Simultaneous Antagonism at H3R/D2R/D3R Reduces Autism-like Self-Grooming and Aggressive Behaviors by Mitigating MAPK Activation in Mice
Nermin Eissa, M. Awad, Shilu Deepa Thomas, Karthikkumar Venkatachalam, Petrilla Jayaprakash, Sicheng Zhong, Holger Stark, Bassem Sadek
Abstract
Dysregulation in brain neurotransmitters underlies several neuropsychiatric disorders, e.g., autism spectrum disorder (ASD). Also, abnormalities in the extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway pave the way for neuroinflammation, neurodegeneration, and altered learning phenotype in ASD. Therefore, the effects of chronic systemic administration of the multiple-targeting antagonist ST-713 at the histamine H3 receptor (H3R) and dopamine D2/D3 receptors (D2/D3R) on repetitive self-grooming, aggressive behaviors, and abnormalities in the MAPK pathway in BTBR T + Itpr3tf/J (BTBR) mice were assessed. The results showed that ST-713 (2.5, 5, and 10 mg/kg, i.p.) mitigated repetitive self-grooming and aggression in BTBR mice (all p < 0.05), and the ameliorative effects of the most promising dose of ST-713 (5 mg/kg, i.p.) on behaviors were completely abrogated by co-administration of the H3R agonist (R)-α-methylhistamine or the anticholinergic drug scopolamine. Moreover, the elevated levels of several MAPK pathway proteins and induced proinflammatory markers such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and IL-6 were significantly suppressed following chronic administration of ST-713 (5 mg/kg, i.p.) (all p < 0.01). Furthermore, ST-713 significantly increased the levels of histamine and dopamine in hippocampal tissue of treated BTBR mice (all p < 0.01). The current observations signify the potential role of such multiple-targeting compounds, e.g., ST-713, in multifactorial neurodevelopmental disorders such as ASD.