Extended Data Fig. 10: Effects of MAP on locomotor activity and dopamine concentrations.

a, Experimental schedule for locomotor sensitization by MAP (1 mg kg⁻¹). b, Representative locomotion traces during sensitization test 0–15 min after administration. Scale bar, 10 cm. c, Plots of average distances travelled in sensitization tests against time. n = 7 (control) and 7 mice (MAP). d, Plots of average distances travelled by control mice (n = 7) and MAP-treated mice (n = 7). Two-sided Mann–Whitney U test (U = 2, **P = 0.004). e, Schematic of virus injection. f, g, Confocal image of GRAB_DA1m expression (f) and locations of the tips of fibres plotted on the reference atlas (g). Grey areas indicate NAc core. Scale bar, 500 μm. h, GRAB_DA1m responses to MAP administration. Saline, 1 mg kg⁻¹ MAP, or 4 mg kg⁻¹ MAP were administered intraperitoneally in the home cage. n = 7 mice. Each experiment was conducted on a separate day and the order of drug administration was counter-balanced. i, Plots of GRAB_DA1m responses 30–90 min after MAP injection. n = 7 mice. Friedman’s test (χ²(2) = 14, P = 9.0 × 10^−4.). Post hoc Steel–Dwass test (saline versus MAP 1 mg kg⁻¹, t = 3.0, **P = 0.008; saline versus MAP 4 mg kg⁻¹, t = 3.1, **P = 0.005; MAP 1 mg kg⁻¹ versus MAP 4 mg kg⁻¹, t = 2.4, *P = 0.048). j, Lick scores of mice injected with GRAB_DA1m and treated with MAP. MAP was administered in the same way as in Fig. 5a. n = 7 mice for saline, n = 6 mice for MAP. k, l, Discrimination learning by mice used for GRAB_DA1m recording. n = 7 mice for saline, n = 6 mice for MAP. Two-sided Mann–Whitney U test (U = 2, **P = 0.005). m, n, GRAB_DA1m responses to CS− (m) and CS+ with US (n) averaged over discrimination task on day 2 and 3 from mice injected with saline (black) or MAP (blue). n = 7 mice for saline, n = 6 mice for MAP. DA dips in CS− trials during discrimination task (m) were tested by two-sided Wilcoxon signed-rank test versus 0 (saline, W = 0, *P = 0.016; MAP, W = 5, P = 0.63). Dip size was evaluated by the z-score trough during 2–3 s after CS onset to avoid contamination by decay of CS responses. Effects of MAP on dip size (m) and phasic DA responses to US (n) were tested by two-sided Mann–Whitney U test (m, U = 6, *P = 0.035; n, U = 13, P = 0.25). Data were sampled during the discrimination sessions as indicated by the light green bar in j. o, p, GRAB_DA1m responses to CS+ and CS− at discrimination test from mice injected with saline (o) or MAP (p). Two-sided Wilcoxon signed-rank test (saline, n = 7 mice, W = 27, *P = 0.031; MAP, n = 6 mice, W = 14, P = 0.56). Data were sampled during the discrimination test as indicated by the green bar in j. q, Schematics of CPP protocol with delays after MAP administration. Allocation of chambers A and B and order of MAP and saline injection were counter-balanced. r, Plots of time spent in chambers. Two-sided Wilcoxon signed-rank test (saline, n = 10 mice, W = 24, P = 0.77; MAP 1 mg kg⁻¹, n = 12 mice, W = 41, P = 0.91; MAP 4 mg kg⁻¹, n = 12 mice, W = 8, *P = 0.012). s, Plots of lick scores of mice treated with MAP and infused with sulpiride in discrimination test. MAP was administered as in Fig. 5a. Pink bar indicates period of intra-NAc infusion of sulpiride. From days 2 to 4, either ACSF or sulpiride was infused for all the conditions to control the manipulation of infusion. n = 5 mice. t, Lick traces in discrimination test (top) and plots of generalization indices (bottom). n = 5 mice. u, Plots of Δgeneralization indices for infusion with ACSF (n = 7 mice, from Fig. 5f), sulpiride during the discrimination period (n = 5 mice, from Fig. 5f) or sulpiride during the discrimination test (n = 5 mice, green). Kruskal–Wallis test (χ²(2) = 10, P = 0.007; post hoc Steel’s test, ACSF versus sulpiride during discrimination, t = 2.8, **P = 0.009; ACSF versus sulpiride in discrimination test, t = 0.08, P = 0.99). v, Schematic of amperometric detection of ChR2-driven dopamine release in the NAc slice (top). Normalized time course of DA concentration in the presence and absence of MAP (3 μM) (bottom). Data shown in Fig. 3k and Fig. 4g are normalized to the baseline concentration. n = 15 slices for no MAP, n = 6 slices for MAP. w, Plots of decay time constant. n = 15 slices for no MAP, n = 6 slices for MAP. Two-sided Mann–Whitney U test (U = 13, *P = 0.012). Error bars and shading indicate s.e.m. Vertical grey shading in m–p indicates CS periods. Samples of mice and slices are biological replicates.

Source data