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. 2016 Sep 26;113(41):11609–11614. doi: 10.1073/pnas.1608362113

Fig. 5.

Fig. 5.

GABAA antagonism restores c-fos induction in the striatum of D2RKO and MSN-D2RKO mice. Bicuculline restored c-fos induction to WT levels in D1R+ cells of the DMS of both D2RKO and MSN-D2RKO mice. (A) Representative images of in situ hybridization for c-fos (green) and D1R (red) in the DMS of WT, D2RKO, and MSN-D2RKO following the different treatments as indicated on the top. (Scale bar, 25 μm.) Arrowheads indicate cells that are both c-fos+ and D1R+. (B) Values are mean ± SEM of c-fos-D1R+ cells per frame (385.7 × 385.7 μm) in the DMS (n = 3 per treatment per genotype). ***P < 0.001 vs. saline-treated mice. ###P < 0.001, ##P < 0.01, #P < 0.05 vs. bicuculline-treated mice; ^^P < 0.01 vs. WT cocaine-treated mice. (C) Model of D2R-mediated control of the acute effects of cocaine in the DMS. (Left) In WT mice, acute cocaine administration increases the release of DA from dopaminergic neurons of the substantia nigra compacta (SNc), activating D1R in MSNs of the direct pathway (dMSNs) and D2R in MSNs of the indirect pathway (iMSNs). As a result, there is a potentiation of the direct pathway and the consequent reduction of the inhibitory input of the substantia nigra reticulata (SNr) to the thalamus, which, in return, stimulates the cortex and the striatum. This chain of events is responsible for the increased locomotor response to cocaine in WT mice. (Right) In MSN-D2RKO mice, absence of D2R in iMSNs prevents the inhibition of these neurons, leading to a potentiation of their inhibitory tone that results in an increased activation of the indirect pathway of SNr neurons. In intrastriatal circuits, the absence of D2Rs in iMSNs leads to an increased collateral inhibition by these neurons of dMSNs activity; this results into decreased inhibition from the direct pathway of SNr activity. Activation of SNr neurons inhibits the thalamus, resulting into a reduced stimulation of the cortex and striatum. The final outcome is reduced motor response to cocaine in MSN-D2RKO mice and altered signal transduction and gene expression in dMSNs. Solid lines indicate a potentiation of the effect whether excitatory or inhibitory, whereas broken lines indicate a reduced effect.