期刊
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
卷 212, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pbb.2021.173304
关键词
Repetitive behaviors; Autism spectrum disorders; Histamine H3 receptor; Behavioral pharmacology; BTBR T+Itpr3tf/J mice
资金
- FSE Postdoctoral Fellowship in Behavioral Neuroscience at the University of Groningen
- Innovative Medicines Initiative 2 Joint Undertaking [777394]
- European Union's Horizon 2020-Research and Innovation Framework Programme
- EFPIA
- AUTISM SPEAKS
- Autistica
- SFARI
The acute manipulation of histamine H3 receptors mainly affected the general motor activity levels in novel environments, with some small effects on repetitive behaviors.
Background: Autism spectrum disorders (ASDs) are a group of neurodevelopmental conditions defined by behavioral deficits in social communication and interactions, mental inflexibility and repetitive behaviors. Converging evidence from observational and preclinical studies suggest that excessive repetitive behaviors in people with ASD may be due to elevated histaminergic H3 receptor signaling in the striatum. We hypothesized that systemic administration of pharmacological histamine H3 receptor antagonists would attenuate the expression of repetitive behaviors in the BTBR T+Itpr3tf/J (BTBR) mouse inbred strain, an established mouse model presenting autism-like repetitive behaviors and novelty-induced hyperactivity. We further aimed to investigate whether agonism of the histamine H3 receptor would be sufficient to induce repetitive behaviors in the C57BL/6J control mouse strain. Methods: Different doses of H3 receptor agonists (i.e., (R)-a-methylhistamine and immethridine) and H3 receptor antagonists/inverse agonists (i.e., ciproxifan and pitolisant) were administered via intraperitoneal (i.p.) injection in male mice to characterize the acute effects of these compounds on ASD-related behavioral readouts. Results: The highly selective H3 receptor agonist immethridine significantly increased the time spent in stereotypic patterns in C57BL/6J mice, but this effect appeared to be driven by general sedative properties of the compound. High doses of pitolisant significantly decreased locomotor hyperactivity in novel environments in BTBR mice, without significant effects on repetitive behaviors. Conclusions: Based on our findings, we conclude that acute H3 receptor manipulation mainly affected general motor activity levels in novel environments. Small changes in stereotyped behaviors were observed but appeared to be driven by altered general activity levels.
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