Figure 4. Reduced p-eIF2α-mediated translation enhances the persistence of cocaine-induced LTP and rectification in VTA DA neurons.
(a–c) Cocaine-induced increase in AMPAR/NMDAR ratios lasted only five days in control mice (5d, p<0.05, n = 5/5/5 saline/5d cocaine/14d cocaine, F2,12 = 8.38), but persisted at least 14 days in ISRIB-injected mice (5d, p<0.05; 14d, p<0.05, n = 5/5/5 saline/5d cocaine/14d cocaine, F2,12 = 6.40). (d–e) Representative AMPAR EPSCs traces and AMPAR/NMDAR ratios. I-V plots (f–g) and summaries (h) illustrate that cocaine-induced rectification lasts only five days in vehicle-injected mice (5d, p<0.05, n = 4/4/4 saline/5d cocaine/14d cocaine, F2,9 = 7.12), but persists at least 14 days in ISRIB-injected mice (5d, p<0.05; 14d, p<0.05, n = 4/4/4 saline/5d cocaine/14d cocaine, F2,9 = 7.53). (i) Knocking down OPHN1 in the VTA prolonged cocaine-induced LTP to 14 days after cocaine withdrawal (p<0.001, n = 9/8 control-shRNA/Ophn1-shRNA, t15 = 4.986).