2. Academic Validation
  3. (+)-Catharanthine and (-)-18-methoxycoronaridine induce antidepressant-like activity in mice by differently recruiting serotonergic and norepinephrinergic neurotransmission

(+)-Catharanthine and (-)-18-methoxycoronaridine induce antidepressant-like activity in mice by differently recruiting serotonergic and norepinephrinergic neurotransmission

  • Eur J Pharmacol. 2023 Jan 15:939:175454. doi: 10.1016/j.ejphar.2022.175454.
Hugo R Arias 1,  Philippe De Deurwaerdère 2,  Ali El-Kasaby 3,  Giuseppe Di Giovanni 4,  Sanung Eom 5,  Junho H Lee 5,  Michael Freissmuth 3,  Abdeslam Chagraoui 6
Affiliations

Affiliations

  • 1 Department of Pharmacology and Physiology, Oklahoma State University College of Osteopathic Medicine, Tahlequah, OK, USA.
  • 2 Centre National de la Recherche Scientifique, Institut des Neurosciences Intégratives et Cognitives d'Aquitaine, UMR, 5287, Bordeaux, France.
  • 3 Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
  • 4 Laboratory of Neurophysiology, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta, Neuroscience Division, School of Biosciences, Cardiff University, Cardiff, United Kingdom.
  • 5 Department of Biotechnology, Chonnam National University, Gwangju, South Korea.
  • 6 Department of Medical Biochemistry, Rouen University Hospital, CHU de Rouen, France; Différenciation et Communication Neuroendocrine, Endocrine et Germinale Laboratory, Institute for Research and Innovation in Biomedicine of Normandy (IRIB), University of Rouen, INSERM 1239, 76000, Rouen, France. Electronic address: abdeslam.chagraoui@univ-rouen.fr.
PMID: 36549498 DOI: 10.1016/j.ejphar.2022.175454
Abstract

The antidepressant-like activity of (+)-catharanthine and (-)-18-methoxycoronaridine [(-)-18-MC] was studied in male and female mice using forced swim (FST) and tail suspension tests (TST). The underlying molecular mechanism was assessed by electrophysiological, radioligand, and functional experiments. The FST results showed that acute administration (40 mg/kg) of (+)-catharanthine or (-)-18-MC induces similar antidepressant-like activity in male and female mice at 1 h and 24 h, whereas the TST results showed a lower effect for (-)-18-MC at 24 h. Repeated treatment at lower dose (20 mg/kg) augmented the efficacy of both congeners. The FST results showed that (-)-18-MC reduces immobility and increases swimming times without changing climbing behavior, whereas (+)-catharanthine reduces immobility time, increases swimming times more markedly, and increases climbing behavior. To investigate the contribution of the serotonin and norepinephrine transporters in the antidepressant effects of (+)-catharanthine and (-)-18-MC, we conducted in vitro radioligand and functional studies. Results obtained demonstrated that (+)-catharanthine inhibits norepinephrine transporter with higher potency/affinity than that for (-)-18-MC, whereas both congeners inhibit Serotonin Transporter with similar potency/affinity. Moreover, whereas no congener activated/inhibited/potentiated the function of serotonin receptor 3A or serotonin receptor 3AB, both increased serotonin receptor 3A receptor desensitization. Depletion of serotonin decreased the antidepressant-like activity of both congeners, whereas norepinephrine depletion only decreased (+)-catharanthine's activity. Our study shows that coronaridine congeners induce antidepressant-like activity in a dose- and time-dependent, and sex-independent, manner. The antidepressant-like property of both compounds involves Serotonin Transporter inhibition, without directly activating/inhibiting serotonin receptors 3, while (+)-catharanthine also mobilizes norepinephrinergic neurotransmission.

Keywords

Antidepressant activity; Coronaridine congeners; Mice; Monoamine transporters; Serotonin receptor 3.

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