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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autism is a complex neurodevelopmental disorder that is characterized by social abnormalities. Genetic, dietary and gut-related factors are implicated in autism, however the causal properties of these factors and how they may interact are unclear. Propionic acid (PPA) is a product of gut microbiota and a food preservative. PPA has been linked to autism, and PPA administration to rats is an animal model of the condition. Seizure-prone (FAST) and seizure-resistant (SLOW) rats were initially developed to investigate differential vulnerability to developing epilepsy. However, FAST rats also display autistic-like features, and have been proposed as a genetic model of autism. Here we examined the effects of PPA on social behavior in FAST and SLOW rats. A single intracerebroventricular injection of PPA, or phosphate-buffered saline (PBS), was administered to young-adult male FAST and SLOW rats. Immediately after treatment, rats were placed in same-treatment and same-strain pairs, and underwent social behavior testing. PPA induced social abnormalities in both FAST and SLOW rat strains. While there was no evidence of social impairment in FAST rats that were not treated with PPA, these rats were hyperactive relative to SLOW rats. Post-mortem immunofluorescence analysis of brain tissue indicated that PPA treatment resulted in increased astrogliosis in the corpus callosum and cortex compared to PBS treatment. FAST rats had increased astrogliosis in the cortex compared to SLOW rats. Together these findings support the use of PPA as a rat model of autism, but indicate there are no interactive effects between the PPA and FAST models.
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PMID:Intracerebroventricular injection of propionic acid, an enteric metabolite implicated in autism, induces social abnormalities that do not differ between seizure-prone (FAST) and seizure-resistant (SLOW) rats. 2544 54

In 2012, the US National Institute of Mental Health launched three clinical trial contracts under a new FAST initiative. The overall goal for these contracts (Fast-Fail Trials) was to focus early-stage trials, testing novel pharmacologic agents that target the central nervous system, on pharmacologic-based designs to objectively identify doses that produce central nervous system effects. The three contracts targeted different psychiatric populations: psychotic (FAST-PS), mood and anxiety (FAST-MAS), and autism spectrum disorders (FAST-AS). The FAST initiative was a first attempt for the National Institute of Mental Health to adapt an experimental medicine approach to its clinical trial portfolio. As the Fast-Fail trials implemented this new approach for the field, we present the rationale for each trial, design considerations, results, and how each one contributed new knowledge to the field of psychopharmacology; important lessons for pharma and biotech. Under the FAST initiative, the National Institute of Mental Health assembled research teams with a broad range of expertise, who developed and validated the outcome measures and study protocol, and conducted multi-site clinical trials, testing candidate compounds. In the FAST-PS contract, the team validated an imaging-based pharmacodynamic biomarker of the effect of ketamine in the brain that could be utilized in subsequent clinical trials. The initial FAST-AS study was an important first step in the design of early-stage target-engagement trials in autism spectrum disorder, suggesting that a resting electroencephalogram can be used as a pharmacodynamic measure in future studies. The FAST-MAS study showed that blocking the kappa-opioid receptor significantly affects functional magnetic resonance imaging ventral striatal activation in the monetary incentive delay task in anticipation of gain. Together, the outcomes of the FAST-FAIL trials demonstrated the importance of rigorously designed and informative central nervous system trials, including the value of pharmacodynamic measures in early-stage trials. Use of these measures furthered our knowledge about the relationship between specific molecular mechanisms, brain effects, and therapeutic effects in patients with mental illnesses.
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PMID:The NIMH 'Fast-Fail Trials' (FAST) Initiative: Rationale, Promise, and Progress. 3270 69