Molenhuis Remco T, Hutten Lianda, Kas Martien J H
Groningen Institute for Evolutionary Life Sciences, University of Groningen, Nijenborgh 7, 9747 AG Groningen, the Netherlands.
Groningen Institute for Evolutionary Life Sciences, University of Groningen, Nijenborgh 7, 9747 AG Groningen, the Netherlands.
Pharmacol Biochem Behav. 2022 Jan;212:173304. doi: 10.1016/j.pbb.2021.173304. Epub 2021 Nov 29.
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.
Different doses of H3 receptor agonists (i.e., (R)-α-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.
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.
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.
自闭症谱系障碍（ASD）是一组神经发育疾病，其特征为社交沟通与互动方面的行为缺陷、思维僵化及重复行为。观察性研究和临床前研究的越来越多证据表明，ASD患者的过度重复行为可能是由于纹状体中组胺能H3受体信号增强所致。我们假设，全身性给予药理学组胺H3受体拮抗剂会减弱BTBR T+Itpr3tf/J（BTBR）近交系小鼠重复行为的表达，BTBR小鼠是一种已确立的呈现自闭症样重复行为和新奇诱导多动的小鼠模型。我们还旨在研究组胺H3受体激动是否足以在C57BL/6J对照小鼠品系中诱导重复行为。
通过腹腔注射向雄性小鼠给予不同剂量的H3受体激动剂（即（R）-α-甲基组胺和异美汀）以及H3受体拮抗剂/反向激动剂（即西普罗芬和匹托品），以表征这些化合物对与ASD相关行为指标的急性影响。
高选择性H3受体激动剂异美汀显著增加了C57BL/6J小鼠刻板行为模式的持续时间，但这种效应似乎是由该化合物的一般镇静特性驱动的。高剂量的匹托品显著降低了BTBR小鼠在新环境中的运动性多动，对重复行为无显著影响。
基于我们的研究结果，我们得出结论，急性H3受体操纵主要影响新环境中的一般运动活动水平。观察到刻板行为有微小变化，但似乎是由改变的一般活动水平驱动的。
