Fig. 4.

Partial reduction of striatal D2Rs is sufficient to trigger D1R hypersensitivity and structural alterations to striatopallidal neurons. a Schematic of the experimental approach showing ChR2 expression in iMSNs and whole-cell recording in neighboring dMSNs in NAc core. b Representative traces of optogenetic-evoked inhibitory post-synaptic currents (oIPSC) recorded at baseline (bsln), in quinpirole (1 µM), and sulpiride (1 µM) in slices from Adora2aCre (top) or iMSN-Drd2HET (bottom) mice. c Time course of oIPSC amplitude normalized to baseline before quinpirole in Adora2aCre (black) or iMSN-Drd2HET (gray). d Summary of the quinpirole and sulpiride effects in control Adora2aCre and iMSN-Drd2HET mice. Posthoc t-tests: Baseline vs. Drug: *p < 0.05, **p < 0.01, ****p < 0.0001; Drd2^loxP/wt vs. iMSN-Drd2HET at quinpirole: **p < 0.01. e Left, Timeline of behavioral experiment (h, habituation, s, saline). Right, Horizontal locomotor activity in response to escalating doses of SKF-81297, shown as a percent of same-day pre-injection baseline, in cocaine-naïve Drd2^loxP/wt control (dark blue), iMSN-Drd2HET (light blue), and iMSN-Drd2KO mice (white). 2-way ANOVA: Main effect of Genotype: **p < 0.01; 2-way ANOVA: Main effect of SKF-81297: ****p < 0.0001. f–h Left, representative images of parasagittal brain sections showing red-fluorescence from D1R-containing neurons in Drd1-tdTomato mice and overlay of the region used for quantification in the striatum (DS or NAC) and the projection areas (SNr, GP, VP). Middle plots represent the mean ± SEM of the fluorescence intensity (in arbitrary units, a.u.) in the striatal and projection regions for Drd2^loxP/wt (black) and iMSN-Drd2HET mice (gray). Right plots represent the mean ± SEM of the normalized fluorescence intensity of the projection regions as a function of the striatal region for Drd2^loxP/wt (black) and iMSN-Drd2HET mice (gray). f Unpaired t-test: ns = not significant. g, h Unpaired t-tests: Drd2^loxP/wt vs. iMSN-Drd2HET: *p < 0.05