Figure 5.

Model of altered Ca²⁺-SK channel feedback following cocaine. Schematic of a VTA DA neuron 24 h after saline treatment (top) and cocaine treatment (bottom). 1. Under baseline conditions, excitatory transmission is mediated by GluN3A-lacking NMDA receptors, which are Ca²⁺-permeable and sensitive to Mg²⁺ block at negative resting membrane potential. After cocaine, the switch in NMDA subunit composition to GluN3A-containing NMDA receptors, which are quasi-Ca²⁺-impermeable and are insensitive to Mg²⁺ block. 2. Under basal conditions Ca²⁺ influx through NMDARs binds to calmodulin through calmodulin-binding domains on SK channels. 3. Ca²⁺ binding induces a conformational change in the SK channel. 4. Upon activation, K⁺ efflux through the SK channel contributes to I_AHP potential of the membrane. 5. At hyperpolarized potentials, NMDARs are subject to Mg²⁺ block and no longer flux Ca²⁺. 6. The net result is an increase in firing rate after cocaine, due to insertion of GluN3A-containing NMDARs.