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-HT_2A receptor (5-HT_2AR) in mice. In that regard, 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.). After 30 min., locomotor activity was recorded followed by mRNA measurements by qPCR (immediate early genes; IEG, glutamate receptors, and 5-HT_2AR 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-HT_2AR 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 5HT_2AR blunted noribo-mediated responses to NMDA synaptic transmission.

Reversible protein acetylation controlled by histone deacetylases (HDACs) regulates neuronal gene expression and, increasingly, membrane physiology. We previously showed that pedunculopontine nucleus (PPN) gamma-band oscillations require class IIa HDAC activity, whereas class I inhibition was comparatively benign for that readout. Whether systemic HDAC inhibition acts uniformly across the forebrain, and across different neuronal nuclei, is unknown. Here we administered acute single systemic doses of the class I inhibitor MS275 (entinostat) and the class IIa inhibitor MC1568 to mice and performed whole-cell recordings in two functionally distinct, anatomically unconnected structures: medial prefrontal cortex (mPFC) and the ventrobasal complex (VB) of the thalamus. In mPFC pyramidal neurons we assessed short-term plasticity using paired-pulse stimulation and quantifying paired-pulse ratio (PPR); in VB neurons we quantified action-potential amplitude and the maximal rate of rise of the spike from phase-plot analysis. MS275 shifted PPR from facilitation toward depression on both mPFC and VB glutamatergic transmission, a significant change relative to vehicle, while MC1568 produced an intermediate, non-significant effect. In addition, MS275 reduced action-potential amplitude and markedly decreased the maximal rate of rise (dV/dt) of the spike in VB neurons. Thus, class I HDAC inhibition predominantly affected presynaptic glutamate release whilst affecting intrinsic properties of thalamocortical neurons. These results suggest that the consequences of systemic HDAC inhibition are class- and region-specific.