(a-b) Left, Representative traces of AMPAR and NMDAR EPSCs recorded from VTA DA neurons 24 hr after i.p. injection of saline or the indicated dose of nicotine. A relatively low dose of nicotine (0.4 mg/kg) induced LTP, shown by an increase in AMPAR/NMDAR ratio in VTA DA neurons (a, Right, P<0.01, n=6,6 saline/0.4 mg/kg nicotine, t10=4.026) from adolescent mice (5 weeks old), but not in those from adult mice (3–5 months old, b, Right, P=0.802, n=6/7/6 saline/0.4 mg/kg nicotine/1.0 mg/kg nicotine, F2,16=9.029). A higher dose of nicotine (1.0 mg/kg) was required to increase the AMPAR/NMDAR ratio in VTA DA neurons from adult mice (b, Right, P<0.05 vs. saline or 1.0 mg/kg nicotine, n=6/7/6 saline/0.4 mg/kg nicotine/1.0 mg/kg nicotine, F2,16=9.029). (c-d) A low dose of nicotine (0.4 mg/kg) reduced p-eIF2α in the VTA of adolescents (c, P<0.05, n=9/5 saline/0.4 mg/kg nicotine, t12=2.479), but not adult mice (d, P=0.5710, n=7/11 saline/0.4 mg/kg nicotine, t16=0.5784). (e) A higher dose of nicotine (1 mg/kg) was required to reduce p-eIF2α in VTA of adult mice (P<0.01, n=11/5 saline/1 mg/kg nicotine, t14=3.428). (f) A low dose of nicotine (0.4 mg/kg) failed to induce LTP in VTA DA neurons from adult WT (Eif2s1S/S) mice (Left, P=0.964, n=5 per group, t8=0.05), but elicited significant LTP in adult Eif2s1S/A mice (Right, P=0.003, n=5 per group, t8=6.73). (g) A low dose of nicotine (0.4 mg/kg) induced LTP in ISRIB-injected adult mice compared to vehicle-injected mice (P<0.001, n=7/7 nicotine+vehicle/nicotine+ISRIB, t12=5.222).