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

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-HT_2A receptor on those effects. Thus, we used male and female, 5-HT_2AR 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-HT_2AR 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.