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Friday, May 8, 2009
Northwest Hall (Chicago Hilton)
11:00 AM
Background: Animal models provide research tools for evaluating proposed treatments for autism. BTBR T+tf/J (BTBR) is an inbred strain of mice that displays behavioral phenotypes with analogies to all three of the diagnostic symptoms of autism, including well-replicated social deficits, unusual patterns of vocalization, and high levels of repetitive self-grooming. These phenotypes offer straightforward behavioral assays to test pharmacological compounds.
Objectives: Pharmacological rescue of the repetitive self-grooming behavior and the social deficits in BTBR mice.
Methods: Adult male and female BTBR and control C57BL/6J (B6) mice were bred in our animal facility and tested in compliance with NIH guidelines for the care and use of laboratory animals. On the day of testing, cages of the subject mice were acclimated to the testing area for 1 hour. Subject mice were administered an intraperitoneal (i.p.) injection of risperidone (0.125 mg/kg, 0.25 mg/kg, or 0.5 mg/kg, Sigma Aldrich, St Louis, MO), MPEP (0.5 mg/kg, 1.0 mg/kg, 10 mg/kg, 30 mg/kg, Sigma Aldrich, St Louis, MO), or saline vehicle and are returned to their home cages for thirty minutes. Each mouse was then tested in one of three behavioral tasks. The social approach task was performed as previously described (Yang et al., 2007), in which approach to a novel object in one side chamber and to a novel mouse in the other side chamber were automatically recorded. Time spent sniffing the novel mouse and novel object was scored with a stopwatch by an observer blinded to drug treatment. Self-grooming behavior was assessed in subjects by placing the mouse in a clean standard mouse cage for a 10 minute habituation period and then a 10 minute test session during which cumulative time spent in self-grooming was scored with a stopwatch. The third task quantified general locomotor activity in a novel open field (AccuScan Instruments,Columbus , OH), as a control measure to detect any confounding behavioral sedation induced by the drug treatments.
Results: Low doses of risperidone significantly reduced repetitive self-grooming behavior in BTBR mice. However, a significant reduction in open field locomotion was seen at doses of risperidone that reduced self-grooming. No significant improvements in social approach were observed after acute risperidone treatment. Preliminary data indicate that MPEP significantly reduced repetitive self-grooming at doses that did not affect open field locomotion. Social approach testing following treatment with acute MPEP is in progress.
Conclusions: Our results indicate that acute treatment with MPEP, an mGluR5 antagonist, may reverse a repetitive behavioral phenotype in the BTBR mouse model of autism. Reductions in repetitive self-grooming by risperidone appears to be due to the sedating effects of acute risperidone in mice. Chronic low-dose treatments with risperidone and MPEP will be important in the future, for understanding the potential efficacy of these two classes of compounds in autism-related behaviors. The BTBR mouse model appears to offer a straightforward preclinical model for discovering treatments that rescue mouse behaviors analogous to the diagnostic symptoms of autism.
Objectives: Pharmacological rescue of the repetitive self-grooming behavior and the social deficits in BTBR mice.
Methods: Adult male and female BTBR and control C57BL/6J (B6) mice were bred in our animal facility and tested in compliance with NIH guidelines for the care and use of laboratory animals. On the day of testing, cages of the subject mice were acclimated to the testing area for 1 hour. Subject mice were administered an intraperitoneal (i.p.) injection of risperidone (0.125 mg/kg, 0.25 mg/kg, or 0.5 mg/kg, Sigma Aldrich, St Louis, MO), MPEP (0.5 mg/kg, 1.0 mg/kg, 10 mg/kg, 30 mg/kg, Sigma Aldrich, St Louis, MO), or saline vehicle and are returned to their home cages for thirty minutes. Each mouse was then tested in one of three behavioral tasks. The social approach task was performed as previously described (Yang et al., 2007), in which approach to a novel object in one side chamber and to a novel mouse in the other side chamber were automatically recorded. Time spent sniffing the novel mouse and novel object was scored with a stopwatch by an observer blinded to drug treatment. Self-grooming behavior was assessed in subjects by placing the mouse in a clean standard mouse cage for a 10 minute habituation period and then a 10 minute test session during which cumulative time spent in self-grooming was scored with a stopwatch. The third task quantified general locomotor activity in a novel open field (AccuScan Instruments,
Results: Low doses of risperidone significantly reduced repetitive self-grooming behavior in BTBR mice. However, a significant reduction in open field locomotion was seen at doses of risperidone that reduced self-grooming. No significant improvements in social approach were observed after acute risperidone treatment. Preliminary data indicate that MPEP significantly reduced repetitive self-grooming at doses that did not affect open field locomotion. Social approach testing following treatment with acute MPEP is in progress.
Conclusions: Our results indicate that acute treatment with MPEP, an mGluR5 antagonist, may reverse a repetitive behavioral phenotype in the BTBR mouse model of autism. Reductions in repetitive self-grooming by risperidone appears to be due to the sedating effects of acute risperidone in mice. Chronic low-dose treatments with risperidone and MPEP will be important in the future, for understanding the potential efficacy of these two classes of compounds in autism-related behaviors. The BTBR mouse model appears to offer a straightforward preclinical model for discovering treatments that rescue mouse behaviors analogous to the diagnostic symptoms of autism.