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 D5dopamine 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.

[1]  D. Sibley,et al.  Behavioral characterization of dopamine D5 receptor null mutant mice. , 2001, Behavioral neuroscience.

[2]  C. Schmauss,et al.  Dopamine receptor functions: lessions from knockout mice , 2001 .

[3]  T. Janáky,et al.  Effects of dopamine and dopamine-active compounds on oxytocin and vasopressin production in rat neurohypophyseal tissue cultures , 2001, Regulatory Peptides.

[4]  R. Mailman,et al.  Quantification of D1B (D5) receptors in dopamine D1A receptor‐deficient mice , 2001, Synapse.

[5]  D. Blackwood,et al.  Markers close to the dopamine D5 receptor gene (DRD5) show significant association with schizophrenia but not bipolar disorder. , 2001, American journal of medical genetics.

[6]  L. Young,et al.  Vasopressin (V1a) Receptor Binding, mRNA Expression and Transcriptional Regulation by Androgen in the Syrian Hamster Brain , 2000, Journal of neuroendocrinology.

[7]  Alessandro Usiello,et al.  Distinct functions of the two isoforms of dopamine D2 receptors , 2000, Nature.

[8]  A. Levey,et al.  Dopamine D5 receptor immunolocalization in rat and monkey brain , 2000, Synapse.

[9]  R. Felder,et al.  C001: Differential expression and regulation of dopamine-1(d1) and dopamine-5(d-5) receptor function in human kidney , 2000 .

[10]  Yu Tian Wang,et al.  Direct protein–protein coupling enables cross-talk between dopamine D5 and γ-aminobutyric acid A receptors , 2000, Nature.

[11]  C. V. van Eden,et al.  The integration of stress by the hypothalamus, amygdala and prefrontal cortex: balance between the autonomic nervous system and the neuroendocrine system. , 2000, Progress in brain research.

[12]  D. Sibley,et al.  Nonconserved residues in the second transmembrane-spanning domain of the D(4) dopamine receptor are molecular determinants of D(4)-selective pharmacology. , 2000, Molecular pharmacology.

[13]  D. Sibley,et al.  Regulation of D(1) dopamine receptors with mutations of protein kinase phosphorylation sites: attenuation of the rate of agonist-induced desensitization. , 1999, Molecular pharmacology.

[14]  R. Campos,et al.  Importance of glycinergic and glutamatergic synapses within the rostral ventrolateral medulla for blood pressure regulation in conscious rats. , 1999, Hypertension.

[15]  G. Slesak,et al.  Inotropic effects of endothelin-1: interaction with molsidomine and with BQ 610. , 1999, Hypertension.

[16]  D. Sibley,et al.  New insights into dopaminergic receptor function using antisense and genetically altered animals. , 1999, Annual review of pharmacology and toxicology.

[17]  K. Mikoshiba,et al.  A novel alternatively spliced variant of synaptotagmin VI lacking a transmembrane domain. Implications for distinct functions of the two isoforms. , 1999, The Journal of biological chemistry.

[18]  K. Migita,et al.  Effects of arginine-vasopressin on neuronal interaction from the area postrema to the nucleus tractus solitarii in rat brain slices , 1998, Neuroscience Letters.

[19]  A. Bonham,et al.  Non-NMDA and NMDA receptors in the synaptic pathway between area postrema and nucleus tractus solitarius. , 1998, American journal of physiology. Heart and circulatory physiology.

[20]  D. Accili,et al.  Disruption of the dopamine D3 receptor gene produces renin-dependent hypertension. , 1998, The Journal of clinical investigation.

[21]  D. Cechetto,et al.  Neurotransmission in the medulla mediating insular cortical and lateral hypothalamic sympathetic responses. , 1998, Canadian journal of physiology and pharmacology.

[22]  M. Boccia,et al.  Effects of a Single Administration of Oxytocin or Vasopressin and Their Interactions with Two Selective Receptor Antagonists on Memory Storage in Mice , 1998, Neurobiology of Learning and Memory.

[23]  M. Vanyukov,et al.  An Association Between a Microsatellite Polymorphism at the DRD5 Gene and the Liability to Substance Abuse: Pilot Study , 1998, Behavior Genetics.

[24]  A. Verberne,et al.  Cortical Modulation of theCardiovascular System , 1998, Progress in Neurobiology.

