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Transcriptional and Epigenetic Substrates of Methamphetamine Addiction and Withdrawal: Evidence from a Long-Access Self-Administration Model in the Rat.
Mol. Neurobiol.
PUBLISHED: 03-06-2014
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Methamphetamine use disorder is a chronic neuropsychiatric disorder characterized by recurrent binge episodes, intervals of abstinence, and relapses to drug use. Humans addicted to methamphetamine experience various degrees of cognitive deficits and other neurological abnormalities that complicate their activities of daily living and their participation in treatment programs. Importantly, models of methamphetamine addiction in rodents have shown that animals will readily learn to give themselves methamphetamine. Rats also accelerate their intake over time. Microarray studies have also shown that methamphetamine taking is associated with major transcriptional changes in the striatum measured within a short or longer time after cessation of drug taking. After a 2-h withdrawal time, there was increased expression of genes that participate in transcription regulation. These included cyclic AMP response element binding (CREB), ETS domain-containing protein (ELK1), and members of the FOS family of transcription factors. Other genes of interest include brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor, type 2 (TrkB), and synaptophysin. Methamphetamine-induced transcription was found to be regulated via phosphorylated CREB-dependent events. After a 30-day withdrawal from methamphetamine self-administration, however, there was mostly decreased expression of transcription factors including junD. There was also downregulation of genes whose protein products are constituents of chromatin-remodeling complexes. Altogether, these genome-wide results show that methamphetamine abuse might be associated with altered regulation of a diversity of gene networks that impact cellular and synaptic functions. These transcriptional changes might serve as triggers for the neuropsychiatric presentations of humans who abuse this drug. Better understanding of the way that gene products interact to cause methamphetamine addiction will help to develop better pharmacological treatment of methamphetamine addicts.
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Enhanced upregulation of CRH mRNA expression in the nucleus accumbens of male rats after a second injection of methamphetamine given thirty days later.
PLoS ONE
PUBLISHED: 01-01-2014
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Methamphetamine (METH) is a widely abused amphetamine analog. Few studies have investigated the molecular effects of METH exposure in adult animals. Herein, we determined the consequences of an injection of METH (10 mg/kg) on transcriptional effects of a second METH (2.5 mg/kg) injection given one month later. We thus measured gene expression by microarray analyses in the nucleus accumbens (NAc) of 4 groups of rats euthanized 2 hours after the second injection: saline-pretreated followed by saline-challenged (SS) or METH-challenged (SM); and METH-pretreated followed by saline-challenged (MS) or METH-challenged (MM). Microarray analyses revealed that METH (2.5 mg/kg) produced acute changes (1.8-fold; P<0.01) in the expression of 412 (352 upregulated, 60 down-regulated) transcripts including cocaine and amphetamine regulated transcript, corticotropin-releasing hormone (Crh), oxytocin (Oxt), and vasopressin (Avp) that were upregulated. Injection of METH (10 mg/kg) altered the expression of 503 (338 upregulated, 165 down-regulated) transcripts measured one month later (MS group). These genes also included Cart and Crh. The MM group showed altered expression of 766 (565 upregulated, 201 down-regulated) transcripts including Avp, Cart, and Crh. The METH-induced increased Crh expression was enhanced in the MM group in comparison to SM and MS groups. Quantitative PCR confirmed the METH-induced changes in mRNA levels. Therefore, a single injection of METH produced long-lasting changes in gene expression in the rodent NAc. The long-term increases in Crh, Cart, and Avp mRNA expression suggest that METH exposure produced prolonged activation of the endogenous stress system. The METH-induced changes in oxytocin expression also suggest the possibility that this neuropeptide might play a significant role in the neuroplastic and affiliative effects of this drug.
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CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat.
Neurobiol. Dis.
PUBLISHED: 03-19-2013
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Neuroplastic changes in the dorsal striatum participate in the transition from casual to habitual drug use and might play a critical role in the development of methamphetamine (METH) addiction. We examined the influence of METH self-administration on gene and protein expression that may form substrates for METH-induced neuronal plasticity in the dorsal striatum. Male Sprague-Dawley rats self-administered METH (0.1mg/kg/injection, i.v.) or received yoked saline infusions during eight 15-h sessions and were euthanized 2h, 24h, or 1month after cessation of METH exposure. Changes in gene and protein expression were assessed using microarray analysis, RT-PCR and Western blots. Chromatin immunoprecipitation (ChIP) followed by PCR was used to examine epigenetic regulation of METH-induced transcription. METH self-administration caused increases in mRNA expression of the transcription factors, c-fos and fosb, the neurotrophic factor, Bdnf, and the synaptic protein, synaptophysin (Syp) in the dorsal striatum. METH also caused changes in ?FosB, BDNF and TrkB protein levels, with increases after 2 and 24h, but decreases after 1month of drug abstinence. Importantly, ChIP-PCR showed that METH self-administration caused enrichment of phosphorylated CREB (pCREB), but not of histone H3 trimethylated at lysine 4 (H3K4me3), on promoters of c-fos, fosb, Bdnf and Syp at 2h after cessation of drug intake. These findings show that METH-induced changes in gene expression are mediated, in part, by pCREB-dependent epigenetic phenomena. Thus, METH self-administration might trigger epigenetic changes that mediate alterations in expression of genes and proteins serving as substrates for addiction-related synaptic plasticity.
