PMID- 36613969 OWN - NLM STAT- MEDLINE DCOM- 20230110 LR - 20230308 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 24 IP - 1 DP - 2022 Dec 28 TI - Simultaneous Antagonism at H3R/D2R/D3R Reduces Autism-like Self-Grooming and Aggressive Behaviors by Mitigating MAPK Activation in Mice. LID - 10.3390/ijms24010526 [doi] LID - 526 AB - 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)-alpha-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-alpha), interleukin-1beta (IL-1beta), 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. FAU - Eissa, Nermin AU - Eissa N AD - Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates. AD - Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates. AD - Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi P.O. Box 59911, United Arab Emirates. FAU - Awad, Mohamed Al AU - Awad MA AUID- ORCID: 0000-0003-2362-1849 AD - Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates. AD - Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates. FAU - Thomas, Shilu Deepa AU - Thomas SD AUID- ORCID: 0000-0003-0778-8833 AD - Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates. AD - Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates. FAU - Venkatachalam, Karthikkumar AU - Venkatachalam K AUID- ORCID: 0000-0002-4290-7239 AD - Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates. AD - Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates. FAU - Jayaprakash, Petrilla AU - Jayaprakash P AD - Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates. AD - Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates. FAU - Zhong, Sicheng AU - Zhong S AD - Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Dusseldorf, Universitaetsstr. 1, 40225 Dusseldorf, Germany. FAU - Stark, Holger AU - Stark H AUID- ORCID: 0000-0003-3336-1710 AD - Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Dusseldorf, Universitaetsstr. 1, 40225 Dusseldorf, Germany. FAU - Sadek, Bassem AU - Sadek B AUID- ORCID: 0000-0002-0320-1487 AD - Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates. AD - Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates. LA - eng GR - 12M099/United Arab Emirates University/ GR - 31R233/United Arab Emirates University/ PT - Journal Article DEP - 20221228 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Receptors, Histamine H3) RN - VTD58H1Z2X (Dopamine) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) SB - IM MH - Mice MH - Animals MH - *Autistic Disorder/genetics MH - *Autism Spectrum Disorder/drug therapy MH - *Receptors, Histamine H3/metabolism MH - Grooming MH - Dopamine/pharmacology MH - Mice, Inbred C57BL MH - Mice, Inbred Strains MH - Extracellular Signal-Regulated MAP Kinases MH - Aggression MH - Disease Models, Animal PMC - PMC9820264 OTO - NOTNLM OT - BTBR mice OT - MAPK proteins OT - aggressive behaviors OT - autistic spectrum disorder OT - dopamine OT - dopamine D2/D3R antagonist OT - histamine OT - histamine H3 receptor antagonist OT - neuroinflammation OT - repetitive self-grooming COIS- The authors declare no conflict of interest. EDAT- 2023/01/09 06:00 MHDA- 2023/01/11 06:00 PMCR- 2022/12/28 CRDT- 2023/01/08 01:23 PHST- 2022/11/23 00:00 [received] PHST- 2022/12/19 00:00 [revised] PHST- 2022/12/20 00:00 [accepted] PHST- 2023/01/08 01:23 [entrez] PHST- 2023/01/09 06:00 [pubmed] PHST- 2023/01/11 06:00 [medline] PHST- 2022/12/28 00:00 [pmc-release] AID - ijms24010526 [pii] AID - ijms-24-00526 [pii] AID - 10.3390/ijms24010526 [doi] PST - epublish SO - Int J Mol Sci. 2022 Dec 28;24(1):526. doi: 10.3390/ijms24010526.