Ibogalogs induce antiseizure activity in rodents by a mechanism involving 5-HT2A/2C receptor activation with a major role of 5-HT2A receptors in the hippocampal CA3 subfield

The antiseizure properties of ibogalogs, including ibogaminalog (DM506), ibogainalog (IBG), and nor-IBG, were assessed in rodents using the pentylenetetrazol (PTZ)-induced seizure test. The behavioral findings indicated that ibogalogs exhibited mild acute antiseizure effects in mice, with endpoint- and time window-dependent differences between the compounds. The antiseizure effect was suppressed by volinanserin and SB242084, consistent with the involvement of 5-HT 2A and 5-HT 2C receptors. The antiseizure activity after repeated administration (7 and 14 days) of subthreshold doses of nor-IBG (3 mg/kg) or DM506 (5 mg/kg) was higher than that after acute treatment, indicating augmented efficacy. Subthreshold doses of DM506 and nor-IBG restored the impact of PTZ on monoamine levels in hippocampal tissue following repeated administration, but not after a single dose. Additionally, the influence of ibogalogs was evaluated on epileptiform discharges induced by kainic acid (KA) in the CA3 region of the hippocampus. The results showed that nor-IBG and DM506 decreased epileptiform discharges in a concentration-dependent manner. Nor-IBG activity was inhibited by volinanserin, supporting a role for the 5-HT 2A R. Functional studies have shown that ibogalogs are more potent agonists at 5-HT 2A/2C Rs than at 5-HT 1A/1B Rs, supporting a role for 5-HT 2A/2C Rs. In conclusion, repetitive treatment with ibogalogs induced antiseizure activity in mice through 5-HT 2A/2C R activation, accompanied by normalization of PTZ-induced alterations in hippocampal monoamines. In the hippocampal CA3 subfield, ibogalogs reduced KA-induced epileptiform discharges, where nor-IBG activity was mediated by 5-HT 2A R activation.