Deletion of histamine H2 receptor in VTA dopaminergic neurons of mice induces behavior reminiscent of mania
Shijia Ma,
Qianyi Ma,
Songhui Hu,
Xinlei Mo,
Chenze Zhu,
Xingxian Zhang,
Zetao Jia,
Lingjie Tang,
Lei Jiang,
Yihui Cui,
Zhong Chen,
Weiwei Hu,
Xiangnan Zhang
Affiliations
Shijia Ma
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, Zhejiang 310058, China
Qianyi Ma
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
Songhui Hu
Jinhua Institute of Zhejiang University, Jinhua, Zhejiang 321299, China
Xinlei Mo
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, Zhejiang 310058, China
Chenze Zhu
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, Zhejiang 310058, China
Xingxian Zhang
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, Zhejiang 310058, China
Zetao Jia
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, Zhejiang 310058, China
Lingjie Tang
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, Zhejiang 310058, China
Lei Jiang
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
Yihui Cui
Department of Neurobiology, Department of Neurology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
Zhong Chen
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, Zhejiang 310058, China; Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
Weiwei Hu
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Corresponding author
Xiangnan Zhang
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, Zhejiang 310058, China; Jinhua Institute of Zhejiang University, Jinhua, Zhejiang 321299, China; Corresponding author
Summary: Hyperfunction of the dopamine system has been implicated in manic episodes in bipolar disorders. How dopaminergic neuronal function is regulated in the pathogenesis of mania remains unclear. Histaminergic neurons project dense efferents into the midbrain dopaminergic nuclei. Here, we present mice lacking dopaminergic histamine H2 receptor (H2R) in the ventral tegmental area (VTA) that exhibit a behavioral phenotype mirroring some of the symptoms of mania, including increased locomotor activity and reduced anxiety- and depression-like behavior. These behavioral deficits can be reversed by the mood stabilizers lithium and valproate. H2R deletion in dopaminergic neurons significantly enhances neuronal activity, concurrent with a decrease in the γ-aminobutyric acid (GABA) type A receptor (GABAAR) membrane presence and inhibitory transmission. Conversely, either overexpression of H2R in VTA dopaminergic neurons or treatment of H2R agonist amthamine within the VTA counteracts amphetamine-induced hyperactivity. Together, our results demonstrate the engagement of H2R in reducing VTA dopaminergic activity, shedding light on the role of H2R as a potential target for mania therapy.
