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PROVIDER: PRJNA124729 | ENA |
REPOSITORIES: ENA
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Project description:Abstract Background Psychostimulant use disorder is a major public health issue, and despite the scope of the problem there are currently no FDA approved treatments. There would be tremendous utility in development of a treatment that could help patients both achieve and maintain abstinence. Previous work from our group has identified granulocyte-colony stimulating factor (G-CSF) as a neuroactive cytokine that alters behavioral response to cocaine, increases synaptic dopamine release, and enhances cognitive flexibility. Here, we investigate the role of G-CSF in affecting extinction and reinstatement of cocaine-seeking and perform detailed characterization of its proteomic effects in multiple limbic substructures. Methods Sprague-Dawley rats were injected with PBS or G-CSF during (1) extinction or (2) abstinence from cocaine self-administration, and drug seeking behavior was measured. Quantitative assessment of changes in the proteomic landscape in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were performed via data-independent acquisition (DIA) mass spectrometry analysis. Results Administration of G-CSF during extinction accelerated the rate of extinction, and administration during abstinence attenuated cue-induced cocaine-seeking. Analysis of global protein expression demonstrated that G-CSF regulated proteins primarily in mPFC that are critical to glutamate signaling and synapse maintenance. Conclusion Taken together, these findings support G-CSF as a viable translational research target with the potential to reduce drug craving or seeking behaviors. Importantly, recombinant G-CSF exists as an FDA-approved medication which may facilitate rapid clinical translation. Additionally, using cutting-edge multi-region discovery proteomics analyses, these studies identify a novel mechanism underlying G-CSF effects on behavioral plasticity.
2021-01-28 | PXD019485 | Pride
Project description:At the core of addiction, drug experiences induce circuit-specific transcriptional adaptations to hijack the native mechanisms of neuroplasticity and promote maladaptive behaviors. In the present study, we utilized 3’-RNA-sequencing to define the transcriptional landscapes of five brain nuclei within the reward circuit following distinct cocaine experiences. We exposed mice to cocaine (20 mg/kg, IP), acutely (single exposure), repeatedly (5 daily exposures) as well as to a challenge cocaine (acute exposure after 21 days of abstinence following repeated cocaine). We then profiled transcription (applying 3’-RNAseq) within key brain structures of the reward circuitry: limbic cortex- medial prefrontal and cingulate together (LCtx), nucleus accumbens (NAc), dorsal striatum (DS), amygdala (Amy), and lateral hypothalamus (LH) at 0, 1, 2, 4 hrs following cocaine exposure.
2021-04-14 | GSE158588 | GEO
Project description:Rat medial prefrontal cortex gene expression following heroin self-administration, abstinence, and extinction
| PRJNA109633 | ENA
Project description:Gene expression profiling in dopaminergic brain structures of rats self-administering cocaine. Effect of histone deacetylase inhibition We have shown that injection of the HDAC inhibitor trichostatin A (TsA) to rats is sufficient to decrease their motivation to self-administer cocaine. The aim of the present study was to investigate alterations in gene expression patterns in the Anterior Cingulate Cortex and Nucleus Accumbens of rats self-administering cocaine and treated repeatedly with TsA, and compare them with rats taking only cocaine. We used Affymetrix microarrays to identify genes the expression of which was up-regulated or downregulated during this process. Drug self-administration was performed in dark operant chambers under a fixed-ratio 1 schedule of reinforcement that was carried out for 4 days during daily 2 h sessions. Each nosepoke into the active hole triggered the i.v. delivery of a 40 μl cocaine solution (0,3 mg/kg/injection) under the control of the computer. Rats were sacrificed 2 h after the 4th self-administration session; the anterior cingulate cortex and the nucleus accumbens were then dissected. Two treatments comparison
