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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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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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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Dissecting the signaling pathways involved in the crosstalk between mGlu5 and CB1 receptors.

“The metabotropic glutamate (mGlu) receptor 5 and the cannabinoid type 1 (CB1) receptor are G-protein-coupled receptors (GPCR) that are widely expressed in the central nervous system (CNS). mGlu5 receptors, present at the postsynaptic site, are coupled to Gαq/11 proteins and display an excitatory response upon activation, while the CB1 receptor, mainly present at presynaptic terminals, is coupled to the Gi/o protein and triggers an inhibitory response. Recent studies suggest that the glutamatergic and endocannabinoid systems exhibit a functional interaction to modulate several neural processes. In this review we discuss possible mechanisms involved in this crosstalk and its relationship with physiological and pathological conditions, including nociception, addiction and fragil X syndrome.”

http://www.ncbi.nlm.nih.gov/pubmed/27338080

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ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

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Endocannabinoid-mediated improvement on a test of aversive memory in a mouse model of fragile X syndrome.

“Silencing the gene FMR1 in fragile X syndrome (FXS) with consequent loss of its protein product, FMRP, results in intellectual disability, hyperactivity, anxiety, seizure disorders, and autism-like behavior. In a mouse model (Fmr1 knockout (KO)) of FXS, a deficit in performance on the passive avoidance test of learning and memory is a robust phenotype.

We report that drugs acting on the endocannabinoid (eCB) system can improve performance on this test.

Our results indicate that the eCB system is involved in FXS and suggest that the eCB system is a promising target for treatment of FXS.”

http://www.ncbi.nlm.nih.gov/pubmed/25979787

http://www.thctotalhealthcare.com/category/fragile-x-syndrome-fxs/

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New insights into the molecular pathophysiology of fragile X syndrome and therapeutic perspectives from the animal model.

“Fragile X syndrome is the most common monogenetic form of intellectual disability and is a leading cause of autism. This syndrome is produced by the reduced transcription of the fragile X mental retardation (FMR1) gene, and it is characterized by a range of symptoms heterogeneously expressed in patients such as cognitive impairment, seizure susceptibility, altered pain sensitivity and anxiety.

The recent advances in the understanding of the pathophysiological mechanisms involved have opened novel potential therapeutic approaches identified in preclinical rodent models as a necessary preliminary step for the subsequent evaluation in patients… New findings in the animal models open other possible therapeutic approaches such as the mammalian target of rapamycin signaling pathway or the endocannabinoid system… emerging data recently obtained in preclinical models of fragile X syndrome supporting these new therapeutic perspectives.”

http://www.ncbi.nlm.nih.gov/pubmed/24831882

http://www.thctotalhealthcare.com/category/fragile-x-syndrome-fxs/

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