Noribogaine altered intrinsic properties of thalamocortical neurons in a sex-dependent manner

Noribogaine, the primary metabolite of the atypical psychedelic ibogaine, alters thalamic calcium channel gene expression and current density in mice in a sex- and 5-HT2A receptor-dependent manner. A single injection of 10 mg/kg noribogaine increased CACNA1g (T-type) mRNA expression only in wild-type males and knockout females, indicating receptor- and sex-specific effects. The same dose increased CACNA1a (P/Q-type) expression in both sexes and decreased HCN2 expression in females of both genotypes but only in knockout males. Bath-applied noribogaine (50 μM) blocked T-type calcium current density only in knockout females, not in wild-type females or males. Baseline calcium current density was also higher in female ventrobasal neurons, further suggesting sex-dependent differences.

Study at a glance

Abstract

Noribogaine (Noribo) is the primary metabolite from ibogaine, an atypical psychedelic. The main objective of this study was to evaluate the effect of Noribo on thalamic physiology of calcium channels voltage activation and gene expression and the potential involvement of the 5-HT2A receptor on those effects. Thus, we used male and female, 5-HT2AR knockout (KO) and wild type (WT) mice, injected with a single Noribo dose (10 or 40 mg/kg; i.p.) and measured thalamic mRNA expression of T-type and P/Q-type calcium channels, as well as HCN2. For CACNA1g (T- type) we found that Noribo 10 increased gene expression of this channel; however, this effect was observed only in WT males and KO females. This result suggests that the effect of Noribo 10 on gene expression is both receptor- and sex-dependent. For CACNA1a (P/Q type), we found that Noribo 10 increased the mRNA expression in both sexes. For HCN2, we found that Noribo 10 decreased the mRNA expression in WT and KO females but only in KO males. We also investigated calcium channel current density by patch-clamp recordings of thalamocortical ventrobasal neurons after bath application of Noribo (50 μM) in slices obtained from WT and KO 5-HT2AR mice, male and female. We found that bath-applied Noribo blocked T-type calcium current density only in KO females but not in WT. However, in males no blocking effect of Noribo was observed for both genotypes. Also, calcium current density values appeared to be drastically increased in ventrobasal neurons from female mice, another indication of sex-dependent differences.