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Ibogalogs improve spatial and recognition memory in rodents through a mechanism involving 5-HT2A receptor activation-enhanced NMDA receptor activity in hippocampal pyramidal CA1 neurons.

Abdeslam Chagraoui,Luis A Haro Santillan,Renata Bocian,Sarah J. Cohen,Yuliana E Sarmiento Ruíz,Marli Knox,Paulina Kaźmierska-Grębowska,Weronika Zimoń,Robert W. Stackman,Jorge Flores-Hernández,Hugo R. Arias

Published 2025 in Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

ABSTRACT

This study evaluated the effects of ibogalogs on recognition and spatial memory in rodents, focusing on potential hippocampal mechanisms. The Barnes maze study demonstrated that ibogaminalog (DM506) and ibogainalog (IBG) improved short- (30 min) and long-term (24 and 72 h) spatial memory in mice, whereas tabernanthalog (TBG) showed less efficacy. The novel object recognition task (NORT) results showed that DM506, but not TBG or IBG, enhanced long-term (24 h) recognition memory. Serotonin type 2 A and 2 C receptors (5-HT2A/2C Rs) involvement, in these effects was demonstrated by their partial inhibition using the selective antagonists volinanserin and SB242084, respectively. Furthermore, in vitro and in vivo electrophysiological studies have demonstrated a mechanistic link between ibogalogs and hippocampal function. TBG (1-5 µM) and DM506 (0.6 µM) significantly increased theta rhythm power and amplitude in CA1. In contrast, volinanserin (alone) and higher concentrations of DM506 (0.8-1 µM) significantly decreased these parameters. In acutely dissociated CA1 pyramidal neurons, DM506 enhanced the N-methyl-D-aspartate receptor (NMDAR)-mediated current peak amplitude (EC50 = 20 ± 15 nM), which was blocked by Mg2 + , indicating NMDAR involvement. Interestingly, TBG had a lower effect than that of DM506 at high concentrations. Importantly, selective 5-HT2A/2CR antagonists inhibited the promnesic effects of ibogalogs, NMDAR enhancement, and theta power increase, indicating the importance of these receptor subtypes. These findings suggest that ibogalogs enhance short- and long-term memory in rodents via 5-HT2A/2CR activation, with a clearer role for 5-HT2ARs in modulating NMDAR activity and theta rhythm in hippocampal CA1 neurons, key processes in memory and attention.

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