PubMed:
Neuropharmacology. 2026 Nov 3:111253. doi: 10.1016/j.neuropharm.2026.111253. Online ahead of print.
ABSTRACT
Cannabidiol (CBD) exerts potent anxiolytic effects, yet the brain nuclei and molecular targets mediating these effects remain poorly defined. Here, using behavioral and electrophysiological approaches, we identify glycine receptors (GlyRs) in the lateral habenula (LHb) as a key mediator of CBD’s anxiolytic action. Pharmacological blockade of LHb GlyRs by intra-LHb strychnine induces robust anxiety-like behaviors, whereas both systemic and intra-LHb CBD administration alleviate them. However, CBD failed to reverse the anxiety-like behaviors induced by prior intra-LHb strychnine. Consistent with this, whole-cell recordings reveal strychnine-sensitive tonic currents in LHb neurons, implicating extrasynaptic GlyRs. To define the responsible subtype, we generated conditional knockouts and found that deletion of α3-containing GlyRs (GlyRα3 cKO), but not α1-containing GlyRs (GlyRα1 cKO), in the LHb produces robust anxiety-like behaviors. Notably, CBD exerts no anxiolytic effect in GlyRα3 cKO mice, establishing GlyRα3 as the subtype required for CBD’s action. Furthermore, CBD elevates the action potential threshold and reduces the firing rate of LHb neurons, effects abolished in GlyRα3 cKO mice, thereby linking GlyRα3 activation to reduced LHb excitability. Collectively, these findings identify LHb GlyRα3 as a novel molecular target underlying CBD’s anxiolytic effects and support CBD as a promising therapeutic for anxiety disorders.
PMID:42977215 | DOI:10.1016/j.neuropharm.2026.111253
