Genetic Manipulation of Noradrenergic Neurons
- Dr. David Robertson, Clinical Research Center, AA3228 MCN, Vanderbilt University, Nashville, TN 37232-2195. E-mail:david.robertson{at}mcmail.vanderbilt.edu
Abstract
The neurotransmitter norepinephrine has been the focus of intense investigation for nearly a century. With advances in technology come novel approaches for testing hypotheses about the physiological roles of norepinephrine and the genes involved in norepinephrine (NE) biosynthesis, metabolism, and noradrenergic signaling. Homologous recombination techniques, which generate mice deficient in specific gene products, aid the integrated physiologist and pharmacologist in the evaluation of protein function. Mouse models lacking proteins involved in NE biosynthesis or metabolism provide tools to expand the knowledge previously gleaned from pharmacologic studies. Removal of the biosynthetic enzymes tyrosine hydroxylase and dopamine-β-hydroxylase yield animals deficient in norepinephrine and have been used to further examine the role of NE in diverse physiologic roles. Complete removal of the vesicular monoamine transporter has demonstrated that mobilizing neurotransmitters to vesicles is required for animal survival. Lastly, the generation of animals in which the ability to remove NE from the synapse is impaired (norepinephrine transporter deficiency and extraneuronal monoamine transporter deficiency) and in which the enzymes responsible for the metabolism of NE have been removed (catechol-O-methyltransferase and monoamine oxidase) has facilitated the study of the long-term physiological consequences of altered NE homeostasis.
Footnotes
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Supported in part by National Institutes of Health Grants P01 HL56693 and M01 RR00095.
- Abbreviations:
- NE
- norepinephrine
- EPI
- epinephrine
- CNS
- central nervous system
- DOPA
- l-dihydroxyphenylalanine
- TH
- tyrosine hydroxylase
- DA
- dopamine
- DBH
- dopamine-β-hydroxylase
- WT
- wild-type
- AADC
- l-aromatic amino acid decarboxylase
- PNMT
- phenylethanolamine-N-methyl transferase
- DOPS
- l-dihydroxyphenylserine
- VMAT
- vesicular monoamine transporter
- HR
- heart rate
- MAP
- mitogen-activated protein
- DAT
- dopamine transporter
- NET
- norepinephrine transporter
- MPTP
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- EMT
- extraneuronal monoamine transporter
- OCT-3
- organic cation transporter 3
- MPP+
- 1-methyl-4-phenylpyridinium
- COMT
- catechol-O-methyltransferase
- MAO
- monoamine oxidase
- 5-HT
- 5-hydroxytryptamine
- PEA
- phenylethylamine
- NMN
- normetanephrine
- DHPG
- dihydroxyphenyl glycol
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- Received August 6, 2001.
- Accepted January 23, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
