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SAM-e appears to suppress the expression of adenosine receptor A2A

adenosine dopamine sam-e addiction

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#1 macrohistory

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Posted 24 August 2019 - 11:10 AM


Wouldn't the implication be that taking exogenous SAM-e could promote addictive-drug-seeking behaviors (and ultimately, addiction itself) by interfering with the braking or modulating effects of adenosine on dopaminergic neurotransmission in paired A2A-D2 receptors in the striatum?

 

 

Purinergic Signal. 2014 Sep;10(3):523-8. doi: 10.1007/s11302-014-9417-4. Epub 2014 Jun 19.

Striatal adenosine A2A receptor expression is controlled by S-adenosyl-L-methionine-mediated methylation.
Author information
1 Institute of Neuropathology, Bellvitge Biomedical Research Institute (IDIBELL), Bellvitge University Hospital-ICS, Av. Gran Via de L'Hospitalet 199, L'Hospitalet de Llobregat, 08908, Spain.
Abstract

Adenosine A2A receptor (A2AR) is a G protein-coupled receptor enriched in the striatum for which an increased expression has been demonstrated in certain neurological diseases. Interestingly, previous in vitro studies demonstrated that A2AR expression levels are reduced after treatment with S-adenosyl-L-methionine (SAM), a methyl donor molecule involved in the methylation of important biological structures such as DNA, proteins, and lipids. However, the in vivo effects of SAM treatment on A2AR expression are still obscure. Here, we demonstrated that 2 weeks of SAM treatment produced a significant reduction in the rat striatal A2AR messenger RNA (mRNA) and protein content as well as A2AR-mediated signaling. Furthermore, when the content of 5-methylcytosine levels in the 5'UTR region of ADORA2A was analyzed, this was significantly increased in the striatum of SAM-treated animals; thus, an unambiguous correlation between SAM-mediated methylation and striatal A2AR expression could be established. Overall, we concluded that striatal A2AR functionality can be controlled by SAM treatment, an issue that might be relevant for the management of these neurological conditions that course with increased A2AR expression.

PMID:   24943396   PMCID:   PMC4152447   DOI:   10.1007/s11302-014-9417-4
[Indexed for MEDLINE]  Free PMC Article

 



#2 Dorian Grey

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Posted 24 August 2019 - 05:10 PM

I've taken low dose SAM-e for over a decade now.  Magical stuff!  https://www.ncbi.nlm...pubmed/15102339

 

I also have a mildly addictive personality.  Still smoking my pipe (in moderation) and several drinks every evening at 62 years old.  Haven't noticed any increase in craving for these substances, but then I'm only taking 200-400mg SAM-e per day.  I've read the therapeutic dose is 1200mg/day for some, so perhaps this might increase the danger of the observed effect on A2A.  

 

Hope we get some more input from those on higher doses.  


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#3 macrohistory

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Posted 08 September 2019 - 05:38 AM

Dorian:

 

Judging from the study whose abstract I paste below, it looks as though supplementing with SAM-e might make it more difficult to shake a pre-existing addiction, but the study doesn't speak to the question of whether taking SAM-e could contribute to developing an addiction in the first place.  It's also a rat study, not a human study.

 

 

J Neurosci. 2015 May 27;35(21):8042-58. doi: 10.1523/JNEUROSCI.3053-14.2015.

Role of DNA methylation in the nucleus accumbens in incubation of cocaine craving.
Author information
1 Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada. 2 Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan 52900, Israel, Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel. 3 Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada, McGill Centre for Bioinformatics, McGill University, Montreal, Quebec H3G 0B1, Canada. 4 McGill Centre for Bioinformatics, McGill University, Montreal, Quebec H3G 0B1, Canada. 5 Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, and. 6 Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada, Sackler Program for Epigenetics and Psychobiology, McGill University, Montreal, Quebec H3G 0B1, Canada moshe.szyf@mcgill.ca yadidg@gmail.comgmail.com. 7 Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan 52900, Israel, Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel, moshe.szyf@mcgill.ca yadidg@gmail.comgmail.com.
Abstract

 

One of the major challenges of cocaine addiction is the high rate of relapse to drug use after periods of withdrawal. During the first few weeks of withdrawal, cue-induced cocaine craving intensifies, or "incubates," and persists over extended periods of time. Although several brain regions and molecular mechanisms were found to be involved in this process, the underlying epigenetic mechanisms are still unknown. Herein, we used a rat model of incubation of cocaine craving, in which rats were trained to self-administer cocaine (0.75 mg/kg, 6 h/d, 10 d), and cue-induced cocaine-seeking was examined in an extinction test after 1 or 30 d of withdrawal. We show that the withdrawal periods, as well as cue-induced cocaine seeking, are associated with broad, time-dependent enhancement of DNA methylation alterations in the nucleus accumbens (NAc). These gene methylation alterations were partly negatively correlated with gene expression changes. Furthermore, intra-NAc injections of a DNA methyltransferase inhibitor (RG108, 100 μm) abolished cue-induced cocaine seeking on day 30, an effect that persisted 1 month, whereas the methyl donor S-adenosylmethionine (500 μm) had an opposite effect on cocaine seeking. We then targeted two proteins whose genes were demethylated by RG108-estrogen receptor 1 (ESR1) and cyclin-dependent kinase 5 (CDK5). Treatment with an intra-NAc injection of the ESR1 agonist propyl pyrazole triol (10 nm) or the CDK5 inhibitor roscovitine (28 μm) on day 30 of withdrawal significantly decreased cue-induced cocaine seeking. These results demonstrate a role for NAc DNA methylation, and downstream targets of DNA demethylation, in incubation of cocaine craving.

Copyright © 2015 the authors 0270-6474/15/358042-17$15.00/0.

KEYWORDS: 

DNA methylation; cocaine addiction; incubation of cocaine craving; nucleus accumbens

PMID: 26019323

PMCID: PMC6605346

DOI: 10.1523/JNEUROSCI.3053-14.2015

A couple of key excerpts (from the full text):

 

 

In contrast to the effect of RG108, treatment with SAM caused a significant increase in active lever pressing during the extinction test (day 30) compared with aCSF-treated rats; this effect remained up to 1 month after the single SAM treatment (day 60) (one-way ANOVA main effect of group: F(2,19) = 9.37; p = 0.0005, Student-Newman-Keuls' test; p < 0.001 for day 30 and p < 0.05 for day 60; Fig. 5F).

 

…In the present study, we show broad, dynamic, and time-dependent increases in DNA methylation alterations in the NAc after cocaine withdrawal and cue-induced cocaine seeking. These methylation changes occurred in gene promoters at the whole-genome level and in selected candidate genes related to drug addiction and were partly negatively correlated to gene expression changes. DNMT inhibition by intra-NAc injection of RG108 significantly attenuated cue-induced cocaine seeking after prolonged withdrawal and up to 1 month after treatment, whereas the methyl donor SAM had the opposite effect, inducing a long-term increase in cue-induced cocaine seeking.

 



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