Figure 3. Cell type-selective blockade of cocaine-induced synaptic plasticity in dopamine neurons.
(A) Schematic diagram of cocaine-induced synaptic plasticity. Cocaine increases extracellular dopamine which leads to NMDA-R dependent upregulation of synaptic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. It is unclear if this is through NMDA receptors on DA neurons or through NMDA-R on other cell types that may have a subsequent effect on AMPA-R activity in DA neurons. (B) Confocal images of ventral tegmental area (VTA) brain slices from dopamine transporter Cre (Slc6a3Cre) mice transduced with Cre-dependent viruses expressing either PLE and mCherry (left) or EGFP (right) on opposite sides of the VTA. Scale, 50 μm. (C) Experimental protocol where VTA-containing brain slices were incubated with CM-MK801 for 40 min, followed by addition of cocaine for 10 min and washout. 3–5 hr later, miniature excitatory postsynaptic AMPA-R currents (mEPSCs) in DA neurons expressing either GFP (PLE−) or mCherry (PLE+) were recorded. Inset, images of (left) patch pipette recording from dopamine neuron (right) expressing mCherry and PLE. Scale, 5 μm. (D) For brain slices treated with CM-MK801, AMPAR-mediated mEPSC amplitude was increased in PLE− VTA DA neurons following cocaine treatment. Synaptic potentiation was blocked in PLE+ neurons treated with cocaine, and the mEPSC amplitude was similar to that in PLE+ or PLE− neurons that were not exposed to cocaine. (E) mEPSC frequency was unaffected by cocaine or CM-MK801. (F) Resting neuronal membrane potential (Vm), input resistance (Rin), and membrane capacitance (Cm) were not changed by expression of PLE, or exposure to cocaine and CM-MK801. Data is represented as mean and error bars indicate s.e.m.