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

## TL;DR

A specific phosphorylation site on dopamine receptors in the brain is linked to increased movement caused by cocaine, suggesting a new target for treatment.

## Contribution

Identifies PKD1-mediated phosphorylation at D2R serine 365 as a novel mechanism underlying cocaine-induced hyperactivity.

## Key findings

- Knockdown of PKD1 in the dorsal striatum reduces cocaine-induced locomotor hyperactivity in rats.
- Phosphorylation of D2R at serine 365 by PKD1 decreases receptor surface localization and increases ERK signaling.
- Peptide Tat-S365 inhibits cocaine-induced hyperactivity by blocking D2R phosphorylation at serine 365.

## Abstract

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.