2010-01-21 | E-GEOD-18055 | biostudies-arrayexpress
Project description:Cocaine administration alters the microRNA (miRNA) landscape in the cortico-accumbal pathway. These changes in miRNA can play a major role in the posttranscriptional regulation of gene expression during withdrawal. This study aimed to investigate the changes in microRNA expression in the cortico-accumbal pathway during acute withdrawal and protracted abstinence following escalated cocaine intake. Small RNA sequencing (sRNA-seq) was used to profile miRNA transcriptomic changes in the cortico-accumbal pathway [infralimbic- and prelimbic-prefrontal cortex (IL and PL) and nucleus accumbens (NAc)] of rats with extended access to cocaine self-administration followed by an 18-h withdrawal or a 4-week abstinence. An 18-h withdrawal led to differential expression (fold-change > 1.5 and p < 0.05) of 21 miRNAs in the IL, 18 miRNAs in the PL, and two miRNAs in the NAc. The mRNAs potentially targeted by these miRNAs were enriched in the following pathways: gap junctions, neurotrophin signaling, MAPK signaling, and cocaine addiction. Moreover, a 4-week abstinence led to differential expression (fold-change > 1.5 and p < 0.05) of 23 miRNAs in the IL, seven in the PL, and five miRNAs in the NAc. The mRNAs potentially targeted by these miRNAs were enriched in pathways including gap junctions, cocaine addiction, MAPK signaling, glutamatergic synapse, morphine addiction, and amphetamine addiction. Additionally, the expression levels of several miRNAs differentially expressed in either the IL or the NAc were significantly correlated with addiction behaviors. Our findings highlight the impact of acute and protracted abstinence from escalated cocaine intake on miRNA expression in the cortico-accumbal pathway, a key circuit in addiction, and suggest developing novel biomarkers and therapeutic approaches to prevent relapse by targeting abstinence-associated miRNAs and their regulated mRNAs.
2023-08-30 | GSE212651 | GEO
Project description:Animal models provide opportunity to study neurobiological aspects of human alcoholism. Changes in gene expression have been implicated in mediating brain function, including reward system and addiction. The current study aimed to identify novel genes that may underlie ethanol preference. Microarray analysis comparing gene expression in nucleus accumbens (NAc), hippocampus (HP) and prefrontal medial cortex (mPFC) was performed in two rat strains selected for extreme levels of ethanol preference - Warsaw High Preferring (WHP) and Warsaw Low Preferring (WLP). The identified candidate genes may underlie differential ethanol preference in rat model of alcoholism. This is analysis of 18 RNA samples, including 9 technical replicates. Two strains of rats selected for extreme levels of ethanol preference (low preferring WLP and high preferring WHP) were compared. Three brain areas (nucleus accumbens, prefrontal medial cortex and hippocampus) were studied. For each brain area, 6 RNA samples (including 3 technical replicates) were analyzed. Each RNA sample consist of of equal amounts of total RNA from 3 male rats. Comparisons: Nucleus accumbens of WHP vs. Nucleus accumbens of WLP; Prefrontal medial cortex of WHP vs. Prefrontal medial cortex of WLP; Hippocampus of WHP vs. Hippocampus of WLP. 3 biological replicates in each comparison.
2015-01-17 | E-GEOD-65064 | biostudies-arrayexpress
Project description:This dataset includes ATAC-Seq and RNA-seq data from rat prefrontal cortex and/or nucleus accumbens (postnatal date, PND 61), as part of characterizing how the rat brain responds to its first encounter with cocaine (PND 60) with or without preexposure to the synthetic cannabinoid WIN 55,212-2 (WIN) during adolescence (PND 42-52). WIN was administered twice daily during the latter eleven consecutive days (2 mg/kg, 3 days; 4 mg/kg, 4 days; 8 mg/kg, 4 days) and, following a week of WIN abstinence, animals were IP challenged with cocaine (10 mg/kg). Brain dissections were performed 24 hours after the cocaine IP challenge.
