Coronaridine congeners induce sedative and anxiolytic-like activity in naïve and stressed/anxious mice by allosteric mechanisms involving increased GABAA receptor affinity for GABA
European Journal of Pharmacology. 2023-08-01; 953: 175854
DOI: 10.1016/j.ejphar.2023.175854
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Arias HR(1), De Deurwaerdère P(2), Scholze P(3), Sakamoto S(4), Hamachi I(4), Di
Giovanni G(5), Chagraoui A(6).
Author information:
(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)Department of Pathobiology of the Nervous System, Center for Brain Research,
Medical University of Vienna, Vienna, Austria.
(4)Department of Synthetic Chemistry and Biological Chemistry, Graduate School
of Engineering, Kyoto University, Kyoto, Japan.
(5)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.
(6)Department of Medical Biochemistry, Rouen University Hospital, CHU de Rouen,
France; Laboratory of Neuronal and Neuroendocrine Differentiation and
Communication, Normandie University, UNIROUEN, INSERM U1239, Institute for
Research and Innovation in Biomedicine of Normandy (IRIB) Rouen, France.
Electronic address: .
The sedative and anxiolytic-like activity of two coronaridine congeners,
(+)-catharanthine and (-)-18-methoxycoronaridine (18-MC), was studied in male
and female mice. The underlying molecular mechanism was subsequently determined
by fluorescence imaging and radioligand binding experiments. The loss of
righting reflex and locomotor activity results showed that both
(+)-catharanthine and (-)-18-MC induce sedative effects at doses of 63 and
72 mg/kg in a sex-independent manner. At a lower dose (40 mg/kg), only (-)-18-MC
induced anxiolytic-like activity in naïve mice (elevated O-maze test), whereas
both congeners were effective in mice under stressful/anxiogenic conditions
(light/dark transition test) and in stressed/anxious mice (novelty-suppressed
feeding test), where the latter effect lasted for 24 h. Coronaridine congeners
did not block pentylenetetrazole-induced anxiogenic-like activity in mice.
Considering that pentylenetetrazole inhibits GABAA receptors, this result
supports a role for this receptor in the activity mediated by coronaridine
congeners. Functional and radioligand binding results showed that coronaridine
congeners interact with a site different from that for benzodiazepines,
increasing GABAA receptor affinity for GABA. Our study showed that coronaridine
congeners induce sedative and anxiolytic-like activity in naïve and
stressed/anxious mice in a sex-independent fashion, likely by a
benzodiazepine-independent allosteric mechanism that increases GABAA receptor
affinity for GABA.
Copyright © 2023 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.ejphar.2023.175854
PMID: 37331683 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper