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Modeling methamphetamine use disorder and relapse in animals: Short- and long-term epigenetic, transcriptional., and biochemical consequences in the rat brain

A figure from this study. Legend: Methamphetamine self-administration causes increased activation of the Ras Signaling Pathway. Extracellular stimuli, mainly growth factors, activate the Ras/Raf/MEK/ERK MAPK signaling cascade. ERK1/2 phosphorylates and activates Rreb1 to regulate its transcriptional activity. We have previously shown that METH results in increased expression of p-Raf, p-MEK, and p-ERK, as demonstrated by the upward green arrows. In the present study, we also observed increased mRNA expression of Rreb1 in the dorsal striatum following 1-month of METH abstinence. We therefore hypothesized that Rreb1’s activity, as both a transcriptional activator and repressor for numerous target genes, might play an important role in regulating methamphetamine-induced gene expression and, thereby, maintain drug self-administration.

Reviews To Read – January 2024.

Published in Neuroscience & Biobehavioral Reviews by Khalid Elhadi, Atul P. Daiwile, and Jean Lud Cadet of the NIDA IRP Molecular Neuropsychiatry Research Section.

Methamphetamine use disorder (MUD) is very widespread in the world because methamphetamine is easy to make and cheap to buy. Heavy users usually take the drug in binges, try to stop on their own or in a treatment program, but often suffer relapses. We and others are trying to identify the basis for MUD by using animal models. We have used different schedules of methamphetamine self-administration to identify epigenetic modifications and changes in gene and protein expression in different brain regions that we think are involved in substance use disorders (SUDs). We have found that there are lots of changes in the rat dorsal striatum following methamphetamine intake. Specifically, we found changes in the expression of genes that regulate transcription, potassium channel function, and neuroinflammation.  Our studies suggest the need for more research in this area because there are still no medications approved by the FDA for MUD.

Khalid Elhadi; Atul P. Daiwile; Jean Lud Cadet

Modeling methamphetamine use disorder and relapse in animals: Short- and long-term epigenetic, transcriptional., and biochemical consequences in the rat brain Journal Article

In: Neuroscience & Biobehavioral Reviews, vol. 155, pp. 105440, 2023, ISSN: 0149-7634.

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