Mice Lacking D₅Dopamine Receptors Have Increased Sympathetic Tone and Are Hypertensive

Abstract

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.

D3 dopamine receptor regulation of D5 receptor expression and function in renal proximal tubule cells

“…In D 5 receptor null (D 5 À/À ) mice, a high salt diet further increases blood pressure, suggesting that the renal D 5 receptor has an important role in the control of blood pressure by regulating renal sodium chloride transport. 28,35 In the present study, we found that activation of D 5 receptor inhibits Na + -K + ATPase activity in D 5 receptor-transfected HEK293 cells.…”

“…28 For b-actin, the forward primer was 5¢-GTGGGTATGGGTCAGAAGGA-3¢ and the reverse primer was 5¢-AGCGCG TAACCCTCATAGAT-3¢. The amplification was performed with the following conditions: 35 cycles of denaturation at 94 1C for 2 min, annealing for 30 s at 52.5 1C and extension for 45 s at 72 1C.…”

Reduction in Acetylcholine Release in the Hippocampus of Dopamine D5 Receptor-Deficient Mice

“…Immunohistochemical detection of d5 receptors revealed that the frontal cortex in the d5À/À mouse was, as expected, completely devoid of this receptor (Hollon et al, 2002). Animals were reproduced in our animal facilities by standard inbreeding.…”

“…The d5À/À mouse with a genetic background of 129/SvJ1 and C57BL/6J was generated as described earlier (Hollon et al, 2002) and provided by one of the authors (D Sibley). Immunohistochemical detection of d5 receptors revealed that the frontal cortex in the d5À/À mouse was, as expected, completely devoid of this receptor (Hollon et al, 2002).…”

“…Females were isolated to give birth and pups were weaned at postnatal day 21. The genotype of each mouse was determined using a PCR technique as previously described (Hollon et al, 2002). Experiments were performed in homozygous d5À/À, heterozygous (d5 þ /À), and wild-type (d5 þ / þ ) littermates.…”