Cell-Autonomous Excitation of Midbrain Dopamine Neurons by Endocannabinoid-Dependent Lipid Signaling

Abstract

The major endocannabinoid in the mammalian brain is the bioactive lipid 2-arachidonoylglycerol (2-AG). The best-known effects of 2-AG are mediated by G-protein-coupled cannabinoid receptors. In principle, 2-AG could modify neuronal excitability by acting directly on ion channels, but such mechanisms are poorly understood. Using a preparation of dissociated mouse midbrain dopamine neurons to isolate effects on intrinsic excitability, we found that 100 nM 2-AG accelerated pacemaking and steepened the frequency-current relationship for burst-like firing. In voltage-clamp experiments, 2-AG reduced A-type potassium current (I_A) through a cannabinoid receptor-independent mechanism mimicked by arachidonic acid, which has no activity on cannabinoid receptors. Activation of orexin, neurotensin, and metabotropic glutamate G_q/11-linked receptors mimicked the effects of exogenous 2-AG and their actions were prevented by inhibiting the 2-AG-synthesizing enzyme diacylglycerol lipase α. The results show that 2-AG and related lipid signaling molecules can directly tune neuronal excitability in a cell-autonomous manner by modulating I_A.