[25]  M. Rubinstein,et al.  Opposite roles of D1 and D5 dopamine receptors in locomotion revealed by selective antisense oligonucleotides , 1998, Neuroreport.

[26]  A. Verberne,et al.  Cortical modulation of the cardiovascular system. , 1998, Progress in neurobiology.

[27]  D. Surmeier,et al.  D5 Dopamine Receptors Enhance Zn2+-Sensitive GABAA Currents in Striatal Cholinergic Interneurons through a PKA/PP1 Cascade , 1997, Neuron.

[28]  G. Bakris,et al.  Role of vasopressin in essential hypertension: Racial differences , 1997, Journal of hypertension.

[29]  S. Rivkees,et al.  Functional D1 and D5 dopamine receptors are expressed in the suprachiasmatic, supraoptic, and paraventricular nuclei of primates , 1997, Synapse.

[30]  D. Sibley,et al.  Cellular distribution of the rat D1B receptor in central nervous system using anti-receptor antisera , 1997, Brain Research.

[31]  B. O’Malley,et al.  In vivo regulation of central nervous system progesterone receptors: cocaine induces steroid-dependent behavior through dopamine transporter modulation of D5 receptors in rats. , 1996, Molecular Endocrinology.

[32]  É. Mezey,et al.  A novel nonneuronal catecholaminergic system: exocrine pancreas synthesizes and releases dopamine. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[33]  S. Watson,et al.  Dopaminergic Regulation of Progesterone Receptors: Brain D5 Dopamine Receptors Mediate Induction of Lordosis by D1-Like Agonists in Rats , 1996, The Journal of Neuroscience.

[34]  W. Young,et al.  Binding preferences of the POU domain protein Brain-4: implications for autoregulation. , 1996, Brain research. Molecular brain research.

[35]  C. Sladek,et al.  Neurophysin expression is stimulated by dopamine D1 agonist in dispersed hypothalamic cultures. , 1996, The American journal of physiology.

[36]  M. Dahmer,et al.  Dopaminergic Inhibition of Catecholamine Secretion from Chromaffin Cells: Evidence that Inhibition Is Mediated by D4 and D5 Dopamine Receptors , 1996, Journal of neurochemistry.

[37]  M. Buuse,et al.  Stimulation of the rat mesolimbic dopaminergic system produces a pressor response which is mediated by dopamine D-1 and D-2 receptor activation and the release of vasopressin , 1995, Brain Research.

[38]  J. Vane,et al.  Roles of endothelin receptors in the regional and systemic vascular responses to ET‐1 in the anaesthetized ganglion‐blocked rat: use of selective antagonists , 1995, British journal of pharmacology.

[39]  J. Roppolo,et al.  Effects of GYKI 52466 and CNQX, AMPA/kainate receptor antagonists, on the micturition reflex in the rat , 1995, Brain Research.

[40]  S. Bealer,et al.  Paraventricular nucleus histamine increases blood pressure by adrenoreceptor stimulation of vasopressin release. , 1995, The American journal of physiology.

[41]  M. Caron,et al.  High agonist-independent activity is a distinguishing feature of the dopamine D1B receptor subtype. , 1994, The Journal of biological chemistry.

[42]  R. Gillis,et al.  Intravenous NBQX inhibits spontaneously occurring sympathetic nerve activity and reduces blood pressure in cats. , 1994, European journal of pharmacology.

[43]  Q. Pittman,et al.  Enhanced pressor responses to ICV vasopressin after pretreatment with oxytocin. , 1994, The American journal of physiology.

[44]  Rudolf Jaenisch,et al.  Targeted mutation of the DNA methyltransferase gene results in embryonic lethality , 1992, Cell.

[45]  T. Insel,et al.  Oxytocin Receptor Distribution Reflects Social Organization in Monogamous and Polygamous Voles , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[46]  R. Bronson,et al.  Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene , 1991, Cell.

[47]  Susan R. George,et al.  Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1 , 1991, Nature.

[48]  R. Buijs,et al.  Oxytocinergic innervation of the brain of the garden dormouse (Eliomys quercinus L.) , 1988, The Journal of comparative neurology.

[49]  P. Soares-da-Silva,et al.  The effects of chemical sympathectomy on dopamine, noradrenaline and adrenaline content in some peripheral tissues , 1985, British journal of pharmacology.

[50]  H. Maeno,et al.  Dopamine Receptors , 2018 .