Consequences of Cannabinoid and Monoaminergic System Disruption in a Mouse Model of Autism Spectrum Disorders

Abstract

Autism spectrum disorders (ASDs) are heterogenous neurodevelopmental disorders characterized by impairment in social, communication skills and stereotype behaviors. While autism may be uniquely human, there are behavioral characteristics in ASDs that can be mimicked using animal models. We used the BTBR T+tf/J mice that have been shown to exhibit autism-like behavioral phenotypes to 1). Evaluate cannabinoid-induced behavioral changes using forced swim test (FST) and spontaneous wheel running (SWR) activity and 2). Determine the behavioral and neurochemical changes after the administration of MDMA (20 mg/kg), methamphetamine (10 mg/kg) or MPTP (20 mg/kg). We found that the BTBR mice exhibited an enhanced basal spontaneous locomotor behavior in the SWR test and a reduced depressogenic profile. These responses appeared to be enhanced by the prototypic cannabinoid, Δ9-THC. MDMA and MPTP at the doses used did not modify SWR behavior in the BTBR mice whereas MPTP reduced SWR activity in the control CB57BL/6J mice. In the hippocampus, striatum and frontal cortex, the levels of DA and 5-HT and their metabolites were differentially altered in the BTBR and C57BL/6J mice. Our data provides a basis for further studies in evaluating the role of the cannabinoid and monoaminergic systems in the etiology of ASDs.

Endocannabinoid Signaling in Autism

“…These drugs could potentially ameliorate the epilepsy-related symptoms that commonly co-occur with ASD. On a final note, it seems of major interest that preliminary data, showing consistency between changes in distinct eCB system elements (i.e., CB 2 ) in animal models of ASD and in peripherabl blood mononuclear cells from young patients with ASD [106,107], support a role for these elements in the (early) diagnosis of the disease. Future work should test expression profiles for key players of the eCB system in prospective samples to test the potential of these as diagnostic biomarkers.…”

“…Preliminary data also addressed CB 2 as a potential target for autism. Indeed, genomic studies have highlighted an upregulation of mRNA levels of the CB 2 A, but not the CB 2 B, isoform in the cerebellum of BTBR T+tF/ J mice [105], which have an autism-like behavioral phenotype [106]. Also, an independent clinical study performed on young (3-9-year-old) children demonstrated that CB 2 is highly expressed, both at transcriptional and translational levels, in peripheral blood mononuclear cells of patients with autism, compared with matched healthy controls [107].…”

Would some cannabinoids ameliorate symptoms of autism?

“…Thus, despite their action on oxytocin and vasopressin release, CBD and delta9-THC may help in improving symptoms of ASD by their sedative, antipsychotic, anticonvulsant and tranquilizing effects. In addition, the cannabinoid system has already been shown to be implicated in social behavior in rats [9].…”

Endocannabinoid System as Novel Therapeutic Target for Autism Treatment

“…Early studies in animal models demonstrated that BTBR mice show an abnormal regulation of dopamine levels functioning with an upregulated CB2A gene expression [5]. In addition, in the valproic acid induced model of autism, alterations in the brain's endocannabinoid system have been reported in a newest research [6].…”

“…anxiety, major depression, bipolar disorder and schizophrenia) [2]. This system is also a key regulator of other metabolic and cellular pathways involved in ASDs, such as food intake, energy metabolism, immune system controlling.Early studies in animal models demonstrated that BTBR mice show an abnormal regulation of dopamine levels functioning with an upregulated CB2A gene expression [5]. In addition, in the valproic acid induced model of autism, alterations in the brain's endocannabinoid system have been reported in a newest research [6].…”