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Genome-wide profiling identifies a subset of methamphetamine (METH)-induced genes associated with METH-induced increased H4K5Ac binding in the rat striatum.
BMC Genomics
PUBLISHED: 02-08-2013
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METH is an illicit drug of abuse that influences gene expression in the rat striatum. Histone modifications regulate gene transcription.
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Methamphetamine-induced dopamine-independent alterations in striatal gene expression in the 6-hydroxydopamine hemiparkinsonian rats.
PLoS ONE
PUBLISHED: 09-23-2010
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Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle are used extensively as a model of Parkinsons disease. The present experiments sought to identify genes that were affected in the dopamine (DA)-denervated striatum after 6-hydroxydopamine-induced destruction of the nigrostriatal dopaminergic pathway in the rat. We also examined whether a single injection of methamphetamine (METH) (2.5 mg/kg) known to cause changes in gene expression in the normally DA-innervated striatum could still influence striatal gene expression in the absence of DA. Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle resulted in METH-induced rotational behaviors ipsilateral to the lesioned side and total striatal DA depletion on the lesioned side. This injection also caused decrease in striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels. DA depletion was associated with increases in 5-HIAA/5-HT ratios that were potentiated by the METH injection. Microarray analyses revealed changes (±1.7-fold, p<0.025) in the expression of 67 genes on the lesioned side in comparison to the intact side of the saline-treated hemiparkinsonian animals. These include follistatin, neuromedin U, and tachykinin 2 which were up-regulated. METH administration caused increases in the expression of c-fos, Egr1, and Nor-1 on the intact side. On the DA-depleted side, METH administration also increased the expression of 61 genes including Pdgf-d and Cox-2. There were METH-induced changes in 16 genes that were common in the DA-innervated and DA-depleted sides. These include c-fos and Nor-1 which show greater changes on the normal DA side. Thus, the present study documents, for the first time, that METH mediated DA-independent changes in the levels of transcripts of several genes in the DA-denervated striatum. Our results also implicate 5-HT as a potential player in these METH-induced alterations in gene expression because the METH injection also caused significant increases in 5-HIAA/5-HT ratios on the DA-depleted side.
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Methamphetamine preconditioning causes differential changes in striatal transcriptional responses to large doses of the drug.
Dose Response
PUBLISHED: 07-02-2010
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Methamphetamine (METH) is a toxic drug of abuse, which can cause significant decreases in the levels of monoamines in various brain regions. However, animals treated with progressively increasing doses of METH over several weeks are protected against the toxic effects of the drug. In the present study, we tested the possibility that this pattern of METH injections might be associated with transcriptional changes in the rat striatum, an area of the brain which is known to be very sensitive to METH toxicity and which is protected by METH preconditioning. We found that the presence and absence of preconditioning followed by injection of large doses of METH caused differential expression in different sets of striatal genes. Quantitative PCR confirmed METH-induced changes in some genes of interest. These include small heat shock 27 kD proteins 1 and 2 (HspB1 and HspB2), brain derived neurotrophic factor (BDNF), and heme oxygenase-1 (Hmox-1). Our observations are consistent with previous studies which have reported that ischemic or pharmacological preconditioning can cause reprogramming of gene expression after lethal ischemic insults. These studies add to the growing literature on the effects of preconditioning on the brain transcriptome.
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Methamphetamine causes differential alterations in gene expression and patterns of histone acetylation/hypoacetylation in the rat nucleus accumbens.
PLoS ONE
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Methamphetamine (METH) addiction is associated with several neuropsychiatric symptoms. Little is known about the effects of METH on gene expression and epigenetic modifications in the rat nucleus accumbens (NAC). Our study investigated the effects of a non-toxic METH injection (20 mg/kg) on gene expression, histone acetylation, and the expression of the histone acetyltransferase (HAT), ATF2, and of the histone deacetylases (HDACs), HDAC1 and HDAC2, in that structure. Microarray analyses done at 1, 8, 16 and 24 hrs after the METH injection identified METH-induced changes in the expression of genes previously implicated in the acute and longterm effects of psychostimulants, including immediate early genes and corticotropin-releasing factor (Crf). In contrast, the METH injection caused time-dependent decreases in the expression of other genes including Npas4 and cholecystokinin (Cck). Pathway analyses showed that genes with altered expression participated in behavioral performance, cell-to-cell signaling, and regulation of gene expression. PCR analyses confirmed the changes in the expression of c-fos, fosB, Crf, Cck, and Npas4 transcripts. To determine if the METH injection caused post-translational changes in histone markers, we used western blot analyses and identified METH-mediated decreases in histone H3 acetylated at lysine 9 (H3K9ac) and lysine 18 (H3K18ac) in nuclear sub-fractions. In contrast, the METH injection caused time-dependent increases in acetylated H4K5 and H4K8. The changes in histone acetylation were accompanied by decreased expression of HDAC1 but increased expression of HDAC2 protein levels. The histone acetyltransferase, ATF2, showed significant METH-induced increased in protein expression. These results suggest that METH-induced alterations in global gene expression seen in rat NAC might be related, in part, to METH-induced changes in histone acetylation secondary to changes in HAT and HDAC expression. The causal role that HATs and HDACs might play in METH-induced gene expression needs to be investigated further.
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