GABAB Receptor Agonist R-Baclofen Reverses Social Deficits and Reduces Repetitive Behavior in Two Mouse Models of Autism
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Autism spectrum disorder (ASD) is diagnosed by two core behavioral criteria, unusual reciprocal social interactions and communication, and stereotyped, repetitive behaviors with restricted interests. Excitatory/inhibitory imbalance is a prominent hypothesis for the etiology of autism. The selective GABAB receptor agonist R-baclofen previously reversed social deficits and reduced repetitive behaviors in a mouse model of Fragile X syndrome, and Arbaclofen improved some clinical symptoms in some Fragile X and ASD patients. To evaluate R-baclofen in a broader range of mouse models of ASD, we tested both the R-baclofen enantiomer and the less potent S-baclofen enantiomer in two inbred strains of mice that display low sociability and/or high repetitive or stereotyped behaviors. R-baclofen treatment reversed social approach deficits in BTBR T+ Itpr3tf/J (BTBR), reduced repetitive self-grooming and high marble burying scores in BTBR, and reduced stereotyped jumping in C58/J (C58), at nonsedating doses. S-baclofen produced minimal effects at the same doses. These findings encourage investigations of R-baclofen in other preclinical model systems. Additional clinical studies may be warranted to further evaluate the hypothesis that the GABAB receptor represents a promising pharmacological target for treating appropriately stratified subsets of individuals with ASD.
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GABAB agonists such as baclofen or arbaclofen correct excessive protein synthesis and multiple phenotypes in Fmr1-knockout mice.
“Administration of GABAB agonists, such as baclofen or arbaclofen, corrects exacerbated protein synthesis and multiple phenotypes in Fmr1-KO mice37–39.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [38]
Arbaclofen has rescued behavioral deficits including social deficits in mouse models of idiopathic ASD, deletion of 16p11.2, and FXS.
“For many subtypes of ASD, there is a GABAB deficit and arbaclofen has rescued the behavioral deficits including social deficits in the mouse models of idiopathic ASD [127], deletion of 16p11.2 [128], and FXS [129].”
From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [127]
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References 89 · Cited by 215
- Authors
- Silverman, J. L., Pride, M. C., Hayes, J. E., Puhger, K. R., Butler-Struben, H. M., Baker, S., & Crawley, J. N.
- Affiliations
- University of California Davis Medical Center (US)
- Corresponding author
- Silverman, J L
- Venue
- Neuropsychopharmacology
- Published
- 2015-03-10
- Volume
- 40
- Issue
- 9
- Pages
- 2228-2239
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4613612
- OpenAlex
- W2032988342
- Cited by
- 215
- References
- 89
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 10 · 2023: 15 · 2022: 18 · 2021: 35 · 2020: 19 · 2019: 25 · 2018: 15 · 2017: 33 · 2016: 15 · 2015: 13
- FWCI
- 15.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- MIND Institute, University of California, Davis
- University of California, Davis
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD079125)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- R-baclofen, GABA-B receptor agonist, autism spectrum disorder, social dysfunction, repetitive behavior, stereotypy, enantiomers, excitatory-inhibitory imbalance, marble burying, self-grooming
- MeSH terms
- Analysis of Variance, Animals, Autistic Disorder, Baclofen, Disease Models, Animal, Dose-Response Relationship, Drug, Exploratory Behavior, Grooming, Locomotion, Mice, Inbred C57BL, Mice, Neurologic Mutants, Cumulative Trauma Disorders, Social Behavior Disorders, Mice, GABA-B Receptor Agonists
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