Mice lacking D5 dopamine receptors have increased sympathetic tone and are hypertensive.
Dopamine is an important transmitter in the CNS and PNS, critically regulating numerous neuropsychiatric and physiological functions. These actions of dopamine are mediated by five distinct receptor subtypes. Of these receptors, probably the least understood in terms of physiological functions is the D5 receptor subtype. To better understand the role of the D5 dopamine receptor (DAR) in normal physiology and behavior, we have now used gene-targeting technology to create mice that lack this receptor subtype. We find that the D5 receptor-deficient mice are viable and fertile and appear to develop normally. No compensatory alterations in other dopamine receptor subtypes were observed. We find, however, that the mutant mice develop hypertension and exhibit significantly elevated blood pressure (BP) by 3 months of age. This hypertension appears to be caused by increased sympathetic tone, primarily attributable to a CNS defect. Our data further suggest that this defect involves an oxytocin-dependent sensitization of V1 vasopressin and non-NMDA glutamatergic receptor-mediated pathways, potentially within the medulla, leading to increased sympathetic outflow. These results indicate that D5 dopamine receptors modulate neuronal pathways regulating blood pressure responses and may provide new insights into mechanisms for some forms of essential hypertension in humans, a disease that afflicts up to 25% of the aged adult population in industrialized societies.
Hollon
Tom R
TR
Molecular Neuropharmacology Section and Basic Neurosciences Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1406, USA.
Bek
Martin J
MJ
Lachowicz
Jean E
JE
Ariano
Marjorie A
MA
Mezey
Eva
E
Ramachandran
Ramesh
R
Wersinger
Scott R
SR
Soares-da-Silva
Patricio
P
Liu
Zhi Fang
ZF
Grinberg
Alexander
A
Drago
John
J
Young
W Scott
WS
Westphal
Heiner
H
Jose
Pedro A
PA
Sibley
David R
DR
D000311:Adrenal Glands / Q000737:chemistry; D000818:Animals; D001794:Blood Pressure; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D004837:Epinephrine / Q000032:analysis; D018390:Gene Targeting; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009638:Norepinephrine / Q000032:analysis; D010121:Oxytocin / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D017447:Receptors, Dopamine D1 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050641:Receptors, Dopamine D5; D018045:Receptors, Oxytocin / Q000032:analysis; D017483:Receptors, Vasopressin / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D014667:Vasopressins / Q000235:genetics
C493606:Drd5 protein, mouse; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D014667:Vasopressins; D050641:Receptors, Dopamine D5; D010121:Oxytocin; D009638:Norepinephrine; D004837:Epinephrine