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Brain-derived neurotrophic factor is ess ... ticity of noradrenergic neurons
Brain-derived neurotrophic factor is essential for opiate-induced plasticity of noradrenergic neurons.
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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.
Akbarian S, Rios M, Liu RJ, Gold SJ, Fong HF, Zeiler S, Coppola V, Tessarollo L, Jones KR, Nestler EJ, Aghajanian GK, Jaenisch R
The Journal of neuroscience : the official journal of the Society for Neuroscience
2002-05-15 00:00
22
10
4153-62
Animals,Behavior, Animal,Brain-Derived Neurotrophic Factor,Ca(2+)-Calmodulin Dependent Protein Kinase,Cell Count,Cyclic AMP,Down-Regulation,Forskolin,Gene Deletion,Genes, Reporter,Genotype,In Situ Hybridization,Integrases,Locus Coeruleus,Mice,Mice, Mutant Strains,Mice, Transgenic,Narcotics,Neuronal Plasticity,Neurons,Norepinephrine,Receptors, Opioid, mu,Recombination, Genetic,Severity of Illness Index,Signal Transduction,Substance Withdrawal Syndrome,Transgenes,Tyrosine 3-Monooxygenase,Viral Proteins,Brain-Derived Neurotrophic Factor,Narcotics,Receptors, Opioid, mu,Viral Proteins,Norepinephrine,Cyclic AMP,Forskolin,Tyrosine 3-Monooxygenase,Ca(2+)-Calmodulin Dependent Protein Kinase,calcium-calmodulin-dependent protein kinase type 2,Cre recombinase,Integrases
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA schahramakbarianumassmededu
J. Neurosci.
NIDA 1-K08-DA00479, NCI 5-R35-CA44339
1529-2401
20026381
22/10/4153
584
True
12019333
