Fig. 3: Effects of chronic social stress and GPR52 inverse agonist on reward effortful motivation and nucleus accumbens dopamine release.

A Experimental design. Surgery + R + AAVV: stereotactic surgery, recovery, expression of AAV vector; C + OF: conditioning sessions with patch cord attached to optic fibre; SIG: fibre photometry signal test; REV: reward-to-effort valuation test; VEH + REV/CPD + REV: each mouse given 1 REV test with VEH and 1 REV test with GPR52-IA using a counterbalanced cross-over design. For other abbreviations, see Fig. 1. B CSS procedure. C Reward-to-effort valuation (REV) test with fibre photometry. Behavior: Statistical analysis was conducted using 2-way ANOVA with a between-subject factor of group (G) and a within-subject factor of GPR52-IA dose (D). Significant interaction effects were analyzed using Sidak’s test. D Number of operant responses. E Number of gustatory rewards earned. F Final ratio attained. G Operant phase duration i.e., time from 1st until 5th operant response. H Discriminative stimulus (DS) phase duration i.e., time from DS onset until feeder response. NAc DA activity: Statistical analysis was conducted using linear mixed models with fixed effects of group (G), dose (D) and interval or time (T, S) and a random effect of mouse subject. Significant main or interaction effects were analyzed using Sidak’s test. *p < 0.05, ***p < 0.001. I Schematic showing unilateral injection site of AAV GRAB-DA Sensor in NAc, and fibre optic probe implantation directly dorsal to the injection site. J PR 5 operant phase z-scored DA activity following time-normalization using 10 equal intervals. For each mouse, the mean score for PR 5 trials was calculated and data are given as mean ± s.e.m. per group. K PR 5 DS phase z-scored DA activity following time-normalizaion using 10 equal intervals. For each mouse, the mean z-score for PR 5 trials was calculated and data are given as mean ± s.e.m. per group, as well as the overall mean and individual scores per group. L PR 5 feeder phase z-scored DA activity divided into 10 intervals of 0.5 s. For each mouse, the mean score for PR 5 trials was calculated and data are given as mean ± s.e.m per group, as well as the overall mean and individual scores per group. M DS-phase inter-individual relationship between absolute change (GPR52-IA test – VEH test) in NAc DA activity scores and rewards earned in CON mice. N DS-phase inter-individual relationship between absolute change (GPR52-IA test – VEH test) in NAc DA activity scores and rewards earned in CSS mice.