Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse

Abstract

Drug abuse is thought to induce long-term cellular and behavioral adaptations as a result of alterations in gene expression. Understanding the molecular consequences of addiction may contribute to the development of better treatment strategies. This study utilized high-throughput Affymetrix microarrays to identify gene expression changes in the post-mortem nucleus accumbens of chronic heroin abusers. These data were analyzed independently and in relation to our previously reported data involving human cocaine abusers, in order to determine which expression changes were drug specific and which may be common to the phenomenon of addiction. A significant decrease in the expression of numerous genes encoding proteins involved in presynaptic release of neurotransmitter was seen in heroin abusers, a finding not seen in the cocaine-abusing cohort. Conversely, the striking decrease in myelin-related genes observed in cocaine abusers was not evident in our cohort of heroin subjects. Overall, little overlap in gene expression profiles was seen between the two drug-abusing cohorts: out of the approximately 39,000 transcripts investigated, the abundance of only 25 was significantly changed in both cocaine and heroin abusers, with nearly one-half of these being altered in opposite directions. These data suggest that the profiles of nucleus accumbens gene expression associated with chronic heroin or cocaine abuse are largely unique, despite what are thought to be common effects of these drugs on dopamine neurotransmission in this brain region. A re-examination of our current assumptions about the commonality of molecular mechanisms associated with substance abuse seems warranted.

Figure 1

Altered transcript abundance in the nucleus accumbens of human cocaine and heroin abusers. The signal log ratio (log base 2) distribution of all transcripts detected in the majority of subject pairs was plotted after binning averages into groups of 0.05 (a:n=18 055, b:n=17 688). Values falling to the left of zero indicate a downregulation of transcript abundance in drug abusers, whereas those to the right of zero are indicative of increases. The mean signal log ratio of myelin-related transcripts (MBP, MOBP, and PLP) for each study was plotted in relation to the normal distribution of all present transcripts, and is represented by black arrows (a:mean=0.13; b:mean=−0.81). The mean signal log ratio for all presynaptic machinery transcripts (listed in Figure 2a) is represented by gray arrows (a:mean=−0.39; b:mean=−0.001). Note that the majority of transcripts are unchanged in either heroin abusers (a) or cocaine abusers (b), and that changes in myelin-related and presynaptic machinery transcripts are drug specific.

Figure 2

Decreased expression of presynaptic machinery genes in human heroin abusers. (a) Specific presynaptic machinery genes, their putative functions, and Affymetrix probe ID numbers are listed. Median and individual signal log ratios for the seven heroin–control pairs are shown (as are median SLR from the cocaine study as a comparison). (b) Quantitative real-time RT-PCR was used to determine the abundance of four representative transcripts (synapsin 2b, synaptotagmin 1a, synaptic vesicle protein 2a, and synaptogyrin 3). All transcript levels were divided by β-actin levels, which did not differ between groups (see Materials and methods). Significant heroin-related decreases in transcript levels were validated in the case of synapsin 2b (p = 0.046), synaptic vesicle protein 2a (p = 0.028), synaptogyrin 3 (p = 0.027), but not synaptotagmin 1a (p = 0.128). Median percent decrease across all subject pairs is also shown for each of the four transcripts.