Thursday 19 October 2017

The epigenetics of addiction

Why do people slip back into unhealthy habits so often? Why is there such a high risk of relapse after abstaining from an addictive substance? A study published in Neuron reveals that the nucleus accumbens, epigenetics and the environment play a crucial role.


An addiction is an irresistible desire to search for rewarding or calming stimuli, irrespective of the negative consequences that these can have. Through repeated contact with the desired stimuli, the sensitivity to that decreases and the search behaviour mentioned above increases. Even if the patient succeeds in getting a grip of this process, patients commonly repeatedly slide back into the old pattern. Why is this?  


The main risk factors for relapse are negative (social) environmental factors. Researchers at the Medical University of South Carolina (US) studied the phenomenon that addicted users build up strong associations with the (social) environment where the substance was first used [1]. In this environment, the risk of release appears to increase significantly.


Epigenetic enzyme HDAC5

To obtain a dose of cocaine, rats first had to press a lever, at which time a sound was played and a lamp illuminated. This resulted in the rats establishing a simple link between cocaine use and the environment. The epigenetic enzyme HDAC5 was then administered to the rats. This enzyme is involved in the transcription of genes that potentially play a role in addiction.


This appeared to have little effect: the rats pressed the lever just as often as before. A week later, the rats were subjected to another experiment: they were placed in a test environment with the lever, whilst a lamp was illuminated and a sound played. This should have reactivated their conditioned response.


The control animals again pressed the lever just as often. In the control animals, there was therefore still a strong association between the environment and administration of cocaine but that wasn’t the case with the animals who were given HDAC5. The epigenetic enzyme had resulted in a weaker association between substance use and cues in the environment. Conclusion: through an epigenetic mechanism, the environment determines, at least partially, whether or not there will be a relapse.


Is there also a link in people?

Although the link hasn’t been proven in people, people do have similar enzyme pathways and brain structures to rodents and other mammals. It is also known that addicted users clearly respond to cues in the environment. Furthermore, in both rodents and people, the nucleus accumbens, part of the reward system, contains large amounts of the enzyme HDAC5, that can be lowered for various reasons.


There are therefore numerous similarities. But why are we so sensitive to addiction?


Dopaminergic reward system

The dopaminergic reward system ensures that we are rewarded when we, for example, search for food, have sexual intercourse and make future plans. This increases the likelihood of surviving and reproducing [2]. The system therefore clearly has an adaptive function. However, when the reward is activated by an addictive substance, this ultimately leads to non-adaptive behaviour.


Addictive substances often give a greater reward stimulus than searching for food or having sexual intercourse. Furthermore, little effort has to be made to obtain a reward. Because of this, the interest in the substance increases, to the detriment of adaptive behaviour. Habituation then occurs, resulting in more and more of the substance having to be taken to obtain a comparable effect. The substance will increasingly define the life of the user and his social environment and survival is threatened.


The role of the environment and epigenetics could play a much more significant role that we have thought to date. In this respect, it is interesting to look at our natural environment. Is addiction a problem there too?


Humans in their natural environment

Many psychotropic substances can also be found in nature that may cause addiction or dependence. For example, the fermented berries or apples that elks sometimes eat (and undoubtedly the great apes too). Although the elks continue to eat until they are very intoxicated, this cannot be called an addiction. After all, an elk stops eating apples once the growing season has passed.


Humans are no longer restricted by that – in our current environment, alcohol is a legalised addictive substance. It has a social function and is available throughout the year. It is these self-created environmental factors that contribute to an addiction. The chronic availability also applies to other addictive substances, although more effort is required for the stronger substances.


Evolutionary mismatch

Availability and the social environment are proximal mechanisms of action. But the ultimate mechanism of action is in our evolutionary background. Ultimately, an addiction to substances can be seen as an evolutionary mismatch [3] that has an adverse effect on our epigenetics. In that respect, it is comparable to our current diet, that is not in keeping with what we ate in nature, nor with how often and how much. This also has an effect on our epigenetic mechanisms.


What form does an evolutionary-based strategy to prevent a relapse take? By ensuring in any case there is an environment with as few cues as possible that could cause a relapse. The epigenetic mechanism would then not fail.


This applies not only to abstinence from cocaine, heroin, nicotine and alcohol, but also to less addictive substances, such as exorphins (opioids) from the incomplete breakdown of proline-rich proteins in, for example, bread (gluten) and cheese (casein). The reason for this is that ultimately this is all about an evolutionary mismatch.



[1]Taniguchi M. et al., HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors, Neuron, Volume 96, Issue 1, p130-144.e6, 27 september 2017.

[2] Schultz W., Neuronal reward and decision signals: from theories to data, Physiological Reviews (2015), 95 (3): 853–951.

[3] Brüne M., Textbook of Evolutionary Psychiatry & Psychosomatic Medicine 2nd edition, Oxford University Press (2016), pp. 253-64.