Central histaminergic H3 receptor (H3R) has been extensively investigated as a potential therapeutic target for various neurological and neurodegenerative disorders. Despite promising results in preclinical rodent models, clinical trials have not provided conclusive evidence for the benefit of H3R antagonists to alleviate cognitive and behavioral symptoms of these disorders. Inconsistent pharmacological efficacies may arise from aberrant changes in H3R over time during disease development. Because H3R is involved in feedback inhibition of histamine synthesis and secretion, the expression of the autoreceptor may also be reciprocally regulated by altered histamine levels in a pathological condition. Thus, we investigated H3R expression in a mouse model of cow’s milk allergy, a condition associated with increased histamine levels. Mice were sensitized to bovine whey proteins (WP) over 5 weeks and H3R protein and transcript levels were examined in the brain. Substantially increased H3R immunoreactivity was observed in various brain regions of WP-sensitized mice compared to sham mice. Elevated H3R expression was also found in the thalamic/hypothalamic region. The expression of histaminergic H1, but not H2, receptor subtype was also increased in this and the midbrain regions. Unlike the brain, all three histaminergic receptors were increased in the small intestine. These results indicated that the central histaminergic receptors were altered in WP-sensitized mice in a subtype- and region-specific manner, which likely contributed to behavioral changes we observed in these mice. Our study also suggests that altered levels of H3R could be considered during a pharmacological intervention of a neurological disease.

中枢组胺能 H3 受体 (H3R) 已被广泛研究作为各种神经和神经退行性疾病的潜在治疗靶点。尽管在临床前啮齿动物模型中取得了有希望的结果，但临床试验并未提供关于 H3R 拮抗剂对减轻这些疾病的认知和行为症状的益处的确凿证据。在疾病发展过程中，H3R 随时间的异常变化可能会导致药理作用不一致。由于 H3R 参与组胺合成和分泌的反馈抑制，自身受体的表达也可能受到病理状态下组胺水平改变的相互调节。因此，我们研究了牛奶过敏小鼠模型中 H3R 的表达，这种情况与组胺水平升高有关。小鼠在 5 周内对牛乳清蛋白 (WP) 敏感，并检查了大脑中的 H3R 蛋白和转录水平。与假小鼠相比，在 WP 致敏小鼠的不同脑区中观察到 H3R 免疫反应性显着增加。在丘脑/下丘脑区域也发现了升高的 H3R 表达。在该区域和中脑区域，组胺能 H1 受体亚型的表达也增加，但 H2 受体亚型没有增加。与大脑不同，小肠中所有三种组胺能受体均增加。这些结果表明 WP 致敏小鼠的中枢组胺能受体以亚型和区域特异性方式发生改变，这可能导致我们在这些小鼠中观察到的行为变化。