Figure 3. Chemogenetic activation of the LC ➔ LH pathway blunts binge-like ethanol intake in TH-ires-cre mice.

LH-targeted CNO, but not vehicle, blunts binge-like ethanol intake in TH-ires-cre mice expressing hM3Dq DREADD (A; n=10) but not control AAV (C; n=6) in LC. LH-targeted CNO, but not vehicle, blunts BECs in TH-ires-cre mice expressing hM3Dq DREADD (B; n=10) but not control AAV (D; n=5) in LH. In TH-ires-cre mice with a history of ethanol consumption in the DID paradigm, LH-targeted CNO failed to alter intake of a 3% sucrose solution in mice expressing hM3Dq DREADD (E; n=10) or control AAV (F; n=5) in the LC. In the OFT, LH-targeted CNO failed to alter total distance travelled in the 2-h test regardless of virus condition (G & H), though distance travelled in the first 5 minutes of testing as increased among mice expressing hM3Dq (G inset). Pathway activation in hM3D(Gq) treated mice increased time spent in chamber center during the first 5 minutes of testing (I inset), but we failed to observe a significant main effect of pathway activation on center time across the 2-h test (I). CNO alone failed to alter center time in control virus treated mice (J). Heat map of hM3Dq DREADD virus spread, with darker areas indicating similar virus expression across mice and lighter areas indicating less-common expression patterns (K). Approximate cannula placements at various anterior-posterior positions within the LH indicated by black dots (L). (M) Further analyses of ethanol intake data indicated that chemogenetic activation of LC TH+ neurons blunted intake in mice with no significant differences between mice with High baseline ethanol intake (upper 50% of a median-split) versus mice with Low baseline intake (lower 50% of a median-split). Data collapsed across sexes due to absence of statistically significant sex differences across experiments. All values indicate mean ± SEM. * indicates p<0.05 in paired t-test.