scholarly journals Cocaine induces paradigm-specific changes to the transcriptome within the ventral tegmental area

2021 ◽  
Author(s):  
Rianne R. Campbell ◽  
Siwei Chen ◽  
Joy H. Beardwood ◽  
Alberto J. López ◽  
Lilyana V. Pham ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ventral Tegmental Area ◽  
Home Cage ◽  
Expression Patterns ◽  
Energy Regulation ◽  
Biological Processes ◽  
Cocaine Exposure ◽  
Self Administration ◽  
Drug Reinforcement ◽  
Ventral Tegmental

AbstractDuring the initial stages of drug use, cocaine-induced neuroadaptations within the ventral tegmental area (VTA) are critical for drug-associated cue learning and drug reinforcement processes. These neuroadaptations occur, in part, from alterations to the transcriptome. Although cocaine-induced transcriptional mechanisms within the VTA have been examined, various regimens and paradigms have been employed to examine candidate target genes. In order to identify key genes and biological processes regulating cocaine-induced processes, we employed genome-wide RNA-sequencing to analyze transcriptional profiles within the VTA from male mice that underwent one of four commonly used paradigms: acute home cage injections of cocaine, chronic home cage injections of cocaine, cocaine-conditioning, or intravenous-self administration of cocaine. We found that cocaine alters distinct sets of VTA genes within each exposure paradigm. Using behavioral measures from cocaine self-administering mice, we also found several genes whose expression patterns corelate with cocaine intake. In addition to overall gene expression levels, we identified several predicted upstream regulators of cocaine-induced transcription shared across all paradigms. Although distinct gene sets were altered across cocaine exposure paradigms, we found, from Gene Ontology (GO) term analysis, that biological processes important for energy regulation and synaptic plasticity were affected across all cocaine paradigms. Coexpression analysis also identified gene networks that are altered by cocaine. These data indicate that cocaine alters networks enriched with glial cell markers of the VTA that are involved in gene regulation and synaptic processes. Our analyses demonstrate that transcriptional changes within the VTA depend on the route, dose and context of cocaine exposure, and highlight several biological processes affected by cocaine. Overall, these findings provide a unique resource of gene expression data for future studies examining novel cocaine gene targets that regulate drug-associated behaviors.

scholarly journals Ibrutinib as a potential therapeutic for cocaine use disorder

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Spencer B. Huggett ◽  
Jeffrey S. Hatfield ◽  
Joshua D. Walters ◽  
John E. McGeary ◽  
Justine W. Welsh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Patterns ◽  
Public Health Problem ◽  
Brain Regions ◽  
Cocaine Exposure ◽  
Self Administration ◽  
Cocaine Use ◽  
Potential Therapeutics

AbstractCocaine use presents a worldwide public health problem with high socioeconomic cost. No current pharmacologic treatments are available for cocaine use disorder (CUD) or cocaine toxicity. To explore pharmaceutical treatments for tthis disorder and its sequelae we analyzed gene expression data from post-mortem brain tissue of individuals with CUD who died from cocaine-related causes with matched cocaine-free controls (n = 71, Mage = 39.9, 100% male, 49% with CUD, 3 samples/brain regions). To match molecular signatures from brain pathology with potential therapeutics, we leveraged the L1000 database honing in on neuronal mRNA profiles of 825 repurposable compounds (e.g., FDA approved). We identified 16 compounds that were negatively associated with CUD gene expression patterns across all brain regions (padj < 0.05), all of which outperformed current targets undergoing clinical trials for CUD (all padj > 0.05). An additional 43 compounds were positively associated with CUD expression. We performed an in silico follow-up potential therapeutics using independent transcriptome-wide in vitro (neuronal cocaine exposure; n = 18) and in vivo (mouse cocaine self-administration; n = 12–15) datasets to prioritize candidates for experimental validation. Among these medications, ibrutinib was consistently linked with the molecular profiles of both neuronal cocaine exposure and mouse cocaine self-administration. We assessed the therapeutic efficacy of ibrutinib using the Drosophila melanogaster model. Ibrutinib reduced cocaine-induced startle response and cocaine-induced seizures (n = 61–142 per group; sex: 51% female), despite increasing cocaine consumption. Our results suggest that ibrutinib could be used for the treatment of cocaine use disorder.

