PKD1-mediated phosphorylation at dopamine D2 receptor serine 365 site in dorsal striatum underlies cocaine-induced locomotor hyperactivity.

Locomotor hyperactivity is an early behavioural adaptation in cocaine use disorder, driven by increased dopamine levels in the striatum. The expression, sensitivity, and availability of dopamine D2 receptor (D2R) are significantly associated with cocaine use disorder. However, neither D2R agonists nor antagonists are optimal for clinical intervention because of their side effects. Therefore, targeting regulatory proteins that can effectively disrupt cocaine-induced D2R malfunction may offer improved strategies for cocaine use disorder. Here, we report that knockdown of protein kinase D1 (PKD1) in the rat dorsal striatum attenuates cocaine-induced locomotor hyperactivity. PKD1 phosphorylates the serine 365 site (S365) of D2R, reduces its surface localisation, and enhances downstream extracellular signal-regulated kinase (ERK) signalling. Tat-S365, an engineered Tat fusion-peptide blocked S365 phosphorylation in D2R, thereby decreasing the pERK levels. In vivo injection of peptide Tat-S365 into the rat dorsal striatum successfully inhibited cocaine-induced locomotor hyperactivity. Thus, targeting S365 of D2R presents a promising strategy for developing pharmacotherapeutic treatments for cocaine sensitisation and other disorders that result from dopamine imbalances.