Brain-Derived Neurotrophic Factor Is Essential for Opiate-Induced Plasticity of Noradrenergic Neurons

Schahram Akbarian, Maribel Rios, Rong Jian Liu, Stephen J. Gold, Hiu Fai Fong, Steven Zeiler, Vincenzo Coppola, Lino Tessarollo, Kevin R. Jones, Eric J. Nestler, George K. Aghajanian, Rudolf Jaenisch

Research output: Contribution to journalArticle

Abstract

Chronic opiate exposure induces numerous neurochemical adaptations in the noradrenergic system, including upregulation of the cAMP-signaling pathway and increased expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. These adaptations are thought to compensate for opiate-mediated neuronal inhibition but also contribute to physical dependence, including withdrawal after abrupt cessation of drug exposure. Little is known about molecules that regulate the noradrenergic response to opiates. Here we report that noradrenergic locus ceruleus (LC) neurons of mice with a conditional deletion of BDNF in postnatal brain respond to chronic morphine treatment with a paradoxical downregulation of cAMP-mediated excitation and lack of dynamic regulation of TH expression. This was accompanied by a threefold reduction in opiate withdrawal symptoms despite normal antinociceptive tolerance in the BDNF-deficient mice. Although expression of TrkB, the receptor for BDNF, was high in the LC, endogenous BDNF expression was absent there and in the large majority of other noradrenergic neurons. Therefore, a BDNF-signaling pathway originating from non-noradrenergic sources is essential for opiate-induced molecular adaptations of the noradrenergic system.

Original languageEnglish (US)
Pages (from-to)4153-4162
Number of pages10
JournalJournal of Neuroscience
Volume22
Issue number10
Publication statusPublished - May 15 2002
Externally publishedYes

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Keywords

  • BDNF
  • cAMP
  • Cre recombinase
  • Locus coeruleus
  • LoxP
  • Norepinephrine
  • Opiates
  • Plasticity

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Akbarian, S., Rios, M., Liu, R. J., Gold, S. J., Fong, H. F., Zeiler, S., ... Jaenisch, R. (2002). Brain-Derived Neurotrophic Factor Is Essential for Opiate-Induced Plasticity of Noradrenergic Neurons. Journal of Neuroscience, 22(10), 4153-4162.