Figure 2. Model of how DA neurons control motor actions by engaging the striatonigral direct pathway circuit via D1R in the striatum and SNr.

In normal conditions, midbrain DA neurons display various firing rates with episodes of bursts and tonic activity interspersed with pauses. Subsequent changes in extracellular DA will engage different subsets of D1-SPNs in the striatum. D1Rs located in the SNr can directly filter D1-SPN GABA output to provide for action selection, represented here as inhibition of different SNr projection neurons. In PD, DA neurons degenerate and homeostatic plasticity develops which leads to increased intrinsic excitability and evoked GABA release from D1-SPN synapses in response DA replacement with L-DOPA. Increased output from D1-SPNs and loss of filtering by presynaptic receptors, for instance by GABA_B receptors (not shown), will result in surges of GABA efflux in the SNr. The lack of selection of GABA output from D1-SPNs will trigger hyperkinetic responses when extracellular DA is produced by L-DOPA administration, such as LID.