ABSTRACT
During development, survival of midbrain dopamine neurons and specification of their phenotype are dependent upon the intracellular expression of a number of transcription factors, including Engrailed 1, Pitx3, and Nurr1. The role of these transcription factors in the maintenance of the dopaminergic phenotype is less clear. In the present study, we show that each of these transcription factors is robustly expressed in adult dopamine neurons in human midbrain, and that cocaine abuse is associated with a significant decrease in the abundance of Nurr1 and Pitx3 in these cells. These data suggest that cocaine abuse leads to a partial loss of dopaminergic phenotype.
Subject(s)
Cocaine-Related Disorders/genetics , Dopamine/genetics , Transcription Factors/genetics , DNA-Binding Proteins/genetics , Homeodomain Proteins/genetics , Humans , Immunohistochemistry , Mesencephalon/cytology , Mesencephalon/physiology , Neurons/physiology , Nuclear Receptor Subfamily 4, Group A, Member 2 , Phenotype , Tissue FixationABSTRACT
Chronic cocaine abuse induces long-term neural adaptations as a consequence of alterations in gene expression. This study was undertaken to identify those transcripts differentially regulated in the nucleus accumbens of human cocaine abusers. Affymetrix microarrays were used to measure transcript abundance in 10 cocaine abusers and 10 control subjects matched for age, race, sex, and brain pH. As expected, gene expression of cocaine- and amphetamine-regulated transcript (CART) was increased in the nucleus accumbens of cocaine abusers. The most robust and consistent finding, however, was a decrease in the expression of a number of myelin-related genes, including myelin basic protein (MBP), proteolipid protein (PLP), and myelin-associated oligodendrocyte basic protein (MOBP). The differential expression seen by microarray for CART as well as MBP, MOBP, and PLP was verified by RT-PCR. In addition, immunohistochemical experiments revealed a decrease in the number of MBP-immunoreactive oligodendrocytes present in the nucleus accumbens and surrounding white matter of cocaine abusers. These findings suggest a dysregulation of myelin in human cocaine abusers.
Subject(s)
Cocaine-Related Disorders/metabolism , Gene Expression Profiling , Gene Expression Regulation , Myelin Sheath/genetics , Nucleus Accumbens/metabolism , Adult , Cell Count , Cocaine-Related Disorders/pathology , Female , Humans , Male , Middle Aged , Myelin Basic Protein/biosynthesis , Myelin Basic Protein/genetics , Myelin Proteins , Myelin Proteolipid Protein/genetics , Myelin-Associated Glycoprotein/genetics , Myelin-Oligodendrocyte Glycoprotein , Nerve Tissue Proteins/genetics , Nucleus Accumbens/pathology , Oligodendroglia/metabolism , Oligodendroglia/pathology , RNA, Messenger/metabolism , Reference Values , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Chronic exposure to cocaine induces long-term adaptations that are likely to involve changes in transcription factor expression. This possibility has not been examined in the cocaine-exposed human brain. The transcription factor nurr1 is highly expressed in rodent midbrain dopamine neurons and is essential for their proper phenotypic development. Here we show that human NURR1 gene expression is robust within control subjects and reduced markedly within the dopamine neurons of human cocaine abusers. NURR1 is known to regulate transcription of the gene encoding the cocaine-sensitive dopamine transporter (DAT). We show here that DAT gene expression also is reduced markedly in the dopamine neurons of NURR1-deficient cocaine abusers, suggesting that NURR1 plays a critical role in vivo in controlling human DAT gene expression and adaptation to repeated exposure to cocaine.
