Distinctive Profiles of Gene Expression in the Human Nucleus Accumbens Associated with Cocaine and Heroin Abuse

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.

[1]  B. Kolachana,et al.  Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse , 2003, The Pharmacogenomics Journal.

[2]  C. Gerfen,et al.  D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. , 1990, Science.

[3]  B. Everitt,et al.  Profiles of Cognitive Dysfunction in Chronic Amphetamine and Heroin Abusers , 2000, Neuropsychopharmacology.

[4]  C. Thaller,et al.  Characterization of synaptogyrin 3 as a new synaptic vesicle protein , 2004, The Journal of comparative neurology.

[5]  Liping Huang,et al.  The pallid gene encodes a novel, syntaxin 13-interacting protein involved in platelet storage pool deficiency , 1999, Nature Genetics.

[6]  G. Bartzokis,et al.  Magnetic resonance imaging evidence of “silent” cerebrovascular toxicity in cocaine dependence , 1999, Biological Psychiatry.

[7]  F. Bloom,et al.  Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats , 2004, Psychopharmacology.

[8]  F. Bloom,et al.  Heroin and cocaine intravenous self-administration in rats: Mediation by separate neural systems , 2004, Psychopharmacology.

[9]  A. Czernik,et al.  Altered expression of a-type but not b-type synapsin isoform in the brain of patients at high risk for Alzheimer's disease assessed by DNA microarray technique , 2001, Neuroscience Letters.

[10]  R. Harris,et al.  Patterns of gene expression are altered in the frontal and motor cortices of human alcoholics , 2002, Journal of neurochemistry.

[11]  Tatia M.C. Lee,et al.  The impact of heroin on frontal executive functions. , 2002, Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists.

[12]  Thorsten Lang,et al.  Membrane fusion. , 2003, Cell.

[13]  M. Bannon,et al.  Gene Expression Profiling in the Brains of Human Cocaine Abusers , 2005, Addiction biology.

[14]  J. Cadet,et al.  Calcineurin/NFAT-induced up-regulation of the Fas ligand/Fas death pathway is involved in methamphetamine-induced neuronal apoptosis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Y. Hurd,et al.  The Role of Dopamine, Dynorphin, and CART Systems in the Ventral Striatum and Amygdala in Cocaine Abuse , 1999, Annals of the New York Academy of Sciences.

[16]  E. Stein,et al.  Dopamine release in the nucleus accumbens during heroin self-administration is modulated by kappa opioid receptors: an in vivo fast-cyclic voltammetry study. , 1998, The Journal of pharmacology and experimental therapeutics.

[17]  J E Smith,et al.  The effects of intravenous heroin administration on extracellular nucleus accumbens dopamine concentrations as determined by in vivo microdialysis. , 1995, The Journal of pharmacology and experimental therapeutics.

[18]  G. Bartzokis,et al.  The incidence of T2-weighted MR imaging signal abnormalities in the brain of cocaine-dependent patients is age-related and region-specific. , 1999, AJNR. American journal of neuroradiology.

[19]  J. Soghomonian,et al.  Tyrosine kinase B and C receptors in the neostriatum and nucleus accumbens are co-localized in enkephalin-positive and enkephalin-negative neuronal profiles and their expression is influenced by cocaine , 2003, Neuroscience.

[20]  T Ernst,et al.  Gender effects on persistent cerebral metabolite changes in the frontal lobes of abstinent cocaine users. , 1999, The American journal of psychiatry.

[21]  E. Bongarzone,et al.  Identification of the Dopamine D3 Receptor in Oligodendrocyte Precursors: Potential Role in Regulating Differentiation and Myelin Formation , 1998, The Journal of Neuroscience.

[22]  E. Castrén,et al.  Neurotrophin-4 mediated TrkB activation reinforces morphine-induced analgesia , 2003, Nature Neuroscience.

[23]  M. Bannon,et al.  Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin , 2004, Journal of neurochemistry.

