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Review
.2015 Apr;51(2):696-717.
doi: 10.1007/s12035-014-8776-8. Epub 2014 Jun 18.

Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat

Affiliations
Review

Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat

Jean Lud Cadet et al. Mol Neurobiol.2015 Apr.

Abstract

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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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Epigenetic and transcriptional events involved in methamphetamine addiction. This figure describes our theoretical approach to methamphetamine addiction. Although the figure suggests that the biochemical and behavioral effects of methamphetamine appear to involve activation of dopaminergic and glutamatergic pathways, we are cognizant of the fact that other neurotransmitter systems might also participate in causing addiction and associated neuropsychiatric consequences. Activation of these neurotransmitter systems is followed by stimulation and/or inhibition of epigenetic and transcriptional events that generate compulsive abuse of the drug. These compulsive behaviors might also be secondary to a cortical disinhibition-induced subcortical hyperconnection syndrome that is characterized by specific cognitive changes in human methamphetamine addicts
Fig. 2
Fig. 2
Microarray analysis of gene expression measured in the rat striatum at 2 h after cessation of methamphetamine self-administration.a Description of microarray results. The total number of genes (21,980) on the array is shown within thelight grey area of the circle. Also listed is the total number of genes (543) that are regulated by methamphetamine. Thelight pink box represents the number (356) of upregulated genes whereas thelight green box shows the number (187) of downregulated genes.b Molecular networks of genes differentially affected by methamphetamine self-administration. These networks were generated using Ingenuity Pathway Analysis. The networks are ranked according to their scores, and eight networks of interest are shown. The number of genes in each network is shown in parentheses. Note that several of the networks contain genes that participate in cell-to-cell signaling and interactions
Fig. 3
Fig. 3
Methamphetamine self-administration causes differential expression of genes involved in several networks.a A network of genes involved in neurological disease, behavior, and cell-to-cell signaling and interaction. This list includes BASP1, BDNF, and some phosphatases.b A network of genes that participate in cell-to-cell signaling and small molecule metabolism. These genes include CCK, ELK1, and neurotensin.c A network of upregulated genes involved in nervous system development and function as well as cellular assembly and organization. Among these genes are neuromedin U and syntaxin 1A. These gene networks emphasize the complex molecular effects of methamphetamine in the brain
Fig. 4
Fig. 4
Methamphetamine self-administration causes co-activation of CREB- and ELK1-dependent pathways in the rat striatum. The scheme shows the potential activation of the MAPK-ERK-ELK1 and PKA-CREB pathways via stimulation of both dopamine and glutamate receptors. The theoretical scheme also suggests that activation of these two pathways would also lead to chromatin changes that might be responsible for the changes in the expression of genes such as BDNF and some immediate early genes (IEGs). Although the scheme has focused on the dopaminergic and glutamatergic systems for the sake of simplicity, other neurotransmitter systems including neuropeptides might also participate in the long-term alterations in gene expression in the striatum (see Krasnova et al.[11])
Fig. 5
Fig. 5
Microarray analysis of striatal gene expression at 1 month after cessation of methamphetamine self-administration.a Description of microarray results. The total number of genes (21, 850) measured on these arrays is shown within thelight grey area of the circle. The number of genes (673) that are regulated by methamphetamine is also shown. Thelight pink box represents the number (82) of upregulated genes whereas thelight green box shows the number (591) of downregulated genes.b Molecular networks of genes differentially affected by methamphetamine self-administration. These networks were generated using IPA. The networks are ranked according to their scores, and eight networks of interest are shown. The number of genes in each network is shown in parentheses. Importantly, very different gene networks are affected at that time point, suggesting considerable differences between early and delayed neuroadaptations after cessation of drug self-administration
Fig. 6
Fig. 6
Withdrawal form methamphetamine self-administration causes differential changes in the expression of genes involved in several networks.a A network of upregulated genes involved in tissue morphology and cellular assembly.b A network of downregulated genes that participate in cell cycle, DNA replication, and repair, as well as cell death and survival.c A network of downregulated genes involved in cellular and tissue development. This network includes several transcription regulators including JunD, KLF12, and RCOR2
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References

    1. Cadet JL, Bisagno V, Milroy CM. Neuropathology of substance use disorders. Acta Neuropathol. 2014;127(1):91–107. - PMC - PubMed
    1. Gonzales R, Mooney L, Rawson RA. The methamphetamine problem in the United States. Annu Rev Public Health. 2010;31:385–398. - PMC - PubMed
    1. Krasnova IN, Cadet JL. Methamphetamine toxicity and messengers of death. Brain Res Rev. 2009;60(2):379–407. - PMC - PubMed
    1. Rusyniak DE. Neurologic manifestations of chronic methamphetamine abuse. Psychiatr Clin N Am. 2013;36(2):261–275. - PMC - PubMed
    1. Dean AC, Groman SM, Morales AM, London ED. An evaluation of the evidence that methamphetamine abuse causes cognitive decline in humans. Neuropsychopharmacology. 2013;38(2):259–274. - PMC - PubMed

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