We know a lot about drugs – new data shows long-term epigenetic changes


There is a belief in the drug community that the war on drugs prevents good research from being done on drug use. While I agree there is a scarcity of research on the potential uses of many abused drugs or how they alter states of consciousness we really do know an amazing amount about what drugs do to our brain. In the early 2000s my worry was always about whether or not marijuana killed brain cells, unfortunately the picture is now more complex with drugs changing the biochemistry inside cells—making long-term epigenetic changes.

Alfred Robinson and Eric Nestler released a new review of long-term transcriptional and epigenetic mechanisms of addiction. The genetic contribution to addiction risk is ~50%, but few specific genes have been implicated. Drug use significantly changes the expression of hundreds of genes, differently for first use, after repeated use, and after repeated use following withdrawal.

The following data is from animals exposed to cocaine:

With repeated drug use, some genes become primed for transcription while others become repressed. These long term changes may be a mechanism for why exposure to drugs in utero increase the risk for addiction years later.
Specifically, histone proteins which bind DNA and regulate whether or not genes are expressed can be acetylated through drug use. In general, cocaine causes H3 and H4 acetyltion in the Nucleus Accumbens (an area implicated in reward pathways and addiction) increases, but other genes show decreased acetylation and it is unclear what influences why some genes are modulated differently than others. Alcohol withdrawal has been shown to remove histone acetylations from the mouse amygdala, inhalants affect H4 acetylation. THC increases HDAC3 expression in trophoblast cells (one of the early stages in the development of the embryo). Whole brain genome screens of Δ9-THC-treated mice did not show altered HDAC3 expression, but this could be due to differential modulation in different cell types or brain regions.

Pharmacological and genetic experiments also indicates that epigenetics is involved in addiction and conditioning. HDAC inhibitors potentiate conditioned place preference to psychostimulants and opiates. Upregulating HDAC4 or HDAC5 or lowering the expression of an opposing HAT enzyme decreases the behavioral effects of cocaine. Deleting HDAC5 has the opposite effect of hyper-sensitizing mice to the chronic effects of cocaine.
Drug administration also alters DNA methylation. Cocaine alters DNA methyl transferase 3A (DNMT3A) expression in the dorsal striatum. Cocaine also increases methyl CpG binding protein (MeCP2), and mice with reduced MeCp2 production show less locomotor sensitization and conditioned place preference after chronic amphetamine administration.

The DNA methylation findings are particularly scary, because if changes also occur in sperm or eggs they could be transferred to offspring. Recent research has shown that cocaine exposure in male adult rats can affect their pups’ response to cocaine.

We’ve known for a long time that drug use during pregnancy can have harmful effects, but these new epigenetic mechanisms show that drug use by men and women–even before conception–could affect the affect the transcription of genes and response to drug use of children. So guys, don’t use drugs during your babymaking.

If you’re interested in learning more about epigenetics in neurons and brains, check out my post: Epigenetics and The Brain — 5-hydroxy-methocytosines


You might also be interested in my post about Mirror Touch Synesthesia, the role of endocannabinoids in anorexia and bulemia, and how the COMT gene and cannabis use may affect risk of schizophrenia and psychosis.

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