Cocaine Exposure Enhances the Activity of Ventral Tegmental Area Dopamine Neurons via Calcium-Impermeable NMDARs

Abstract

We show that cocaine-evoked synaptic changes onto ventral tegmental area (VTA) dopamine (DA) neurons leads to long-lasting increases in their burst firing. This increase is due to impaired function of Ca²⁺-activated small-conductance calcium-dependent potassium (SK) channels; SK channels regulate firing of VTA DA neurons, but this regulation was absent after cocaine. Cocaine exposure drives the insertion of GluN3A-containing NMDARs onto VTA DA neurons. These receptors are Ca²⁺-impermeable, and thus SK channels are not efficiently activated by synaptic activity. In GluN3A knock-out mice, cocaine did not alter SK channel function or VTA DA neuron firing. This study directly links synaptic changes to increased intrinsic excitability of VTA DA neurons after cocaine, and explains how acute cocaine induces long-lasting remodeling of the mesolimbic DA system.