Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin

Abstract

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. Keywords: cocaine, human, microarray, myelin basic protein, nucleus accumbens, post-mortem. Drug addiction, which constitutes a serious threat to public health, is a multifaceted disorder involving tolerance, dependence, craving, and relapse (Nestler 2002). A better understanding of the molecular mechanisms underlying drug addiction would presumably facilitate the development of more successful treatment strategies. Although the molecular basis of drug abuse is not fully understood, more is known about the neural systems subserving this disorder. In particular, animal studies have identified the nucleus accumbens as a brain region that plays a critical role in addiction (Dackis and O'Brien 2001;Everitt and Wolf 2002). Furthermore, in animal models, chronic exposure to cocaine induces structural and functional changes in the nucleus accumbens that are presumably mediated by altered gene expression (Toda et al. 2002;Norrholm et al. 2003).Although animal models continue to advance our understanding of the neurobiological underpinnings of drug abuse, it is difficult to model some uniquely human aspects of cocaine abuse, namely the spontaneous self-administration of cocaine, most often in a binging pattern of abuse, over a period of years or decades. Analysis of post-mortem brain provides a unique opportunity to examine changes in gene expression in the human drug abuser (Hurd and Herkenham 1993;Segal et al. 1997;Bannon et al. 2002). Recently, microarray technology has been employed to analyze gene expression in complex brain disorders (Mirnics et al. 2001). In the present study, we used DNA microarrays to investigate changes in gene expression in the nucleus accumbens of chronic cocaine abusers relative to carefully matched control subjects. Received September 8, 2003; revised manuscript received October 30, 2003; accepted October 31, 2003. Address corresponde...

Brain macrostructural and microstructural abnormalities in cocaine dependence

“…The decrease in MBP preceded the decrease in NFH, leading the authors to conclude that the change in myelin is the primary pathological event in cerebral WM under chronic hypoperfusion. Relatedly, a gene expression study of the nucleus accumbens in cocaine users found a reduction in the expression of myelinrelated genes (Albertson et al, 2004).…”

Expression of Transcripts for Myelin Related Genes in Postmortem Brain from Cocaine Abusers

“…A recent unbiased gene-array study with subsequent target validation by real-time quantitative polymerase chain reaction (Q-PCR) led to the identification of cocaine-induced altered expression in the NAc of multiple genes, including a group of myelin-related proteins that is involved in establishment and maintenance of myelin sheaths [25]. Altered myelin-associated gene expression has also been associated with excessive alcohol consumption in human alcoholic brain [26][27][28] and in animals treated chronically with ethanol [29].…”

“…Myelin in the CNS, which exists as compact and non-compact forms, is essential for nervous system function. We have included molecules that were previously identified as abnormally expressed in NAc [18,25], as well as six additional white matter-related transcripts that have previously been found to be abnormally regulated in other neuropsychiatric illnesses, including schizophrenia [38][39][40][41][42]. Although these myelin proteins presently are not well characterized, they can be divided into two groups; a group of transmembrane glycoproteins, which include the MOBP, PLP1, CLDN-11, EDG2 and MAG molecules and a group of cytosolic proteins consisting of the MBP, CNP, QKI and transferrin proteins [43].…”

Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

“…The microarray method allows high-throughput analysis of gene expression patterns (Khan et al, 1999;Lipshutz et al, 1999), and it is particularly useful for studying cocaineinduced gene expression changes (Bibb et al, 2001;Freeman et al, 2001a, b;Toda et al, 2002;McClung and Nestler, 2003;Yuferov et al, 2003;Tang et al, 2003;Yao et al, 2004;Albertson et al, 2004). Despite these studies, the gene expression profile induced by chronic cocaine through the DA D1 receptors remains unclear.…”