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First ever study identifies epigenetic markers that influence addiction in animal model.

Approximately 16% of adults in the United States report drug use, however, not everyone who experiments with drugs becomes an addict. Environmental and societal factors play a role in addiction liability, and there is ample evidence demonstrating a role for genetic factors. However, studying the interplay among these factors is difficult in human studies because of the inability to control for environmental factors and the challenge of parsing causes from consequences. Preclinical animal models are therefore essential for defining the complex interactions between genes and environment, and uncovering the neural mechanisms that might render an individual more susceptible to drug addiction.  Now, a study from researchers at the University of Michigan shows that epigenetic differences in vulnerability to cocaine addiction exist in the rat.  The team state that their findings reveal new information about the roles played by both inherited traits and addiction-related changes in the brain.  The opensource study is published in the Proceedings of the National Academy of Sciences.

Previous studies show that, like humans, only some rats readily self-administer drugs and this propensity to take drugs could be predicted by a behavioural trait, referred to as ‘sensation-seeking’.  These high-responder (HR) rats were more likely to self-administer cocaine relative to low-responder rats (LR), or those with low levels of activity in a novel environment. Subsequent studies showed that these rats differ in their stress response, with HRs exhibiting increased and prolonged corticosterone response to mild stress and greater stress-induced elevations of dopamine activity relative to LRs. Thus, these rats presented a model that captured both behavioural and neurobiological features associated with drug-taking behaviour.  The current study investigates HR and LR rats to show that low D2 mRNA levels in the nucleus accumbens core, an area of the brain known to play a major role in addiction, via epigenetic modifications, may render individuals more susceptible to cocaine addiction.

The current study observed rats’ brains for the genetic instructions needed to make a key ‘pleasure receptor’, called D2, that allows brain cells to receive signals sent by the brain chemical dopamine, or cocaine. Results show that more addiction-prone rats had lower levels of D2 instructions to begin with, compared with other rats, in the nucleus accumbens core.  Data findings show that the addiction-prone rats also were more likely to carry a specific mark on their DNA called an epigenetic tag; this tag, known as H3K9me3, kept their brain cells from reading the gene for D2 receptors.

Results show that after the rats became hooked on cocaine, the addiction-prone rats had the same levels of D2 as the less addiction-prone ones.  Data findings show that when the cocaine was taken away for a while, these rats were more likely to relapse to addictive behavior if they had started out with the epigenetic tag that kept their cells from reading the D2 gene; meanwhile, a comparison group of rats didn’t show signs of addiction, and didn’t relapse following abstinence.

The lab state that they found these ‘addiction-resilient’ rats started out with lower levels of instructions for making a different brain molecule also known to play a role in addiction, called FGF2. They also observed that these rats were also more likely to carry an epigenetic mark that kept them from reading the FGF2 gene, and this might have helped protect them from becoming addicted.

The group explain that because they had access to these rats that were bred for certain traits, and were able to control for environmental factors, such as the amount of drug exposure, they could assess differences in the brain both before and after the rats became addicted.  They go on to add that by studying their gene expression and epigenetics, as well as their response to drug availability and drug-related cues, they can link these differences in the brain to addiction-like behaviors, such as relapse; this allows them to hone in on the biology of addiction even further.

The team surmise that, to their knowledge, theirs it the first study to show in selectively bred animals that the propensity for addiction is linked to differences in expression of genes for specific molecules in a specific brain region. They go on to add that it’s also the first demonstration that an epigenetic marker can predispose an individual to addiction and relapse.  For the future, the researchers state that this kind of understanding could be a model to help the broader understanding of addiction in humans as well. They conclude that their genetic findings will point to potential biomarkers and more targeted treatment strategies for substance use disorders.

Source: University of Michigan Medical School


In these images of rat brains, differences in gene expression of genes for fibroblast growth factor 2 (FGF2, top set) and dopamine 2 receptor (D2, bottom sett) can be seen in rats of two breeds before (left) and after (right) cocaine exposure. The addiction-prone bHR rats differed significantly in several ways from the timid bLR rats.  Credit: Flagel Lab, University of Michigan.
In these images of rat brains, differences in gene expression of genes for fibroblast growth factor 2 (FGF2, top set) and dopamine 2 receptor (D2, bottom sett) can be seen in rats of two breeds before (left) and after (right) cocaine exposure. The addiction-prone bHR rats differed significantly in several ways from the timid bLR rats. Credit: Flagel Lab, University of Michigan.



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