Integrative Biological Analysis of Histamine Depletion on Neuroinflammation, Dopamine D2 Receptor, and Glutamate in Experimental Tic Disorder

Tic disorder (TD) is a common neurodevelopmental disorder in children. Acute histamine deficiency may be involved in the pathogenesis of TDs. In this study, we demonstrate that histamine depletion exacerbates tic-like behaviors in a rat model of TD. Sprague–Dawley rats were divided into control, TD model, TD plus saline, and TD plus α-fluoromethylhistidine (α-FMH) groups. TD was induced by intraperitoneal iminodipropionitrile, and α-FMH was administered intracerebroventricularly. Behavioral assessments showed that α-FMH treatment significantly increased stereotyped and motor behavior scores compared with TD groups ( p < 0.05). Immunohistochemistry revealed marked microglial activation in the striatum of TD groups, which was exacerbated by histamine deficiency. Striatal IL-6 and TNF-α levels were elevated in all TD groups; IL-6 was significantly higher in the α-FMH group than in TD groups ( p < 0.05). Striatal dopamine receptor D2 (DRD2) expression was also upregulated in TD groups, with the highest levels observed after histamine depletion ( p < 0.05). Liquid chromatography-tandem mass spectrometry result showed that glutamate levels were significantly reduced in the α-FMH group compared to the TD-NaCl group ( p < 0.05). No significant differences were observed in the levels of dopamine, serotonin, or acetylcholine between the TD-NaCl and TD-α-FMH groups. Overall, our findings suggest that acute histamine deficiency aggravates TD-related behaviors by promoting neuroinflammation and upregulating DRD2 expression, highlighting the therapeutic potential of targeting histamine signaling in TD.