D1 dopamine receptor coupling to PLCβ regulates forward locomotion in mice.
Several studies have reported the coupling of dopamine signaling to phospholipase C β (PLCβ) 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 D1 and D2 receptor knock-out animals, we show that the production of IP3 is mediated by the D1 receptor, but not the D2 receptor. A selective blocker of PLCβ, U73122, was used to assess the physiological relevance of D1-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 D1- and D2-mediated signaling following U73122 treatment modifies the locomotor output of animals from horizontal locomotor activity to vertical activity, further highlighting the importance of the PLCβ pathway in the regulation of forward locomotion via dopamine receptors.
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada, Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy, Skolkovo Institute of Science and Technology, Skolkovo, Moscow Region, 143025, Russia, Faculty of Biology and Soil Science, St. Petersburg State University, St. Petersburg 199034, Russia, and Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University and Institut Universitaire en Santé Mentale de Québec, Québec City, Québec G1J 2G3, Canada.
Ivan O
IO
Medvedev
Amy J
AJ
Ramsey
Shababa T
ST
Masoud
Marie Kristel
MK
Bermejo
Nikhil
N
Urs
Tatyana D
TD
Sotnikova
Jean-Martin
JM
Beaulieu
Raul R
RR
Gainetdinov
Ali
A
Salahpour
D000818:Animals; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology*; D054799:Phospholipase C beta / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017447:Receptors, Dopamine D1 / Q000378:metabolism*
D017447:Receptors, Dopamine D1; D054799:Phospholipase C beta