Anxiolytic and antidepressant-like activities of the novel and potent non-imidazole histamine H₃ receptor antagonist ST-1283

Abstract

Previous studies have suggested a potential link between histamine H₃ receptors (H₃R) signaling and anxiolytic-like and antidepressant-like effects. The aim of this study was to investigate the acute effects of ST-1283, a novel H₃R antagonist, on anxiety-related and depression-related behaviors in comparison with those of diazepam and fluoxetine. The effects of ST-1283 were evaluated using the elevated plus maze test, open field test, marbles burying test, tail suspension test, novelty suppressed feeding test, and forced swim test in male C57BL/6 mice. The results showed that, like diazepam, ST-1283 (7.5 mg/kg) significantly modified all the parameters observed in the elevated plus maze test. In addition, ST-1283 significantly increased the amount of time spent in the center of the arena without altering general motor activity in the open field test. In the same vein, ST-1283 reduced the number of buried marbles as well as time spent digging in the marbles burying test. The tail suspension test and forced swim test showed that ST-1283 was able to reduce immobility time, like the recognized antidepressant drug fluoxetine. In the novelty suppressed feeding test, treatment with ST-1283 decreased latency to feed with no effect on food intake in the home cage. Importantly, pretreatment with the H₃R agonist R-α-methylhistamine abrogated the anxiolytic and antidepressant effects of ST-1283. Taken together, the present series of studies demonstrates the novel effects of this newly synthesized H₃R antagonist in a number of preclinical models of psychiatric disorders and highlights the histaminergic system as a potential therapeutic target for the treatment of anxiety-related and depression-related disorders.

Keywords:

• anxiety
• depression
• histamine
• H₃ receptor
• R-α-methylhistamine
• ST-1283

Acknowledgments

This work was supported by grants from the United Arab Emirates University (to AB and BS) and by the EU COST Actions (BM0806, BM1007, CM1103, and CM1207), Hesse LOEWE Schwerpunkte Fh-TMP, OSF and NEFF, the Else KrönerStiftung, TRIP, and the Deutsches Konsortium für Translationale Krebsforschung DKTK (to HS). The funders played no part in the study design, or in the collection, analysis, or interpretation of the data, writing of the report, or the decision to submit the paper for publication. The authors would like to thank Dr Essam Emam (Department of Medicine, Tawam Hospital, Al Ain, United Arab Emirates) for providing the diazepam used in this study, Mohamed Elwasila and Mohamed Shafiullah for their technical assistance, and Dr Mahmoud Hag Ali from the Central Animal Facility for his advice regarding veterinary care. The authors would also like to acknowledge Professor Keith Bagnall for his critical and careful proofreading.

Disclosure

The authors have no financial interests that might be perceived to influence the results or the discussion reported in this article.