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A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration
Published on: January 22, 2016
Repeated methamphetamine and modafinil induce differential cognitive effects and specific histone acetylation and DNA
Betina González1, Subramaniam Jayanthi2, Natalia Gomez1
1Instituto de Investigaciones Farmacológicas, Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
Abstract:
Methamphetamine (METH) and modafinil are psychostimulants with different long-term cognitive profiles: METH is addictive and leads to cognitive decline, whereas modafinil has little abuse liability and is a cognitive enhancer. Increasing evidence implicates epigenetic mechanisms of gene regulation behind the lasting changes that drugs of abuse and other psychotropic compounds induce in the brain, like the control of gene expression by histones 3 and 4 tails acetylation (H3ac and H4ac) and DNA cytosine methylation (5-mC). Mice were treated with a seven-day repeated METH, modafinil or vehicle protocol and evaluated in the novel object recognition (NOR) test or sacrificed 4days after last injection for molecular assays. We evaluated total H3ac, H4ac and 5-mC levels in the medial prefrontal cortex (mPFC), H3ac and H4ac promotor enrichment (ChIP) and mRNA expression (RT-PCR) of neurotransmitter systems involved in arousal, wakefulness and cognitive control, like dopaminergic (Drd1 and Drd2), α-adrenergic (Adra1a and Adra1b), orexinergic (Hcrtr1 and Hcrtr2), histaminergic (Hrh1 and Hrh3) and glutamatergic (AMPA Gria1 and NMDA Grin1) receptors. Repeated METH and modafinil treatment elicited different cognitive outcomes in the NOR test, where modafinil-treated mice performed as controls and METH-treated mice showed impaired recognition memory. METH-treated mice also showed i) decreased levels of total H3ac and H4ac, and increased levels of 5-mC, ii) decreased H3ac enrichment at promoters of Drd2, Hcrtr1/2, Hrh1 and Grin1, and increased H4ac enrichment at Drd1, Hrh1 and Grin1, iii) increased mRNA of Drd1a, Grin1 and Gria1. Modafinil-treated mice shared none of these effects and showed increased H3ac enrichment and mRNA expression at Adra1b. Modafinil and METH showed similar effects linked to decreased H3ac in Hrh3, increased H4ac in Hcrtr1, and decreased mRNA expression of Hcrtr2. The specific METH-induced epigenetic and transcriptional changes described here may be related to the long-term cognitive decline effects of the drug and its detrimental effects on mPFC function. The lack of similar epigenetic effects of chronic modafinil administration supports this notion.
Insights
Methamphetamine (METH) impairs memory by altering brain epigenetics, while modafinil does not. This study reveals METH-induced changes in histone acetylation and DNA methylation, contrasting with modafinil
Area of Science:
- Neuroscience
- Epigenetics
- Pharmacology
Background:
- Methamphetamine (METH) causes addiction and cognitive decline, while modafinil enhances cognition with low abuse potential.
- Epigenetic mechanisms, including histone acetylation (H3ac, H4ac) and DNA methylation (5-mC), are implicated in lasting drug-induced brain changes.
- The medial prefrontal cortex (mPFC) is crucial for cognitive control and is affected by psychostimulants.
Purpose of the Study:
- To investigate the distinct long-term epigenetic and transcriptional effects of METH and modafinil in the mouse mPFC.
- To correlate these molecular changes with cognitive outcomes in the novel object recognition (NOR) test.
- To elucidate the role of epigenetic modifications in METH-induced cognitive deficits versus modafinil's cognitive enhancement.
Main Methods:
- Mice received daily METH, modafinil, or vehicle for seven days.
- Cognitive performance was assessed using the NOR test.
- Epigenetic markers (H3ac, H4ac, 5-mC) and gene expression (RT-PCR) in the mPFC were analyzed post-treatment.
- Chromatin immunoprecipitation (ChIP) was used to assess promoter enrichment of H3ac and H4ac.
Main Results:
- METH-treated mice exhibited impaired recognition memory in the NOR test, unlike modafinil-treated mice or controls.
- METH induced decreased H3ac/H4ac and increased 5-mC in the mPFC, with altered promoter enrichment and gene expression of key neurotransmitter systems (dopaminergic, orexinergic, histaminergic, glutamatergic).
- Modafinil treatment showed distinct effects, including increased H3ac and mRNA at Adra1b, with no shared detrimental epigenetic changes observed with METH.
Conclusions:
- METH-induced epigenetic and transcriptional alterations in the mPFC are linked to long-term cognitive decline.
- The absence of similar epigenetic changes with modafinil supports its role as a cognitive enhancer without significant abuse liability.
- These findings highlight the critical role of specific epigenetic modifications in mediating the differential long-term effects of psychostimulants on cognitive function.
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