The psychoactive compound ibogaine sex-dependently alters the firing rate and afterhyperpolarization of Ih-negative neurons in the mouse ventral tegmental area

Ibogaine, a psychedelic alkaloid from root bark, shows potential for treating depression and substance use disorder, but its cellular effects are unclear. In this study, ibogaine (100 µM) was applied to putative GABAergic neurons in the ventral tegmental area (VTA) from male and female mice. No effects were observed on membrane currents, membrane potential, or spontaneous excitatory postsynaptic currents in either sex. However, ibogaine increased intracellular calcium in both sexes, decreased action potential firing rate in males only, and altered afterhyperpolarization kinetics in females only. At baseline, male VTA neurons fired at higher frequencies than female ones. These sex-differentiated effects may contribute to ibogaine's therapeutic actions.

Study at a glance

Abstract

Depression and substance use disorder affect millions world-wide, and risk factors include sex. Conventional pharmacotherapies show at best a 50 % success rate. Psychedelics exhibit both anti-addictive and anti-depressive properties. One of these, ibogaine, a root bark sourced alkaloid, interacts with receptors implicated in anti-depressive and anti-addictive effects with affinities in the micromolar range. However, cellular actions underlying therapeutic properties are not well understood. In this study, for the first time, we evaluated the cellular effects of 100 µM ibogaine on putative GABAergic neurons of the ventral tegmental area (VTA), as activity of neurons in this nucleus, which includes dopamine neurons, modulates emotion and motivated behavior. Neurons from male (n = 14) and female mice (n = 16) were putatively identified as GABAergic based on lack of I h -current. While we detected no ibogaine induced effects on membrane currents, membrane potential, I-V relationship, rheobase or spontaneous excitatory postsynaptic currents (sEPSCs) in either sex, rises in intracellular calcium were induced in males and females. Further, ibogaine decreased the action potential firing rate in males, but not in females, whereas altered afterhyperpolarization kinetics were noted in females, but not males. Interestingly, at baseline, male I h -negative VTA neurons fired action potentials at a significantly higher frequency than females, however, membrane currents, I-V relationship, membrane potential, rheobase, and sEPSCs did not differ between sexes. Our data suggest that sex-based firing differences exist in a subpopulation of VTA neurons and further, ibogaine induces changes in neuronal signaling in this population that differ between males and females, which could contribute to therapeutic actions.