Ruth Williams reports :: September 2006

Psychoactive drugs can rewrite the epigenetic code of your brain cells according to recent research. The new findings provide clues that might help to explain how transient changes in the brain environment – the presence of a drug – translate into the long term changes in the brain’s cell connections that can ultimately lead to addiction.

The brain’s ability to learn is an iterative process that continually links events with outcomes until associative memories are formed. Psychoactive drugs that induce a ‘high’ (or reward) stimulate this learning circuitry and it’s thought that, in addiction, the reward-related learning system essentially enters pathological overdrive leading to compulsion. Regular (chronic) compulsive drug taking then further reinforces the learnt association and exacerbates the problem.

On a physical level, learning promotes the strength of connection and communication between particular brain cells. Although little is known about the molecular mechanisms that lead to this strengthening, it is thought to involve the switching on of genes that control the physical remodelling of the connections.

A number of genes are switched on in brain cells following administration of drugs such as cocaine and new research shows this switch mechanism involves epigenetic modifications - chemical changes to either the DNA (that codes the gene) or the DNA-associated proteins (histones).

Epigenetic modifications do not change the DNA code itself, but rather, influence the availability of the code to the factors that read it and translate it into its product. Hence epigenetic modifications can make a gene accessible and thus increase the amount that it is read (increase the level of product), or make it inaccessible – effectively switching it off. Cocaine has been shown to lead to the acetylation of histones at genes that it switches on – a modification known to be associated with accessible active DNA.

Cocaine not only alters the epigenetic status of genes but also induces particular epigenetic modifications depending on the frequency of the drug’s administration. Certain genes are switched on by infrequent (acute) administration, while others are switched on only after chronic administration (such as in addiction). Some are switched on by both. The genes switched on by acute administration, get their associated histone H4 proteins acetylated, while genes switched on by chronic drug administration get their associated histone H3 proteins acetylated. Lastly, genes that are switched on by both types of drug exposure, show H4 acetylation during initial cocaine exposure and then switch to H3 acetylation as the administration becomes chronic.

Importantly, at a number of genes induced by chronic cocaine exposure, H3 acetylation persists long after the drug’s withdrawal. This prolonged molecular mark might thus lead to long-term activation of the genes and accumulation of their remodelling products, which could, in turn, explain the long-lasting physical changes required to strengthen brain cell connections during learning and addiction.

The same genes switched on by cocaine can also be switched on by other drugs of abuse. If it turns out that these other drugs are also acting epigenetically and with long-lasting effect, then investigating how to erase the epigenetic modifications in specific areas of the brain could lead to a potential treatment for addiction.

Original article
Related articles: Levine et al 2005 and Tsankova et al 2006