D1 Dopamine Receptor Coupling to PLCβ Regulates Forward Locomotion in Mice

Several studies have reported the coupling of dopamine signaling to phospholipase C beta (PLC beta) both in vitro and in vivo. However, the precise physiological relevance of this signaling pathway in mediating dopamine behaviors is still unclear. Here we report that stimulation of dopamine receptor signaling in vivo with systemic administration of apomorphine, amphetamine, and cocaine leads to increased production of inositol triphosphate (IP3) in the mouse striatum. Using selective antagonists and dopamine D-1 and D-2 receptor knock-out animals, we show that the production of IP3 is mediated by the D-1 receptor, but not the D-2 receptor. A selective blocker of PLC beta, U73122, was used to assess the physiological relevance of D-1-mediated IP3 production. We show that U73122 inhibits the locomotor-stimulating effects of apomorphine, amphetamine, cocaine, and SKF81297. Furthermore, U73122 also suppresses the spontaneous hyperactivity exhibited by dopamine transporter knock-out mice. Importantly, the effects of U73122 are selective to dopamine-mediated hyperactivity, as this compound does not affect hyperactivity induced by the glutamate NMDA receptor antagonist MK801. Finally, we present evidence showing that an imbalance of D-1- and D-2-mediated signaling following U73122 treatment modifies the locomotor output of animals from horizontal locomotor activity to vertical activity, further highlighting the importance of the PLC beta pathway in the regulation of forward locomotion via dopamine receptors.