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Influence of stimulant-induced hyperactivity on social approach in the BTBR mouse model of autism.

ABSTRACT: Translational research is needed to discover pharmacological targets and treatments for the diagnostic behavioral domains of autism spectrum disorders. Animal models with phenotypic relevance to diagnostic criteria offer clear experimental strategies to test the efficacy and safety of novel treatments. Antagonists of mGluR5 receptors are in clinical trials for Fragile X syndrome and under investigation for the treatment of autism spectrum disorders. However, in preclinical studies of mGluR5 compounds tested in our laboratory and others, increased locomotion following mGluR5 modulation has been observed. Understanding the influence of general activity on sociability and repetitive behaviors will increase the accuracy of interpretations of positive outcomes measured from pharmacological treatment that produces locomotor activating or sedating effects. In the present studies, dose-response curves for d-amphetamine (AMPH)-induced hyperlocomotion were similar in standard B6 mice and in the BTBR mouse model of autism. AMPH produced significant, robust reductions in the high level of repetitive self-grooming that characterizes BTBR, and also reduced the low baseline grooming in B6, indicating that AMPH-induced hyperlocomotion competes with time spent engaged in self-grooming. We then tested AMPH in B6 and BTBR on the 3-chambered social approach task. One component of sociability, the time spent in the chamber with the novel mouse, in B6 mice was reduced, while the sniffing time component of sociability in BTBR mice was enhanced. This finding replicated across multiple cohorts treated with AMPH and saline vehicle. In-depth analysis revealed that AMPH increased the number and decreased the duration of sniffing bouts in BTBR, suggesting BTBR treated with AMPH mostly engaged in brief sniffs rather than true social interactions with the novel mouse during the social approach task. Our data suggest that compounds with stimulant properties may have some direct benefits on reducing repetitive behaviors in autism spectrum disorders, particularly in the subset of autistic individuals with hyperactivity. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'.

SUBMITTER: Silverman JL

PROVIDER: S-EPMC3522798 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Influence of stimulant-induced hyperactivity on social approach in the BTBR mouse model of autism.

Silverman Jill L JL Babineau Brooke A BA Oliver Chicora F CF Karras Michael N MN Crawley Jacqueline N JN

Neuropharmacology 20120808

Translational research is needed to discover pharmacological targets and treatments for the diagnostic behavioral domains of autism spectrum disorders. Animal models with phenotypic relevance to diagnostic criteria offer clear experimental strategies to test the efficacy and safety of novel treatments. Antagonists of mGluR5 receptors are in clinical trials for Fragile X syndrome and under investigation for the treatment of autism spectrum disorders. However, in preclinical studies of mGluR5 comp ...[more]

PMID: 22968082

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Project description:Autism is a neurodevelopmental disorder in which the first diagnostic symptom is unusual reciprocal social interactions. Approximately half of the children diagnosed with an autism spectrum disorder also have intellectual impairments. General cognitive abilities may be fundamental to many aspects of social cognition. Cognitive enhancers could conceivably be of significant benefit to children and adults with autism. AMPAKINE compounds are a novel class of pharmacological agents that act as positive modulators of AMPA receptors to enhance excitatory glutamatergic neurotransmission. This class of compounds was reported to improve learning and memory in several rodent and non-human primate tasks, and to normalize respiratory abnormalities in a mouse model of Rett syndrome. Here we evaluate the actions of AMPA compounds in adult male and female BTBR mice, a well characterized mouse model of autism. Acute treatment with CX1837 and CX1739 reversed the deficit in sociability in BTBR mice on the most sensitive parameter, time spent sniffing a novel mouse as compared to time spent sniffing a novel object. The less sensitive parameter, time in the chamber containing the novel mouse versus time in the chamber containing the novel object, was not rescued by CX1837 or CX1739 treatment. Preliminary data with CX546, in which β-cyclodextrin was the vehicle, revealed behavioral effects of the acute intraperitoneal and oral administration of vehicle alone. To circumvent the artifacts introduced by the vehicle administration, we employed a novel treatment regimen using pellets of peanut butter for drug delivery. Absence of vehicle treatment effects when CX1837 and CX1739 were given in the peanut butter pellets, to multiple cohorts of BTBR and B6 control mice, confirmed that the pharmacologically-induced improvements in sociability in BTBR were not confounded by the administration procedures. The highest dose of CX1837 improved the cognitive deficit in novel object recognition in BTBR. No drug effects were detected on the high levels of repetitive self-grooming in BTBR. In open field tests, CX1837 and CX1739 did not induce hyperactivity or sedation in either strain. It is interesting to speculate that the ability of CX1837 and CX1739 to restore aspects of sociability in BTBR mice could utilize synaptic mechanisms regulating social cognition, suggesting a potential pharmacological target for interventions to treat symptoms of autism. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Dataset Information

Influence of stimulant-induced hyperactivity on social approach in the BTBR mouse model of autism.

Publications

Influence of stimulant-induced hyperactivity on social approach in the BTBR mouse model of autism.

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