Anandamide reduces excitability by preferentially targeting somatic VGSCs via CB1

Abstract

Endogenous cannabinoid signaling is vital for important brain functions and can be modified pharmacologically to treat pain, epilepsy, and posttraumatic stress disorder. Endocannabinoid mediated changes to excitability are predominantly attributed to 2-arachidonoylglycerol at synapses. Here we identify a pathway in the neocortex by which anandamide, the other major endocannabinoid, powerfully inhibits sodium conductances in the soma resulting in a loss of neuronal excitability. This pathway is mediated by the cannabinoid receptor, and its activation results in a decrease of recurrent action potential generation. The synthetic cannabinoid, WIN 55,212-2, also inhibits VGSC currents indicating this pathway is positioned to mediate the actions of exogenous cannabinoids. HighlightsAnandamide (AEA), a major endocannabinoid, indirectly inhibits VGSC currents in neocortical neurons. This prevalent signaling pathway involves AEA activation of CB1 and other G-protein-coupled receptors localized to the intracellular compartment of neurons. CB1 activation by AEA reduces VGSC availability at the soma but not at the axonal compartment suggesting tighter functional coupling between VGSCs and CB1 at the cell body. Cannabinoid action on somatic CB1 inhibits VGSCs with high efficacy, providing a parallel pathway outside of nerve terminals, by which these ligands reduce neuronal excitability in the neocortex.