Abstract
Background
Global changes in gene expression underlying circuit and behavioral dysregulation
associated with cocaine addiction remain incompletely understood. Here, we show how
a history of cocaine self-administration (SA) reprograms transcriptome-wide responses
throughout the brain’s reward circuitry at baseline and in response to context and/or
cocaine re-exposure after prolonged withdrawal (WD).
Methods
We assigned male mice to one of six groups: saline/cocaine SA + 24-hour WD or saline/cocaine
SA + 30-day WD + an acute saline/cocaine challenge within the previous drug-paired
context. RNA sequencing was conducted on six interconnected brain reward regions.
Using pattern analysis of gene expression and factor analysis of behavior, we identified
genes that are strongly associated with addiction-related behaviors and uniquely altered
by a history of cocaine SA. We then identified potential upstream regulators of these
genes.
Results
We focused on three patterns of gene expression that reflect responses to 1) acute
cocaine, 2) context re-exposure, and 3) drug + context re-exposure. These patterns
revealed region-specific regulation of gene expression. Further analysis revealed
that each of these gene expression patterns correlated with an addiction index—a composite
score of several addiction-like behaviors during cocaine SA—in a region-specific manner.
Cyclic adenosine monophosphate response element binding protein and nuclear receptor
families were identified as key upstream regulators of genes associated with such
behaviors.
Conclusions
This comprehensive picture of transcriptome-wide regulation in the brain’s reward
circuitry by cocaine SA and prolonged WD provides new insight into the molecular basis
of cocaine addiction, which will guide future studies of the key molecular pathways
involved.
Keywords
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References
- Neural mechanisms of addiction: The role of reward-related learning and memory.Annu Rev Neurosci. 2006; 29: 565-598
- Neurobiology of addiction: A neurocircuitry analysis.Lancet Psychiatry. 2016; 3: 760-773
- Opponent process model and psychostimulant addiction.Pharmacol Biochem Behav. 1997; 57: 513-521
- Glutamate-dopamine interactions mediate the effects of psychostimulant drugs.Addict Biol. 1999; 4: 141-150
- Neuroadaptations involved in amphetamine and cocaine addiction.Drug Alcohol Depend. 1998; 51: 141-153
- Bidirectional synaptic structural plasticity after chronic cocaine administration occurs through Rap1 small GTPase signaling.Neuron. 2016; 89: 566-582
- Opposing role for Egr3 in nucleus accumbens cell subtypes in cocaine action.J Neurosci. 2015; 35: 7927-7937
- Transforming growth factor beta receptor 1 is increased following abstinence from cocaine self-administration, but not cocaine sensitization.PLoS One. 2013; 8: e83834
- Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse.Nat Neurosci. 2007; 10: 1029-1037
- Persistent alterations in mesolimbic gene expression with abstinence from cocaine self-administration.Neuropsychopharmacology. 2008; 33: 1807-1817
- Molecular neuroadaptations in the accumbens and ventral tegmental area during the first 90 days of forced abstinence from cocaine self-administration in rats.J Neurochem. 2003; 85: 1604-1613
- Striatal regulation of DeltaFosB, FosB, and cFos during cocaine self-administration and withdrawal.J Neurochem. 2010; 115: 112-122
- Cocaine administration and its withdrawal enhance the expression of genes encoding histone-modifying enzymes and histone acetylation in the rat prefrontal cortex.Neurotox Res. 2017; 32: 141-150
- Transcriptomic profiling of the ventral tegmental area and nucleus accumbens in rhesus macaques following long-term cocaine self-administration.Drug Alcohol Depend. 2017; 175: 9-23
- Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration.BMC Neurosci. 2010; 11: 29
- Circuit-wide transcriptional profiling reveals brain region-specific gene networks regulating depression susceptibility.Neuron. 2016; 90: 969-983
- Ketamine and imipramine reverse transcriptional signatures of susceptibility and induce resilience-specific gene expression profiles.Biol Psychiatry. 2017; 81: 285-295
- Sex-specific transcriptional signatures in human depression.Nat Med. 2017; 23: 1102-1111
- voom: Precision weights unlock linear model analysis tools for RNA-seq read counts.Genome Biol. 2014; 15: R29
- Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2.Science. 2017; 356: 1185-1188
- Opposite molecular signatures of depression in men and women.Biol Psychiatry. 2018; 84: 18-27
- Drug experience epigenetically primes Fosb gene inducibility in rat nucleus accumbens.J Neurosci. 2012; 32: 10267-10272
- Essential role of the histone methyltransferase G9a in cocaine-induced plasticity.Science. 2010; 327: 213-216
- Reflections on: “A general role for adaptations in G-Proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function”.Brain Res. 2016; 1645: 71-74
