Abstract
Opioid dependence may be associated with adaptive changes in gene expression in the brain. In the present study we used DNA microarrays (U34A; Affymetrix) to analyze the expression of about 8000 genes in the frontal cortex of rats chronically treated with morphine and in rats after naloxone precipitated withdrawal. Chronic treatment for 10 days with ascending doses of morphine (10-50 mg/kg twice daily) resulted in a more than twofold induction of 14 genes after the last injection of morphine. The majority of these genes code for heat shock proteins (hsp70, hsp 27, hsp 40, hsp105, GRP78, etc.). The expression of the heat shock genes in the morphine-treated animals was reversed by naloxone (10 mg/kg). The opioid antagonist, in turn, precipitated withdrawal and increased the expression of a set of genes which are predominantly transcription factors (krox20, CREM, NGFI-B, IkappaB, etc). Only a few genes remained increased after naloxone application. Such persistently changed genes code for arc, a cytoskeleton-associated protein which is induced by synaptic activity, ania-3, a splice variant of the Homer 1 protein which is critically involved in activity-dependent alterations of synaptic function and rPer2, a protein regulating circadian rhythms. For selected genes the changes in gene expression were confirmed by real time PCR and by in situ hybridization. These findings indicate that the persistent changes in long-lasting plasticity during opiate dependence do not primarily depend on the increased expression levels of genes encoding for neurotransmitter, receptor and/or ion channel proteins, but rather on altered pattern of synaptic connectivity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / biosynthesis
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Carrier Proteins / genetics
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Cell Cycle Proteins
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Cytoskeletal Proteins
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DNA, Complementary / analysis
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DNA, Complementary / genetics
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Dose-Response Relationship, Drug
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Drug Administration Schedule
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Frontal Lobe / drug effects*
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Frontal Lobe / metabolism
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Frontal Lobe / physiopathology
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / genetics
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Homer Scaffolding Proteins
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Immediate-Early Proteins / biosynthesis
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Immediate-Early Proteins / genetics
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Male
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Morphine / pharmacology*
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Morphine Dependence / genetics*
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Morphine Dependence / metabolism*
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Naloxone / pharmacology
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Narcotic Antagonists / pharmacology
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Nerve Tissue Proteins / biosynthesis
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Nerve Tissue Proteins / drug effects
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Nerve Tissue Proteins / genetics
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Neuronal Plasticity / drug effects*
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Neuronal Plasticity / genetics
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Neuropeptides / biosynthesis
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Neuropeptides / genetics
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / genetics
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Oligonucleotide Array Sequence Analysis
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Period Circadian Proteins
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Presynaptic Terminals / drug effects*
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Presynaptic Terminals / metabolism
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Rats
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Rats, Wistar
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Substance Withdrawal Syndrome / genetics*
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Substance Withdrawal Syndrome / metabolism*
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Synaptic Transmission / drug effects
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Synaptic Transmission / genetics
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Transcription Factors
Substances
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Carrier Proteins
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Cell Cycle Proteins
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Cytoskeletal Proteins
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DNA, Complementary
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Homer Scaffolding Proteins
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Immediate-Early Proteins
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Narcotic Antagonists
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Nerve Tissue Proteins
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Neuropeptides
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Nuclear Proteins
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Per2 protein, rat
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Period Circadian Proteins
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Transcription Factors
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activity regulated cytoskeletal-associated protein
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Naloxone
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Morphine