5-HT2A Receptor Knockout Mice Show Sex-Dependent Differences following Acute Noribogaine Administration.

Noribogaine, the primary metabolite of ibogaine, produces sexually dimorphic effects in mice, with some responses depending on the 5-HT2A receptor. A single 40 mg/kg dose reduced locomotion in male but not female wild-type mice. Gene expression of immediate early genes and glutamate receptors differed by sex and genotype. 5-HT2A receptor mRNA increased in the medial prefrontal cortex after noribogaine at 10 mg/kg in males and 40 mg/kg in females. Electrophysiology showed that 40 mg/kg reduced NMDA-mediated postsynaptic current density in layer V pyramidal neurons of the medial prefrontal cortex only in male wild-type mice, an effect absent in 5-HT2A receptor knockout males and all females. The genetic removal of the 5-HT2A receptor blunted noribogaine's effects on NMDA synaptic transmission.

Study at a glance

Abstract

Noribogaine (noribo) is the primary metabolite from ibogaine, an atypical psychedelic alkaloid isolated from the root bark of the African shrub Tabernanthe iboga. The main objective of this study was to test the hypothesis that molecular, electrophysiological, and behavioral responses of noribo are mediated by the 5-HT2A receptor (5-HT2AR) in mice. In that regard, 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.). After 30 min., locomotor activity was recorded followed by mRNA measurements by qPCR (immediate early genes; IEG, glutamate receptors, and 5-HT2AR levels) and electrophysiology recordings of layer V pyramidal neurons from the medial prefrontal cortex. Noribo 40 decreased locomotion in male, but not female WT. Sex and genotype differences were observed for IEG and glutamate receptor expression. Expression of 5-HT2AR mRNA increased in the mPFC of WT mice following Noribo 10 (males) or Noribo 40 (females). Patch-clamp recordings showed that Noribo 40 reduced the NMDA-mediated postsynaptic current density in mPFC pyramidal neurons only in male WT mice, but no effects were found for either KO males or females. Our results highlight that noribo produces sexually dimorphic effects while the genetic removal of 5HT2AR blunted noribo-mediated responses to NMDA synaptic transmission.