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Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal

Molecular Psychiatry volume 6, pages 593–604 (2001)Cite this article

Abstract

Somatic symptoms and aversion of opiate withdrawal, regulated by noradrenergic signaling, were attenuated in mice with a CNS-wide conditional ablation of neurotrophin-3. This occurred in conjunction with altered cAMP-mediated excitation and reduced upregulation of tyrosine hydroxylase in A6 (locus coeruleus) without loss of neurons. Transgene-derived NT-3 expressed by noradrenergic neurons of conditional mutants restored opiate withdrawal symptoms. Endogenous NT-3 expression, strikingly absent in noradrenergic neurons of postnatal and adult brain, is present in afferent sources of the dorsal medulla and is upregulated after chronic morphine exposure in noradrenergic projection areas of the ventral forebrain. NT-3 expressed by non-catecholaminergic neurons may modulate opiate withdrawal and noradrenergic signalling.

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Acknowledgements

The authors thank Ruth Curry, Valyphone Phantharagnsy, Cathy Steffen, Victoria Stewart and Jeannie Reis for technical assistance, Drs Maribel Rios, Christine Konradi and William Carlezon Jr for experimental advice. This work was supported by NARSAD (National Alliance for Research on Schizophrenia and Depression), by the National Institute of Drug Abuse (NIDA) grant 1-K08-DA00479 to SA, by NCI/NIH grant 5-R35-CA44339 to RJ and by the Fidelity Foundation.

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Author notes

  1. S Akbarian and B Bates: SA and BB contributed equally to this work.

Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, Cambridge, MA, USA

    S Akbarian, B Bates, G Fan & R Jaenisch

  2. Dept of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    S Akbarian

  3. Dept of Psychiatry, Yale University, New Haven, CT, USA

    R-J Liu, J R Taylor, E J Nestler & G K Aghajanian

  4. Dept of Physiology and Biophysics, University of Washington, Seattle, WA, USA

    S L Skirboll & M Bothwell

  5. Dept of Neurology, Massachusetts General Hospital, Boston, MA, USA

    T Pejchal & B E Kosofsky

  6. National Cancer Institute, Frederick, MD, USA

    V Coppola & L Tessarollo

  7. Dept of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA

    L D Sun, M A Wilson & R Jaenisch

  8. Dept of Neurology, Boston University, MA, USA

    J Kucera

  9. Genetics Institute, Cambridge, MA

    B Bates

  10. Division of Neurosurgery, University of New Mexico, Albuquerque, NM

    S L Skirboll

  11. Dept of Psychiatry, UT Southwestern, Dallas, TX

    E J Nestler

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Correspondence to R Jaenisch.

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Akbarian, S., Bates, B., Liu, RJ. et al. Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal. Mol Psychiatry 6, 593–604 (2001). https://doi.org/10.1038/sj.mp.4000897

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  • DOI: https://doi.org/10.1038/sj.mp.4000897

Keywords

  • locus coeruleus
  • morphine
  • addiction
  • norepinephrine
  • cre recombinase
  • pons
  • medulla

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