2019-07-27 | GSE134935 | GEO
Project description:Enduring patterns of epigenomic and transcriptional plasticity within the mesolimbic dopamine system contribute importantly to persistent behavioral adaptations that characterize substance use disorders (SUD). While drug addiction has long been thought of as a disorder of dopamine (DA) neurotransmission, therapeutic interventions targeting receptor mediated DA-signaling have not yet resulted in efficacious treatments. Our laboratory recently identified a non-canonical, neurotransmission-independent signaling moiety for DA in brain, termed dopaminylation, whereby DA itself acts as a donor source for the establishment of post-translational modifications (PTM) on substrate proteins (e.g., histone H3 at glutamine 5; H3Q5dop). In our previous studies, we demonstrated that H3Q5dop plays a critical role in the regulation of neuronal transcription and, when perturbed within monoaminergic neurons of the ventral tegmental area (VTA), critically contribute to pathological states, including relapse vulnerability to both psychostimulants (e.g., cocaine) and opiates (e.g., heroin). Importantly, H3Q5dop is also observed throughout the mesolimbic DA reward pathway (e.g., in nucleus accumbens/NAc and medial prefrontal cortex/mPFC, which receive DA input from VTA). As such, we investigated whether H3Q5dop may similarly be altered in its expression in response to drugs of abuse in these non-dopamine-producing regions. In rats undergoing extended abstinence from cocaine self-administration (SA), we observed both acute and prolonged accumulation of H3Q5dop in NAc, but not mPFC. Attenuation of H3Q5dop in NAc during drug abstinence reduced cocaine-seeking and affected cocaine-induced gene expression programs associated with altered dopamine signaling and neuronal function. These findings thus establish H3Q5dop in NAc, but not mPFC, as an important mediator of cocaine-induced behavioral and transcriptional plasticity during extended cocaine abstinence.
2023-06-14 | GSE221177 | GEO
Project description:Environmental enrichment (EE) is a robust intervention for reducing cocaine-seeking behaviors in animals when given during abstinence. However, the mechanisms that underlie these effects have not been well-established. We investigated the adult male rat transcriptome using RNA-sequencing (RNA-seq) following differential housing during abstinence from cocaine self-administration for either 1 or 21 days. Rats housed for 21 days of abstinence in EE displayed a significant reduction in cocaine-seeking behavior compared to rats housed in isolation. RNA-seq of the nucleus accumbens shell revealed hundreds of differentially regulated transcripts between rats of different abstinence length and housing environment, as well as within specific contrasts such as enrichment (isolated 21 days vs. enriched 21 days) or incubation (isolated 1 day vs. isolated 21 days). Ingenuity Pathway Analysis affirmed several pathways as differentially enriched based on housing condition and abstinence length including RELN, the Eif2 signaling pathway, synaptogenesis and neurogenesis pathways. Additionally, multiple pathways reversed their directionality between enrichment and incubation contrasts, potentially indicating oppositional roles across housing and abstinence length. Together, these findings reveal novel mechanisms potentially involved in the protective effects of EE against cocaine seeking, which may inform efforts to develop new pharmacological and gene therapies for treating cocaine use disorders.
2020-07-15 | GSE144606 | GEO
Project description:Many studies of cocaine-responsive gene expression have focused on changes occurring during cocaine exposure, but few studies have examined the persistence of these changes with cocaine abstinence. Persistent changes in gene expression, as well as alterations induced during abstinence may underlie long-lasting drug craving and relapse liability. Results: Whole-genome expression analysis was conducted on a rat cocaine binge-abstinence model that has previously been demonstrated to engender increased drug seeking and taking with abstinence. Gene expression changes in two mesolimbic terminal fields (mPFC and NAc) were identified in a comparison of cocaine-naïve rats with rats after 10 days of cocaine selfadministration followed by 1, 10, or 100 days of enforced abstinence (n=6-11 per group). A total of 1,461 genes in the mPFC and 414 genes in the NAc were altered between at least two time points (ANOVA, p<0.05; ±1.4 fold-change). These genes can be subdivided into: 1) changes with cocaine self-administration that do not persist into periods of abstinence, 2) changes with cocaine self-administration that persist with abstinence, 3) and those not changed with cocaine self-administration, but changed during enforced abstinence. qPCR analysis was conducted to confirm gene expression changes observed in the microarray analysis.
2010-03-16 | GSE20885 | GEO