scholarly journals Ibrutinib as a Potential Therapeutic for Cocaine Use Disorder

2021 ◽  
Author(s):  
Spencer B. Huggett ◽  
Jeffrey S. Hatfield ◽  
Joshua D. Walters ◽  
John E. McGeary ◽  
Justine W. Welsh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Expression Patterns ◽  
Public Health Problem ◽  
Therapeutic Effects ◽  
Cocaine Exposure ◽  
Self Administration ◽  
Cocaine Use

ABSTRACTCocaine use presents a worldwide public health problem with high socioeconomic cost. Current treatments for cocaine use disorder (CUD) are suboptimal and rely primarily on behavioral interventions. To explore pharmaceutical treatments for CUD, we analyzed genome-wide gene expression data from publically availble human brain tissues (midbrain, hippocampus and prefrontal cortex neurons) from 71 individuals (mean age = 39.9, 100% male, 36 with CUD and 35 matched controls). We leveraged the L1000 database to investigate molecular associations between neuronal mRNA profiles from 825 repurposable compounds (e.g., FDA approved) with human CUD gene expression in the brain. We identified 16 compounds that were negatively associated with CUD gene expression patterns across all brain regions (padj < 0.05), all of which outperformed current targets undergoing clinical trials for CUD (all padj > 0.05). We tested the effectiveness of these compounds using independent transcriptome-wide in vitro (neuronal cocaine exposure; n=18) and in vivo (mouse cocaine self-administration; prefrontal cortex, hippocampus and midbrain; n = 12-15) datasets. Among these medications, Ibrutinib demonstrated negative associations with both neuronal cocaine exposure and mouse cocaine self-administration. To obtain experimental confirmation of therapeutic effects of Ibrutinib on CUD, we used the Drosophila melanogaster model, which enables highthroughput quantification of behavioral responses in defined genetic backgrounds and controlled environmental conditions. Ibrutinib altered cocaine-induced changes in startle response and reduced the occurrence of cocaine-induced seizures (n = 61-142 per group; sex: 51%female). Our results identify Ibrutinib, an FDA approved medication, as a potential therapeutic for cocaine neurotoxicity.

scholarly journals Cocaine Administration and Its Abstinence Conditions Modulate Neuroglia

2020 ◽  
Vol 21 (21) ◽  
pp. 7970
Author(s):  
Kinga Gawlińska ◽  
Małgorzata Frankowska ◽  
Dawid Gawliński ◽  
Marcin Piechota ◽  
Michał Korostyński ◽  
...  
Keyword(s):  
Gene Expression ◽  
Home Cage ◽  
Cell Activity ◽  
Lymphocyte Activation ◽  
Extinction Training ◽  
Rat Striatum ◽  
Cocaine Exposure ◽  
Self Administration ◽  
Protein Levels ◽  
Drug Abstinence

Cocaine induces neuronal changes as well as non-neuronal (astrocytes, microglia, oligodendroglia) mechanisms, but these changes can also be modulated by various types of drug abstinence. Due to the very complex and still incompletely understood nature of cocaine use disorder, understanding of the mechanisms involved in addictive behavior is necessary to further search for effective pharmacotherapy of this disease. The aim of this study was to investigate changes at the gene and protein levels associated with glial cell activity after cocaine exposure, as well as during early cocaine abstinence (3 days) with extinction training or in home cage isolation. Cocaine self-administration significantly decreased myelin regulatory factor (MYRF) and cyclic nucleotide phosphodiesterase (CNP) expression in the hippocampus as well as pleckstrin (PLEK) and T-lymphocyte activation antigen (CD86) in the rat striatum. Depending on cocaine abstinence conditions, microglial PLEK expression was increased through extinction training but did not change in the home cage isolation. In addition, downregulation of gene expression associated with oligodendrocytes (CNP, MYRF) and microglia regulator of G protein signaling 1 (RGS1) was observed in the hippocampus, regardless of the type of drug abstinence, while downregulation of myelin and lymphocyte protein (MAL) expression was found only in rats exposed to abstinence in the home cage. Taken together, the presented results strongly suggest that cocaine abstinence evokes significant changes in gene expression associated with the proper functioning of glial cells, suggesting their significant involvement in adaptive changes in the brain associated with cocaine exposure. Interestingly, drug abstinence conditions are important factors influencing observed changes at the transcript levels of selected genes, which may be of clinical interest.

