Microarray analysis of genes expressed in the frontal cortex of rats chronically treated with morphine and after naloxone precipitated withdrawal.
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.
Ammon
Susanne
S
Institute of Pharmacology and Toxicology, Otto von Guericke University, Leipziger Str. 44, D-39120, Magdeburg, Germany.
Mayer
Peter
P
Riechert
Uta
U
Tischmeyer
Helga
H
Höllt
Volker
V
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D000072233:Homer Scaffolding Proteins; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000235:genetics* / Q000378:metabolism*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics; D009479:Neuropeptides / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D056950:Period Circadian Proteins; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000235:genetics* / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D000072233:Homer Scaffolding Proteins; D017874:Immediate-Early Proteins; D009292:Narcotic Antagonists; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; C513311:Per2 protein, rat; D056950:Period Circadian Proteins; D014157:Transcription Factors; C092069:activity regulated cytoskeletal-associated protein; D009270:Naloxone; D009020:Morphine