R-Baclofen, a Gabab Agonist, Reduced Stereotyped and Repetitive Behavior in the BTBR and C58 Mouse Models of Autism
Objectives: The specific objective of this proposal is to test the hypothesis that enhanced inhibitory transmission, via the GABAB agonist R+-baclofen, will reduce high levels of repetitive behavior in two mouse models of non-syndromic autism. BTBR displays multiple behavioral phenotypes with face validity to both of the diagnostic symptoms of autism, including well-replicated low sociability, low levels of vocalizations in social settings, and high levels of repetitive self-grooming. R+-baclofen was similarly tested in C58/J mice (C58), which display high levels of stereotyped jumping and repetitive grooming. The control strain, C57BL/6J (B6), displays high sociability and no detectable stereotyped or repetitive behaviors.
Methods: BTBR, C58 and B6 were given an intraperitoneal injection of R+-baclofen (1.0 mg/kg, or 3.0 mg/kg) or saline, 30 or 60 minutes before behavioral testing. BTBR, C58 and B6 were tested in three behavioral tasks: 1) marble burying in an empty mouse cage (Thomas et al., 2012), 2) self-grooming in a clean standard mouse cage for a 10 minute test session (Silverman et al., 2012) and 3) open field locomotor activity, as a control measure to detect confounding drug-induced behavioral sedation.
Results: R+-baclofen reduced repetitive self-grooming and marble burying in two cohorts of BTBR mice. R+-baclofen also reduced stereotyped jumping in C58 mice. Effective doses of R+-baclofen on repetitive or stereotyped behavior in BTBR or C58 mice did not produce signs of sedation, as measured in the open field locomotor exploration test, 1 hour post drug administration.
Conclusions: Two mouse models of non-syndromic ASD provide corroborative preclinical evidence that a GABAB agonist may be effective for decreasing stereotyped and repetitive and behaviors in autism spectrum disorder.