The psychoplastogens ibogaminalog and ibogainalog induce antidepressant-like activity in naïve and depressed mice by mechanisms involving 5-HT2A receptor activation and serotonergic transmission

The antidepressant-like activity of two psychoplastogens, ibogainalog (IBG) and ibogaminalog (DM506), was studied in naïve mice using the forced swim test (FST) and tail suspension test (TST). The behavioral results showed that a single administration of 25 mg/kg DM506 or 10 mg/kg IBG induced antidepressant-like activity in naïve mice in a volinanserin-sensitive manner that persisted for 72 h. Similar results were observed using the chronic immobilization stress (CIS) test, in which depression symptoms were reduced for 48 h. To assess the contribution of serotonergic and/or norepinephrinergic neurotransmission, serotonin (5-HT) and norepinephrine (NE) levels were depleted. The reduction in 5-HT levels, but not NE levels, inhibited the antidepressant-like activity of ibogalogs, suggesting that serotonergic transmission may play a more significant role than norepinephrinergic transmission. Concurrently, DM506, IBG, and TBG (derived from tabernanthine) inhibited monoamine transporters with the following order of selectivity: SERT > NE transporter > dopamine transporter. The IBG exhibited the highest selectivity for SERT. Only TBG inhibited monoamine oxidase A activity, indicating its relatively minor role. Radioligand and functional assays showed that all ibogalogs bind to the 5-HT2 receptor subfamily (DM506 > IBG > TBG) and fully activate 5-HT2A/2C receptors with similar potency in the nM range. However, they act as competitive antagonists of the 5-HT2B receptor, with DM506 as an exception, exhibiting partial but potent agonist activity. In conclusion, ibogalogs induce acute and sustained antidepressant-like activity in naïve and depressed mice through mechanisms involving 5-HT2A receptor activation and serotonergic transmission.