Effects of acute "binge" cocaine on preprodynorphin, preproenkephalin, proopiomelanocortin, and corticotropin-releasing hormone receptor mRNA levels in the striatum and hypothalamic-pituitary-adrenal axis of mu-opioid receptor knockout mice.
Cocaine administration increases activity at dopamine receptors, increases preprodynorphin (ppDyn) gene expression in the caudate-putamen (CPu), and activates the stress responsive hypothalamic-pituitary-adrenal (HPA) axis. To examine the hypothesis that mu-opioid receptors (MOR) may play roles in these cocaine effects, we tested the effects of acute "binge" pattern cocaine administration in mice with targeted disruption of the MOR gene. Wild-type (+/+) and homozygous MOR-deficient (-/-) mice received three injections of 15 mg/kg cocaine at 1-h intervals. Mice were sacrificed 30 min after the last injection and mRNAs for ppDyn and preproenkephalin (ppEnk) in the CPu and nucleus accumbens (NAc), and for type I corticotropin-releasing hormone receptor (CRH(1) receptor) and pro-opiomelanocortin (POMC) in the hypothalamus and pituitary, were measured by solution hybridization RNase protection assays. Cocaine elevated ppDyn mRNA in the CPu, but not NAc, of both the MOR -/- and wild-type mice. ppEnk mRNA in the CPu, but not NAc, was lower in MOR -/- mice than in wild-type mice following cocaine administration. Hypothalamic CRH(1) receptor and POMC mRNAs were expressed at similar levels in untreated and in cocaine-treated mice of each genotype. However, there were lower basal levels of CRH(1) receptor mRNA in the anterior pituitary of the MOR -/- mice than in wild-type mice and the MOR -/- mice failed to show the cocaine-induced decreases in CRH(1) receptor mRNA found in the wild-type mice. Cocaine activated the HPA axis similarly in MOR -/- and wild-type mice, as reflected in similar increases in plasma corticosterone levels in both genotypes. These results support a specific role for MORs in acute cocaine effects on striatal ppEnk gene expression and fail to support critical roles for these receptors in acute cocaine's effects on either ppDyn gene expression or HPA activation. MOR -/- mice are useful models for studying cocaine effects on ppEnk gene expression that could aid interpretation of the similar postmortem phenomena found in human cocaine addicts.
Zhou
Yan
Y
Laboratory of the Biology of Addictive Diseases, Box 171, The Rockefeller University, New York, NY 10021, USA. zhouya@mail.rockefeller.edu
Spangler
Rudolph
R
Schlussman
Stefan D
SD
Yuferov
Vadim P
VP
Sora
Ichiro
I
Ho
Ann
A
Uhl
George R
GR
Kreek
Mary Jeanne
MJ
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000235:genetics*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004399:Dynorphins / Q000235:genetics*; D004745:Enkephalins / Q000235:genetics*; D005625:Frontal Lobe / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D011149:Pons / Q000187:drug effects / Q000502:physiology; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D017450:Receptors, Opioid, mu / Q000235:genetics*
D018765:Dopamine Uptake Inhibitors; D004745:Enkephalins; D011498:Protein Precursors; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; C036448:pre-prodynorphin; D011333:Pro-Opiomelanocortin; D004399:Dynorphins; D003346:Corticotropin-Releasing Hormone; C033660:preproenkephalin; D003042:Cocaine