TY - JOUR
T1 - (+)-Catharanthine and (-)-18-methoxycoronaridine induce antidepressant-like activity in mice by differently recruiting serotonergic and norepinephrinergic neurotransmission
AU - Arias, Hugo R.
AU - De Deurwaerdère, Philippe
AU - El-Kasaby, Ali
AU - Di Giovanni, Giuseppe
AU - Eom, Sanung
AU - Lee, Junho H.
AU - Freissmuth, Michael
AU - Chagraoui, Abdeslam
N1 - Funding Information:
This research was supported by grants from the Vienna Science and Technology Fund / WWTF (LSC17-026) (to M.F.), the National Research Foundation (NRF) by Korea government (grant # 2021R1A4A1031220 ) (to J.H.L.), and OVPR Pilot/Seed Grants ( Oklahoma State University Center for Health Sciences) (to H.R.A.). We thank A. Abou-Elazab and F. Steudle for excellent technical assistance with the radioligand binding experiments, Sonia Mason for oocyte harvesting, and Han-Shen Tae for helpful comments on the electrophysiological studies.
Publisher Copyright:
© 2022 Elsevier B.V.
PY - 2023/1/15
Y1 - 2023/1/15
N2 - 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.
AB - 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.
KW - Antidepressant activity
KW - Coronaridine congeners
KW - Mice
KW - Monoamine transporters
KW - Serotonin receptor 3
UR - http://www.scopus.com/inward/record.url?scp=85144553085&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2022.175454
DO - 10.1016/j.ejphar.2022.175454
M3 - Article
C2 - 36549498
AN - SCOPUS:85144553085
SN - 0014-2999
VL - 939
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
M1 - 175454
ER -