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The Journal of Neuroscience, May 15, 2002, 22(10):4153-4162

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

Schahram Akbarian^{1, 2, *}, Maribel Rios^{1, *}, Rong-Jian Liu³, Stephen J. Gold⁴, Hiu-Fai Fong¹, Steve Zeiler⁵, Vincenzo Coppola⁶, Lino Tessarollo⁶, Kevin R. Jones⁵, Eric J. Nestler⁴, George K. Aghajanian³, and Rudolf Jaenisch¹

¹ Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, ² Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01613-2795, ³ Department of Psychiatry, Yale University, New Haven, Connecticut 06520, ⁴ Department of Psychiatry, University of Texas Southwestern, Dallas, Texas 75390, ⁵ Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309, and ⁶ National Cancer Institute, Frederick, Maryland 21702

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.

Key words: norepinephrine; locus coeruleus; Cre recombinase; loxP; BDNF; opiates; plasticity; cAMP

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^* S.A. and M.R. contributed equally to this work.

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22104153-10$05.00/0

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