2. Academic Validation
  3. Coronaridine congeners potentiate GABAA receptors and induce sedative activity in mice in a benzodiazepine-insensitive manner

Coronaridine congeners potentiate GABAA receptors and induce sedative activity in mice in a benzodiazepine-insensitive manner

  • Prog Neuropsychopharmacol Biol Psychiatry. 2020 Jul 13;101:109930. doi: 10.1016/j.pnpbp.2020.109930.
Hugo R Arias 1,  Jean Luc Do Rego 2,  Jean Claude Do Rego 2,  Zhenglan Chen 3,  Youssef Anouar 4,  Petra Scholze 5,  Eric B Gonzales 3,  Renqi Huang 3,  Abdeslam Chagraoui 6
Affiliations

Affiliations

  • 1 Department of Pharmacology and Physiology, Oklahoma State University College of Osteopathic Medicine, Tahlequah, OK, USA. Electronic address: hugo.arias@okstate.edu.
  • 2 Behavioral Analysis Platform SCAC, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen Normandy, Rouen, France.
  • 3 Department of Pharmacology and Neuroscience, Institute for Health Aging, University of North Texas Health Science Center at Fort Worth, TX, USA.
  • 4 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.
  • 5 Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
  • 6 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; Department of Medical Biochemistry, Rouen University Hospital, CHU de Rouen, France. Electronic address: abdeslam.chagraoui@univ-rouen.fr.
PMID: 32194202 DOI: 10.1016/j.pnpbp.2020.109930
Abstract

To determine whether (+)-catharanthine induces sedative- or anxiolytic/anxiogenic-like activity in male mice, proper animal paradigms were used. The results showed that (+)-catharanthine induces sedative-like activity in the 63-72 mg/Kg dose range in a flumazenil-insensitive manner, but neither this effect nor anxiolytic/anxiogenic-like activity was observed at lower doses. To determine the underlying molecular mechanism of the sedative-like activity, electrophysiological and radioligand binding experiments were performed with (+)-catharanthine and (±)-18-methoxycoronaridine [(±)-18-MC] on GABAA (GABAARs) and glycine receptors (GlyRs). Coronaridine congeners both activated and potentiated a variety of human (h) GABAARs, except hρ1. (+)-Catharanthine-induced potentiation followed this receptor selectivity (EC50's in μM): hα1β2 (4.6 ± 0.8) > hα2β2γ2 (12.6 ± 3.8) ~ hα1β2γ2 (14.4 ± 4.6) indicating that both α1 and α2 are equally important, whereas γ2 is not necessary. (+)-Catharanthine was >2-fold more potent and efficient than (±)-18-MC at hα1β2γ2. (+)-Catharanthine also potentiated, whereas (±)-18-MC inhibited, hα1 GlyRs with very low potency. Additional [3H]-flunitrazepam competition binding experiments using rat cerebellum membranes clearly demonstrated that these ligands do not bind to the benzodiazepine site. This is supported by the observed activity at hα1β2 (lacking the BDZ site) and similar effects between α1- and α2-containing GABAARs. Our study shows, for the first time, that (+)-catharanthine induced sedative-like effects in mice, and coronaridine congeners potentiated human α1β2γ2, α1β2, and hα2β2γ2, but not ρ1, GABAARs, both in a benzodiazepine-insensitive fashion, whereas only (+)-catharanthine slightly potentiated GlyRs.

Keywords

Coronaridine congeners; GABA(A) receptors; Glycine receptors; Positive allosteric modulators; Sedative activity.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z