Cocaine addiction and genes

Scientists have discovered a gene that increases the risk of cocaine addiction, according to a front-page story in The Guardian yesterday. They claim the discovery could lead to genetic screening for the “CAMK4 gene” to identify those most at risk.

The researchers behind the study looked at the role of the gene in normal and genetically engineered mice, then analysed the DNA of “670 cocaine addicts and more than 700 matched non-users”. They found that “addicts were 25% more likely to carry the gene than people who did not use cocaine.”

The strength of this study is that it has not only found the gene can affect cocaine-related behaviours in mice but has also shown a link between a variation in this gene and cocaine addiction in humans.

However, cocaine addiction is be affected by a variety of factors, both environmental and genetic, and more than one gene is likely to play a role. At the moment, screening for this variant gene alone is unlikely to prove very helpful in identifying those most at risk of addiction, as the variant is relatively common in the population, even among those without cocaine addiction.

Where did the story come from?

Dr Ainhoa Bilbao and colleagues from the Central Institute of Mental Health in Mannheim, Germany and other research centres in Germany, Brazil, Spain and the UK carried out this research.

The study was funded by the National Genome Research Network, the research organisations Deutsche Forschungsgemeinschaft, EU/IMAGEN and EU/PHECOMP. The study was published in the peer-reviewed scientific journal, Proceedings of the National Academy of Sciences of the USA.

What kind of scientific study was this?

This study comprised of an animal study in mice, followed by a case-control study in humans. Overall the study aimed to investigate whether the gene Camk4 plays a role in addiction.

This gene contains instructions for the cell on how to make the protein CaMKIV, which plays an important role in switching on other genes in response to various stimuli. This process causes changes in nerve cells in the brain that are associated with learning and memory.

Addiction has been linked to changes in certain areas of the brain called the striatum and nucleus accumbens, and researchers had a theory that the CaMKIV protein might play a role in these changes.

The researchers genetically engineered mice so that they lacked a working copy of the Camk4 gene, stopping the mouse’s cells from producing the CaMKIV protein. They then injected the normal mice and the mice lacking the Camk4 gene with cocaine, and looked at what genes were switched on in the striatum area of the brain.

They also observed the behaviour of both sets of mice when injected with cocaine. Injections were repeated each day for 5 days. The mice were again injected on days 12 and 19 and their behaviour observed. The researchers also carried out tests looking at whether mice lacking the CaMKIV protein and normal mice differed in their cocaine seeking behaviour after being exposed to cocaine.

For the human study researchers obtained DNA samples from 670 cocaine users (cases) and 726 people who were not addicted to cocaine (controls) from Brazil. They then looked at sites within and around the CAMK4 gene in cases and controls. The CAMK4 gene is the human form of the Camk4 gene found in mice, but is always written in upper case letters to identify it as a human gene.

Researchers analysed whether any particular genetic variants were more or less common in cases than controls. In their analysis they took into account the different ethnic background of the cases and controls, as different groups may have differing genetic make ups.

What were the results of the study?

The researchers found that removing Camk4 gene in mice did not cause any major changes to the other genes that are normally switched on in response to cocaine in the brain. The mice lacking the Camk4 gene were more sensitive to cocaine, showing a greater increase in activity in the 10 minutes after cocaine injection than normal mice.

When the injections were repeated daily over 5 days, the normal mice showed increasing level of activity in response to the injections, showing that they were gradually becoming more sensitive to the cocaine. However, the mice lacking the Camk4 gene did not show a change in their level of activity between the first and fifth injections.

When injected on days 12 and 19, mice lacking the Camk4 gene once again showed greater sensitivity to cocaine and activity than the normal mice. Camk4 -lacking mice also showed greater cocaine seeking behaviour than normal mice.

Finally the researchers compared the CAMK4 gene in humans in people with, and without cocaine addiction. They found that a variation at one genetic site called “rs919334” was more common in people with cocaine addiction (cases) than those without (controls). About 50% of those with cocaine addiction carried two copies of this variant, while it was found in 40% of people without cocaine addiction.

What interpretations did the researchers draw from these results?

The researchers concluded that their findings show “the activity of CaMKIV [protein] regulated susceptibility to cocaine in laboratory animals and in humans”.

What does the NHS Knowledge Service make of this study?

This study identified a potential role for the CaMKIV protein in cocaine addiction. The strength of this study is that it has shown that removing CaMKIV can have an effect on cocaine seeking behaviour in animals, as well as showing that a variation in the gene in humans is associated with cocaine addiction.

Whether or not a person develops cocaine addiction will be affected by a variety of factors, both environmental and genetic, and more than one genetic variant will probably play a role. Further research will be needed to look at whether the variant identified affects the function of the Camk4 gene, and to identify whether this information might help to develop approaches to treat cocaine addiction.

At present treatments available for giving up cocaine and stimulants include specialist drugs counselling and social support, and information about these can be provided by local Drug Action Teams (featured in the useful link section).

Sir Muir Gray adds...

For all addictions, including tobacco, there is a balance of genetic and environmental factors; some people are more susceptible than others because of their genetic makeup, but everyone is at risk.