Differential distribution of CREB in the mesolimbic dopamine reward pathway.
The transcription factor cAMP response element binding protein (CREB) has been implicated in the long-term neuronal plasticity associated with addiction. While CREB is expressed in many cells throughout the brain, very little is known about the relative concentrations of CREB protein in various brain regions. Studies in which CREB levels have been altered, either constitutively throughout the brain via gene targeting or transiently in specific brain regions, demonstrate variable roles for this protein in mediating reinforcing properties of drugs of abuse. To investigate the complex nature of CREB function in addiction, we examined the distribution of CREB protein in the nucleus accumbens (NAc) and ventral tegmental area (VTA), two brain regions that are part of the well-defined mesolimbic dopamine pathway involved in reward processing. Our data demonstrate significantly more CRE binding activity and CREB protein in the NAc compared to levels present in the VTA of wild-type mice. Phospho-CREB levels are increased in the NAc of both wild-type and CREBalphaDelta mutant animals after cocaine. However, morphine-induced increases of phospho-CREB levels are seen in the VTA of wild-type mice but not CREBalphaDelta mutant mice. Consequently, the 90% reduction of CREB in CREBalphaDelta mutant mice differentially affects CREB phosphorylation and induction of downstream targets of CREB in the NAc and VTA.
Walters
Carrie L
CL
Department of Pharmacology, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA.
Kuo
Yuo-Chen
YC
Blendy
Julie A
JA
D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism; D013287:Illicit Drugs / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009020:Morphine / Q000494:pharmacology; D009434:Neural Pathways / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012201:Reward; D019966:Substance-Related Disorders / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D013287:Illicit Drugs; D004399:Dynorphins; D009020:Morphine; D004247:DNA; D014446:Tyrosine 3-Monooxygenase; D017868:Cyclic AMP-Dependent Protein Kinases; D003042:Cocaine; D004298:Dopamine