The α2/TLR4 signal in the VTA regulates binge alcohol drinking. pHSVsiTLR4 (A) and pHSVsiLA2 (C) microinjection in the VTA from the P rats reduced binge alcohol drinking on days 3–11 and 3–14 post-surgery, respectively. pHSVsiTLR4- or pHSVsiLA2-infused rats had virtually no alcohol intake on days 3–6 after surgery. Thereafter, drinking increased with time, returning to the original pre-surgery levels on days 12–14 after infusion, respectively. pHSVsiNC did not alter responding for alcohol (A,C) (* p ≤ 0.05). Microinjection of pHSVsiTLR4 and pHSVsiNC (B) or pHSVsiLA2 and pHSVsiNC (D) into the VTA did not alter responding for sucrose. Average responding for (A) 10% alcohol and (B) 3% sucrose after a 90-min operant session prior to and for 10 days following the infusion of pHSVsiTLR4 or pHSVsiNC (scrambled amplicon) into the VTA. Significant Treatment x Day effects were seen following pHSVsiTLR4 treatment for alcohol drinking (F(20,80) = 3.957, p < 0.001) but not for sucrose drinking (F(10,40) = 0.761, p = 0.664). Significant Treatment x Day effects were also seen following pHSVsiLA2 treatment for alcohol drinking (F(12,60) = 4.839, p <0.001) (C) but not for sucrose drinking (F(12,48) = 1.288, p = 0.257) (D).