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

Potentiation of excitatory inputs onto dopamine neurons of the ventral tegmental area (VTA) induced by cocaine exposure allows remodeling of the mesocorticolimbic circuitry, which ultimately drives drug-adaptive behavior. This potentiation is mediated by changes in NMDAR and AMPAR subunit composition. It remains unknown how this synaptic plasticity affects the activity of dopamine neurons. Here, using rodents, we demonstrate that a single cocaine injection increases the firing rate and bursting activity of VTA dopamine neurons, and that these increases persist for 7 d. This enhanced activity depends on the insertion of low-conductance, Ca2+-impermeable NMDARs that contain GluN3A. Since such receptors are not capable of activating small-conductance potassium channels, the intrinsic excitability of VTA dopamine neurons increases. Activation of group I mGluRs rescues synaptic plasticity and restores small-conductance calcium-dependent potassium channel function, normalizing the firing activity of dopamine neurons. Our study characterizes a mechanism linking drug-evoked synaptic plasticity to neural activity, revealing novel targets for therapeutic interventions. SIGNIFICANCE STATEMENT: 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.