[24]  J. Kleinman,et al.  Reduction of synapsin in the hippocampus of patients with bipolar disorder and schizophrenia , 2002, Molecular Psychiatry.

[25]  Linda Chang,et al.  Neurochemical alterations in asymptomatic abstinent cocaine users: A proton magnetic resonance spectroscopy study , 1997, Biological Psychiatry.

[26]  A. Campagnoni,et al.  Postnatal localization and morphogenesis of cells expressing the dopaminergic D2 receptor gene in rat brain: Expression in non‐neuronal cells , 1998, The Journal of comparative neurology.

[27]  T. Südhof.  The synaptic vesicle cycle , 2004 .

[28]  C D Marsden,et al.  Tissue pH as an indicator of mRNA preservation in human post-mortem brain. , 1995, Brain research. Molecular brain research.

[29]  B. Budziszewska,et al.  Effects of single and repeated morphine administration on the prodynorphin, proenkephalin and dopamine D2 receptor gene expression in the mouse brain , 1997, Neuropeptides.

[30]  M. Kreek,et al.  Pharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments , 2005, Pharmacological Reviews.

[31]  D. Mash,et al.  Molecular profiling of midbrain dopamine regions in cocaine overdose victims , 2003, Journal of neurochemistry.

[32]  Nunzio Pomara,et al.  Reduced frontal white matter integrity in cocaine dependence: a controlled diffusion tensor imaging study , 2002, Biological Psychiatry.

[33]  J. García-Sevilla,et al.  Chronic morphine induces up‐regulation of the pro‐apoptotic Fas receptor and down‐regulation of the anti‐apoptotic Bcl‐2 oncoprotein in rat brain , 2001, British journal of pharmacology.

[34]  S. Hemby,et al.  Synergistic elevations in nucleus accumbens extracellular dopamine concentrations during self-administration of cocaine/heroin combinations (Speedball) in rats. , 1999, The Journal of pharmacology and experimental therapeutics.

[35]  Yufang Shi,et al.  Fas-mediated cell death promoted by opioids , 1999, Nature.

[36]  P. Camilli,et al.  Accessory factors in clathrin-dependent synaptic vesicle endocytosis , 2000, Nature Reviews Neuroscience.

[37]  R. Scheller,et al.  Amisyn, a Novel Syntaxin-binding Protein That May Regulate SNARE Complex Assembly* , 2002, The Journal of Biological Chemistry.

[38]  Pat Levitt,et al.  Molecular Characterization of Schizophrenia Viewed by Microarray Analysis of Gene Expression in Prefrontal Cortex , 2000, Neuron.

[39]  D. Haverstick,et al.  Preprotachykinin gene expression in the human basal ganglia: characterization of mRNAs and pre-mRNAs produced by alternate RNA splicing. , 1992, Brain research. Molecular brain research.

[40]  A. Miralles,et al.  Modulation of Fas receptor proteins and dynamin during opiate addiction and induction of opiate withdrawal in rat brain , 2003, Naunyn-Schmiedeberg's Archives of Pharmacology.

[41]  Jim Mintz,et al.  Brain maturation may be arrested in chronic cocaine addicts , 2002, Biological Psychiatry.

[42]  R. Harris,et al.  Gene expression in human alcoholism: microarray analysis of frontal cortex. , 2000, Alcoholism, clinical and experimental research.

[43]  P. Kalivas,et al.  Repeated cocaine administration alters the expression of genes in corticolimbic circuitry after a 3‐week withdrawal: a DNA macroarray study , 2002, Journal of neurochemistry.

[44]  S. Hemby,et al.  Self-Administered Heroin and Cocaine Combinations in the Rat: Additive Reinforcing Effects—Supra-Additive Effects on Nucleus Accumbens Extracellular Dopamine , 2006, Neuropsychopharmacology.

[45]  R. Wise,et al.  Elevations of nucleus accumbens dopamine and DOPAC levels during intravenous heroin self‐administration , 1995, Synapse.