Coronaridine congeners induce sedative and anxiolytic-like activity in naïve and stressed/anxious mice by allosteric mechanisms involving increased GABAA receptor affinity for GABA

Arias, Hugo R., De Deurwaerdère, Philippe, Scholze, Petra, Sakamoto, Seiji, Hamachi, Itaru, Di Giovanni, Giuseppe and Chagraoui, Abdeslam 2023. 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 953 , 175854. 10.1016/j.ejphar.2023.175854 Item availability restricted.

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Elsevier
ISSN:	0014-2999
Date of First Compliant Deposit:	11 August 2023
Date of Acceptance:	12 June 2023
Last Modified:	17 Nov 2023 15:47
URI:	https://orca.cardiff.ac.uk/id/eprint/161577

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