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Effects of stress and MDMA on hippocampal gene expression.

ABSTRACT: MDMA (3,4-methylenedioxymethamphetamine) is a substituted amphetamine and popular drug of abuse. Its mood-enhancing short-term effects may prompt its consumption under stress. Clinical studies indicate that MDMA treatment may mitigate the symptoms of stress disorders such as posttraumatic stress syndrome (PTSD). On the other hand, repeated administration of MDMA results in persistent deficits in markers of serotonergic (5-HT) nerve terminals that have been viewed as indicative of 5-HT neurotoxicity. Exposure to chronic stress has been shown to augment MDMA-induced 5-HT neurotoxicity. Here, we examine the transcriptional responses in the hippocampus to MDMA treatment of control rats and rats exposed to chronic stress. MDMA altered the expression of genes that regulate unfolded protein binding, protein folding, calmodulin-dependent protein kinase activity, and neuropeptide signaling. In stressed rats, the gene expression profile in response to MDMA was altered to affect sensory processing and responses to tissue damage in nerve sheaths. Subsequent treatment with MDMA also markedly altered the genetic responses to stress such that the stress-induced downregulation of genes related to the circadian rhythm was reversed. The data support the view that MDMA-induced transcriptional responses accompany the persistent effects of this drug on neuronal structure/function. In addition, MDMA treatment alters the stress-induced transcriptional signature.

SUBMITTER: Weber GF

PROVIDER: S-EPMC3910535 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Effects of stress and MDMA on hippocampal gene expression.

Weber Georg F GF Johnson Bethann N BN Yamamoto Bryan K BK Gudelsky Gary A GA

BioMed research international 20140109

MDMA (3,4-methylenedioxymethamphetamine) is a substituted amphetamine and popular drug of abuse. Its mood-enhancing short-term effects may prompt its consumption under stress. Clinical studies indicate that MDMA treatment may mitigate the symptoms of stress disorders such as posttraumatic stress syndrome (PTSD). On the other hand, repeated administration of MDMA results in persistent deficits in markers of serotonergic (5-HT) nerve terminals that have been viewed as indicative of 5-HT neurotoxic ...[more]

PMID: 24511526

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Project description:Chronic and acute stressors have been linked to changes in hippocampal function and anxiety-like behaviors. Both produce changes in gene expression, but the extent to which these changes endure beyond the end of stress remains poorly understood. As an essential first step to characterize abnormal patterns of gene expression after stress, this study demonstrates how chronic restraint stress (CRS) modulates gene expression in response to a novel stressor in the hippocampus of wild-type mice and the extent to which these changes last beyond the end of CRS. Male C57/bl6 mice were subjected to (1) a forced swim test (FST), (2) corticosterone (Cort) or vehicle injections, (3) CRS for 21 days and then a FST, or (4) allowed to recover 21 days after CRS and subjected to FST. Hippocampal mRNA was extracted and used to generate cDNA libraries for microarray hybridization. Naive acute stressors (FST and vehicle injection) altered similar sets of genes, but Cort treatment produced a profile that was distinct from both FST and vehicle. Exposure to a novel stress after CRS activated substantially more and different genes than naive exposure. Most genes increased by CRS were decreased after recovery but many remained altered and did not return to baseline. Pathway analysis identified significant clusters of differentially expressed genes across conditions, most notably the nuclear factor kappa-light-chain-enhancer of B cells (NF-?B) pathway. Quantitative reverse transcription-PCR (qRT-PCR) validated changes from the microarrays in known stress-induced genes and confirmed alterations in the NF-?B pathway genes, Nfkbia, RelA and Nfkb1. FST increased anxiety-like behavior in both the naive and recovery from CRS conditions, but not in mice 24h subsequent to their CRS exposure. These findings suggest that the effects of naive stress are distinct from Cort elevation, and that a history of stress exposure can permanently alter gene expression patterns in the hippocampus and the behavioral response to a novel stressor. These findings establish a baseline profile of normal recovery and adaptation to stress. Importantly, they will serve as a conceptual basis to facilitate the future study of the cellular and regional basis of gene expression changes that lead to impaired recovery from stress, such as those that occur in mood and anxiety disorders.

Project description:Objective: This study examined the effect of Xiaoyaosan and its anti-stress mechanism in rats subjected to chronic immobilization stress at the whole genome level. Methods: Rat whole genome expression chips (Illumina) were used to detect differences in hippocampal gene expression in rats from the control group (CN group), model group (M group) and Xiaoyaosan group (XYS group) that were subjected to chronic immobilization stress. The Gene Ontology terms and signaling pathways that were altered in the hippocampus gene expression profile were analyzed. The network regulating the transcription of the differentially expressed genes was also established. To verify the results from the gene chips, real-time quantitative polymerase chain reaction was used to determine the expression of the GABRA1, FADD, CRHR2, and CDK6 genes in hippocampal tissues. In situ hybridization (ISH) and immunohistochemistry were used to determine the expression of the GABRA1 and CRHR2 genes and proteins, respectively. Results: Compared with the CN group, 566 differentially expressed genes were identified in the M group. Compared with the M group, 544 differentially expressed genes were identified in the XYS group. In the M and XYS groups, multiple significantly upregulated or downregulated genes functioned in various biological processes. The cytokine receptor interaction pathway was significantly inhibited in the hippocampus of the model group. The actin cytoskeleton regulation pathway was significantly increased in the hippocampus of the XYS group. The inhibition of hippocampal cell growth was the core molecular event of network regulating the transcription of the differentially expressed genes in the model group. Promotion of the regeneration of hippocampal neurons was the core molecular event of the transcriptional regulatory network in the XYS group. The levels of the GABRA1, FADD, CRHR2 and CDK6 mRNAs, and proteins were basically consistent with the results obtained from the gene chip. Conclusion: XYS may have the ability of resistance to stress, enhancement immunity and promotion nerve cell regeneration by regulating the expression of multiple genes in numerous pathways and repaired the stress-induced impairments in hippocampal structure and function by inducing cytoskeletal reorganization. These results may provide the possible target spots in the treatment of stress in rats with XYS.

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Effects of stress and MDMA on hippocampal gene expression.

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Effects of stress and MDMA on hippocampal gene expression.

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