Abstract
Drug addiction is viewed as a form of neural plasticity, and neurotrophic factors have been implicated in many forms of plasticity in the adult nervous system. Here we show that the fibroblast growth factor-1 (FGF-1), that is expressed on dopamine and GABA neurons of the ventral tegmental area (VTA), is involved in the sensitizing effects of morphine. The receptor FGFR-1 is expressed on VTA astrocytes, as well as dopamine and GABA neurons. FGF-1 or anti-FGF-1 infusions into the VTA during the induction (not expression) phase of sensitization advanced or blocked morphine's activating motor effects respectively, in a dose-dependent manner. Infusions into the adjacent substantia nigra, whose neurons also express FGF-1 and FGFR-1, did not modify normal morphine-induced sensitization. Biochemical traits related to morphine's sensitizing effects were altered by intra-VTA anti-FGF-1 because morphine-induced upregulation of both tyrosine hydroxylase (TH) and N-methyl d-aspartate glutamate receptor 1 (NMDAR1) in the VTA was blocked after anti-FGF-1. Changes in the activation state of VTA calcium/calmodulin-dependent kinase type II seem to participate in FGF-1-induced effects as well. We conclude that the FGF-1 system of the ventral tegmental area is required for biochemical and behavioral sensitization to this drug.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies / pharmacology
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Astrocytes / metabolism
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Cells, Cultured
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Cyclic AMP-Dependent Protein Kinases / biosynthesis
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Dopamine / metabolism
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Fibroblast Growth Factor 1 / immunology
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Fibroblast Growth Factor 1 / pharmacology
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Fibroblast Growth Factor 1 / physiology*
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JNK Mitogen-Activated Protein Kinases / biosynthesis
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Male
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Mitogen-Activated Protein Kinase 1 / biosynthesis
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Mitogen-Activated Protein Kinase 3 / biosynthesis
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Morphine / pharmacology*
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Motor Activity / drug effects*
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Neurons / metabolism
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Nucleus Accumbens / drug effects
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Nucleus Accumbens / metabolism
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Prefrontal Cortex / drug effects
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Prefrontal Cortex / metabolism
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Proto-Oncogene Proteins c-akt / biosynthesis
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Rats
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Rats, Wistar
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Receptor, Fibroblast Growth Factor, Type 1 / metabolism
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Receptors, N-Methyl-D-Aspartate / biosynthesis
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Tyrosine 3-Monooxygenase / biosynthesis
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Ventral Tegmental Area / drug effects
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Ventral Tegmental Area / physiology*
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gamma-Aminobutyric Acid / metabolism
Substances
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Antibodies
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NMDA receptor A1
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Receptors, N-Methyl-D-Aspartate
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Fibroblast Growth Factor 1
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gamma-Aminobutyric Acid
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Morphine
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Tyrosine 3-Monooxygenase
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Receptor, Fibroblast Growth Factor, Type 1
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Proto-Oncogene Proteins c-akt
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Cyclic AMP-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Dopamine