- Transcriptional and epigenetic mechanisms of addiction.Nat Rev Neurosci. 2011; 12: 623-637
- Rank-rank hypergeometric overlap: Identification of statistically significant overlap between gene-expression signatures.Nucleic Acids Res. 2010; 38: 169
- A quantitative framework to evaluate modeling of cortical development by neural stem cells.Neuron. 2014; 83: 69-86
- Transcription factor E2F3a in nucleus accumbens affects cocaine action via transcription and alternative splicing.Biol Psychiatry. 2018; 84: 167-179
- Threonine 149 phosphorylation enhances DeltaFosB transcriptional activity to control psychomotor responses to cocaine.J Neurosci. 2014; 34: 11461-11469
- Chronic cocaine-regulated epigenomic changes in mouse nucleus accumbens.Genome Biol. 2014; 15: R65
- Regulation of gene expression and cocaine reward by CREB and DeltaFosB.Nat Neurosci. 2003; 6: 1208-1215
- Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins.Neuron. 2009; 62: 335-348
- Serum response factor promotes resilience to chronic social stress through the induction of DeltaFosB.J Neurosci. 2010; 30: 14585-14592
- Pharmacological activators of the NR4A nuclear receptors enhance LTP in a CREB/CBP-dependent manner.Neuropsychopharmacology. 2017; 42: 1243-1253
- Transcriptomics of environmental enrichment reveals a role for retinoic acid signaling in addiction.Front Mol Neurosci. 2016; 9: 119
- LMTK3 deficiency causes pronounced locomotor hyperactivity and impairs endocytic trafficking.J Neurosci. 2014; 34: 5927-5937
- Signaling by the germinal center kinase family of protein kinases.J Biol Chem. 1999; 274: 5259-5262
- The kinase LMTK3 promotes invasion in breast cancer through GRB2-mediated induction of integrin beta(1).Sci Signal. 2014; 7: ra58
- MAP4K family kinases in immunity and inflammation.Adv Immunol. 2016; 129: 277-314
- Immune modulation of learning, memory, neural plasticity and neurogenesis.Brain Behav Immun. 2011; 25: 181-213
- The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL.J Biol Chem. 2001; 276: 37258-37265
- Synaptic plasticity mediating cocaine relapse requires matrix metalloproteinases.Nat Neurosci. 2014; 17: 1655-1657
- The glutamate homeostasis hypothesis of addiction.Nat Rev Neurosci. 2009; 10: 561-572
- Neurobiology of the incubation of drug craving.Trends Neurosci. 2011; 34: 411-420
- Neural substrates of cocaine-cue associations that trigger relapse.Eur J Pharmacol. 2005; 526: 140-146
- The many faces of CREB.Trends Neurosci. 2005; 28: 436-445
- Low expression of D2R and Wntless correlates with high motivation for heroin.Behav Neurosci. 2015; 129: 744-755
- Individual differences in gene expression of vasopressin, D2 receptor, POMC and orexin: Vulnerability to relapse to heroin-seeking in rats.Physiol Behav. 2015; 139: 127-135
- Epigenetic control of EMT/MET dynamics: HNF4alpha impacts DNMT3s through miRs-29.Biochim Biophys Acta. 2015; 1849: 919-929
- Aberrant epigenome in iPSC-derived dopaminergic neurons from Parkinson's disease patients.EMBO Mol Med. 2015; 7: 1529-1546
- Targeting the HDAC2/HNF-4A/miR-101b/AMPK pathway rescues tauopathy and dendritic abnormalities in Alzheimer's disease.Mol Ther. 2017; 25: 752-764
- Hepatocyte nuclear factor 4 alpha is a key factor related to depression and physiological homeostasis in the mouse brain.PLoS One. 2015; 10: e0119021
- Role of nuclear receptors in central nervous system development and associated diseases.J Exp Neurosci. 2015; 9: 93-121
Article info
Publication history
Published online: April 25, 2018
Accepted:
April 17,
2018
Received in revised form:
March 15,
2018
Received:
October 16,
2017
Footnotes
JF is currently affiliated with the Department of Biological Science, Program in Neuroscience, Florida State University, Tallahassee, Florida. JWK is currently affiliated with the Department of Neural Development and Disease, Korea Brain Research Institute, Daegu, Republic of Korea; BL is currently affiliated with the Department of Psychiatry and Neurosciences, Faculty of Medicine, Laval University, Québec City, Québec, Canada. RCB is currently affiliated with the Department of Psychology, McGill University, Montréal, Québec, Canada.
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Copyright
© 2018 Society of Biological Psychiatry.
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- Persistence of Drug Memories: Melting TranscriptomesBiological PsychiatryVol. 84Issue 12
- PreviewOne of the defining characteristics of drug dependence is relapse after a period of abstinence. Cue-induced drug craving and relapse risk not only persist during abstinence, but increase over time, a phenomenon termed incubation (1). This progressive increase in risk factors likely requires enduring “memory-like” changes in synaptic plasticity, but there has been little exploration of the underlying molecular mechanisms. It is assumed that this remodeling of the brain is initiated by changes in gene expression (2).
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