Reduction of morphine abstinence in mice with a mutation in the gene encoding CREB.
Chronic morphine administration induces an up-regulation of several components of the cyclic adenosine 5'-monophosphate (cAMP) signal transduction cascade. The behavioral and biochemical consequences of opiate withdrawal were investigated in mice with a genetic disruption of the alpha and Delta isoforms of the cAMP-responsive element-binding protein (CREB). In CREBalphadelta mutant mice the main symptoms of morphine withdrawal were strongly attenuated. No change in opioid binding sites or in morphine-induced analgesia was observed in these mutant mice, and the increase of adenylyl cyclase activity and immediate early gene expression after morphine withdrawal was normal. Thus, CREB-dependent gene transcription is a factor in the onset of behavioral manifestations of opiate dependence.
Maldonado
R
R
Département de Pharmacochimie Moléculaire et Structurale, Unité de Recherche Associée D1500 CNRS, Université René Descartes, Faculté de Pharmacie, Paris, France.
Blendy
J A
JA
Tzavara
E
E
Gass
P
P
Roques
B P
BP
Hanoune
J
J
Schütz
G
G
D000262:Adenylyl Cyclases / Q000378:metabolism; D000698:Analgesia; D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000201:enzymology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000502:physiology*; D004361:Drug Tolerance; D005786:Gene Expression Regulation; D018390:Gene Targeting; D017781:Genes, Immediate-Early; D008125:Locus Coeruleus / Q000378:metabolism; D051379:Mice; D009020:Morphine / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D009021:Morphine Dependence / Q000209:etiology* / Q000378:metabolism; D009154:Mutation; D009270:Naloxone / Q000494:pharmacology; D011957:Receptors, Opioid / Q000378:metabolism; D015398:Signal Transduction; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
D017362:Cyclic AMP Response Element-Binding Protein; D011957:Receptors, Opioid; D009270:Naloxone; D009020:Morphine; D000262:Adenylyl Cyclases