Time-dependent regulation of NMDAR-mediated synaptic transmission in NAc core MSNs during withdrawal from extended-access cocaine self-administration. A, Training data for rats used in electrophysiological experiments. Male rats self-administered saline (n = 41) or cocaine (n = 92) 6 h/day for 10 consecutive days. B, Whole-cell patch-clamp recordings of NMDAR-mediated EPSCs were performed in NAc core MSNs of saline rats (23 cells/15 rats) on or after WD 16 and from cocaine rats (29 cells/22 rats) between WD39 and WD68. These saline and/or cocaine data are reproduced for comparative purposes in Figures 2–4. Left, I–V plot of response amplitudes at different membrane holding potentials. Right, Summary data at 40 mV and –80 mV holding potentials (individual data points and mean ± SEM are shown). Cocaine cells exhibit increased response amplitudes at –80 and 40 mV compared with saline cells. –80 mV: saline versus cocaine, unpaired t test, t(50) = 3.58, p = 0.0008; 40 mV: saline versus cocaine, unpaired t test, t(50) = 4.394, p < 0.0001; *p < 0.05. C, Representative traces of saline (black) and cocaine WD > 39 (red) cells at 40 mV and –80 mV. Calibration: 40 mV: 50 pA × 250 ms; –80 mV: 20 pA × 250 ms. D, I–V plots of NMDAR-mediated synaptic transmission of cocaine cells at different withdrawal time points: WD1-WD3 (15 cells/7 rats), WD4 (16 cells/8 rats), WD5 (11 cells/7 rats), and WD13-WD20 (15 cells/12 rats). E, Response amplitudes for saline and each cocaine withdrawal group. ANOVA was used to analyze data for each holding potential, with comparisons conducted using Holm–Sidak post hoc tests. 40 mV: F(5,102) = 7.918, p < 0.0001; saline versus WD5, p = 0.0226; saline versus WD13-WD20, p = 0.0266; saline versus WD > 39, p < 0.0001; WD1-WD3 versus WD5, p = 0.0266; WD1-WD3 versus WD13-WD20, p = 0.0298; WD1-WD3 versus WD > 39, p = 0.0002; WD4 versus WD > 39, p = 0.0266. –80 mV: F(5,102) = 7.670, p < 0.0001; saline versus WD13-WD20, p = 0.0178; saline versus WD > 39, p = 0.001; WD1-WD3 versus WD > 39, p = 0.0365; WD4 versus WD13-WD20, p = 0.001; WD4 versus WD > 39, p < 0.0001; *p < 0.05.