Simultaneous Antagonism at H3R/D2R/D3R Reduces Autism-like Self-Grooming and Aggressive Behaviors by Mitigating MAPK Activation in Mice

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.

Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder

“…Several histological observations and MRI assessments support separated hippocampal commissure and increased hippocampal volume in BTBR mice relative to controls, and these anatomical changes may underlie their behavioral phenotypes ( 243 – 246 ). Moreover, the hippocampus has lower 5-HT, acetylcholine, dopamine, and histamine content in the BTBR animals than in the C57BL/6J strain ( 246 – 248 ). In particular, immunofluorescent labeling of 5-HT transporter axons revealed a reduction in the density of innervation to the hippocampus in BTBR mice ( 246 ).…”

“…In particular, immunofluorescent labeling of 5-HT transporter axons revealed a reduction in the density of innervation to the hippocampus in BTBR mice ( 246 ). Premature changes in hippocampal neuronal excitability, involving elevated ERK signaling ( 248 ) and increased GABAergic neurotransmission ( 249 ) during neonatal development in the BTBR mice, may also contribute to the high susceptibility to epilepsy and aggressive behaviors observed in these mice ( 248 , 250 ). As for adult and aged BTBR animals, significant reductions in mRNA or protein levels of BDNF, as well as neurogenesis in the hippocampus have previously been reported ( 241 , 245 , 250 ).…”

“…Thus, selective H3R antagonists can improve the cognitive impairment in ASD. It is evident from the observation that the administration of histamine H3R antagonists ST-2223 ( 247 ) and ST-713 ( 248 ) significantly elevated the levels of histamine, dopamine, and acetylcholine in the hippocampal tissue of BTBR mice with anxiolytic-like effects. Administration of ciproxifan could improve the VPA-induced LTP decline in the CA1 area and hippocampus-dependent learning and memory capacity ( 202 ).…”

The Potent and Selective Histamine H3 Receptor Antagonist E169 Counteracts Cognitive Deficits and Mitigates Disturbances in the PI3K/AKT/GSK-3β Signaling Pathway in MK801-Induced Amnesia in Mice

“…Importantly, in 2016, the European Medical Agency approved a marketing application for pitolisant (WakixR) as an orphan drug for narcolepsy and in 2021 for obstructive sleep apnea (OzawadeR) [ 8 ]. Recently, cognitive disorders have been related to neuroinflammation, as this immunogenic response in the brain occurs mainly due to microglia which are resident macrophages of the CNS with various essential functions, including neuronal well-being and normal function and neuroprotection [ 9 , 10 ]. As a result, ongoing activation of the innate and adaptive immune system is a key factor in the development of several dementias and AD [ 11 , 12 , 13 ].…”