic acid (VPA) is a known, although still underestimated, environmental risk factor for ASD.

Altered endocannabinoid activity has been observed in autistic patients, and endocannabinoids are known to modulate behavioral traits that are typically affected in ASD. On this basis, we tested the hypothesis that changes in the endocannabinoid tone contribute to the altered phenotype induced by prenatal VPA exposure in rats, with focus on behavioral features that resemble the core and associated symptoms of ASD.

In the course of development, VPA-exposed rats showed early deficits in social communication and discrimination, compromised sociability and social play behavior, stereotypies and increased anxiety, thus providing preclinical proof of the long-lasting deleterious effects induced by prenatal VPA exposure. At the neurochemical level, VPA-exposed rats displayed altered phosphorylation of CB1 cannabinoidreceptors in different brain areas, associated with changes in anandamide metabolism from infancy to adulthood.

Interestingly, enhancing anandamide signaling through inhibition of its degradation rescued the behavioral deficits displayed by VPA-exposed rats at infancy, adolescence and adulthood.

This study therefore shows that abnormalities in anandamide activity may underlie the deleterious impact of environmental risk factors on ASD-relevant behaviors and that the endocannabinoid system may represent a therapeutic target for the core and associated symptoms displayed by autistic patients.”

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Endocannabinoid signaling in social functioning: an RDoC perspective.

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“Core deficits in social functioning are associated with various neuropsychiatric and neurodevelopmental disorders, yet biomarker identification and the development of effective pharmacological interventions has been limited.

Recent data suggest the intriguing possibility that endogenous cannabinoids, a class of lipid neuromodulators generally implicated in the regulation of neurotransmitter release, may contribute to species-typical social functioning.

Systematic study of the endogenous cannabinoid signaling could, therefore, yield novel approaches to understand the neurobiological underpinnings of atypical social functioning.

This article provides a critical review of the major components of the endogenous cannabinoid system (for example, primary receptors and effectors-Δ9-tetrahydrocannabinol, cannabidiol, anandamide and 2-arachidonoylglycerol) and the contributions of cannabinoid signaling to social functioning.

Data are evaluated in the context of Research Domain Criteria constructs (for example, anxiety, chronic stress, reward learning, motivation, declarative and working memory, affiliation and attachment, and social communication) to enable interrogation of endogenous cannabinoid signaling in social functioning across diagnostic categories.

The empirical evidence reviewed strongly supports the role for dysregulated cannabinoid signaling in the pathophysiology of social functioning deficits observed in brain disorders, such as autism spectrum disorder, schizophrenia, major depressive disorder, posttraumatic stress disorder and bipolar disorder.

Moreover, these findings indicate that the endogenous cannabinoid system holds exceptional promise as a biological marker of, and potential treatment target for, neuropsychiatric and neurodevelopmental disorders characterized by impairments in social functioning.”

https://www.ncbi.nlm.nih.gov/pubmed/27676446

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Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model.

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“Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability.

The cognitive deficits in the mouse model for this disorder, the Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mouse, have been restored by different pharmacological approaches, among those the blockade of cannabinoid type 1 (CB1) receptor.

In this regard, our previous study showed that the CB1 receptor antagonist/inverse agonist rimonabant normalized a number of core features in the Fmr1 knockout mouse. Rimonabant was commercialized at high doses for its anti-obesity properties, and withdrawn from the market on the bases of mood-related adverse effects.

In this study we show, by using electrophysiological approaches, that low dosages of rimonabant (0.1 mg/kg) manage to normalize metabotropic glutamate receptor dependent long-term depression (mGluR-LTD). In addition, low doses of rimonabant (from 0.01 mg/kg) equally normalized the cognitive deficit in the mouse model of FXS.

These doses of rimonabant were from 30 to 300 times lower than those required to reduce body weight in rodents and to presumably produce adverse effects in humans. Furthermore, NESS0327, a CB1 receptor neutral antagonist, was also effective in preventing the novel object-recognition memory deficit in Fmr1 KO mice.

These data further support targeting CB1 receptors as a relevant therapy for FXS.”

http://www.ncbi.nlm.nih.gov/pubmed/27589806

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Deficient Adolescent Social Behavior Following Early-Life Inflammation is Ameliorated by Augmentation of Anandamide Signaling.

“Early-life inflammation has been shown to exert profound effects on brain development and behavior, including altered emotional behavior, stress responsivity and neurochemical/neuropeptide receptor expression and function.

The current study extends this research by examining the impact of inflammation, triggered with the bacterial compound lipopolysaccharide (LPS) on postnatal day (P) 14, on social behavior during adolescence.

We investigate the role that the endocannabinoid (eCB) system plays in sociability after early-life LPS.

These data suggest that alterations in eCB signaling following postnatal inflammation contribute to impairments in social behavior during adolescence and that inhibition of FAAH could be a novel target for disorders involving social deficits such as social anxiety disorders or autism.”

http://www.ncbi.nlm.nih.gov/pubmed/27453335

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