scholarly journals Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area   Opioid Receptors

2015 ◽  
Vol 35 (35) ◽  
pp. 12217-12231 ◽  
Author(s):  
L. Hipolito ◽  
A. Wilson-Poe ◽  
Y. Campos-Jurado ◽  
E. Zhong ◽  
J. Gonzalez-Romero ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Opioid Receptors ◽  
Inflammatory Pain ◽  
Self Administration ◽  
Ventral Tegmental

Acute cocaine exposure alters spine density and long-term potentiation in the ventral tegmental area

2007 ◽  
Vol 26 (3) ◽  
pp. 749-756 ◽  
Author(s):  
Federica Sarti ◽  
Stephanie L. Borgland ◽  
Viktor N. Kharazia ◽  
Antonello Bonci
Keyword(s):  
Ventral Tegmental Area ◽  
Long Term Potentiation ◽  
Spine Density ◽  
Cocaine Exposure ◽  
Term Potentiation ◽  
Ventral Tegmental

scholarly journals Toxoplasma infection alters dopamine-sensitive behaviors and host gene expression patterns associated with neuropsychiatric disease

2021 ◽  
Author(s):  
Graham L. Cromar ◽  
Jonathan Epp ◽  
Ana Popovic ◽  
Yusing Gu ◽  
Violet Ha ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differentially Expressed Genes ◽  
Expression Patterns ◽  
Neurocognitive Disorders ◽  
Differentially Expressed ◽  
Gene Expression Patterns ◽  
Low Grade ◽  
Cocaine Exposure ◽  
Multiple Testing Correction ◽  
The Impact

ABSTRACTToxoplasma gondii is a single celled parasite thought to infect 1 in 3 worldwide. During chronic infection, T. gondii can migrate to the brain where it promotes low-grade neuroinflammation with the capacity to induce changes in brain morphology and behavior. Consequently, infection with T. gondii has been linked with a number of neurocognitive disorders including schizophrenia (SZ), dementia, and Parkinson’s disease. Beyond neuroinflammation, infection with T. gondii can modulate the production of neurotransmitters, such as dopamine. To further dissect these pathways and examine the impact of altered dopaminergic sensitivity in T. gondii-infected mice on both behavior and gene expression, we developed a novel mouse model, based on stimulant-induced (cocaine) hyperactivity. Employing this model, we found that infection with T. gondii did not alter fear behavior but did impact motor activity and neuropsychiatric-related behaviurs. While both behaviors may help reduce predator avoidance, consistent with previous studies, the latter finding is reminiscent of neurocognitive disorders. Applying RNASeq to two relevant brain regions, striatum and hippocampus, we identified a broad upregulation of immune responses. However, we also noted significant associations with more meaningful neurologically relevant terms were masked due to the sheer number of terms incorporated in multiple testing correction. We therefore performed a more focused analysis using a curated set of neurologically relevant terms revealing significant associations across multiple pathways. We also found that T. gondii and cocaine treatments impacted the expression of similar functional pathways in the hippocampus and striatum although, as indicated by the low overlap among differentially expressed genes, largely via different proteins. Furthermore, while most differentially expressed genes reacted to a single condition and were mostly upregulated, we identified gene expression patterns indicating unexpected interactions between T. gondii infection and cocaine exposure. These include sets of genes which responded to cocaine exposure but not upon cocaine exposure in the context of T. gondii infection, suggestive of a neuroprotective effect advantageous to parasite persistence. Given its ability to uncover such complex relationships, we propose this novel model offers a new perspective to dissect the molecular pathways by which T. gondii infection contributes to neuropsychiatric disorders such as schizophrenia.

Alpha-melanocyte stimulating hormone modulates ethanol self-administration in posterior ventral tegmental area through melanocortin-4 receptors

2014 ◽  
Vol 20 (2) ◽  
pp. 302-315 ◽  
Author(s):  
Gajanan P. Shelkar ◽  
Atmaram D. Kale ◽  
Uday Singh ◽  
Praful S. Singru ◽  
Nishikant K. Subhedar ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Self Administration ◽  
Melanocyte Stimulating Hormone ◽  
Ventral Tegmental ◽  
Stimulating Hormone
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