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“You didn’t know how rock-n-roll looked
Until you caught your sister with the guys from the group
Halfway home in the parking lot
By the look in her eye she was giving what she got
My my my, once bitten, twice shy babe…”

Great White - “Once Bitten, Twice Shy”

Somewhere, a science reporter is missing a lead: “Scientists discover the Homer Simpson gene”. The lovable buffoon, infamous for failing to learn from his mistakes is probably short more than just a few dopamine receptors. However, this week researchers from the Max Planck Institute for Human Cognitive and Brain Sciences in Germany published results in Science that link a mutation in a dopamine receptor to just that sort of Homer-esque behavior - a decreased sensitivity to negative consequences.

Dopamine is a neurotransmitter - a chemical that allows communication within the nervous system and the brain. Dopamine plays a number of roles in the brain including sleep, mood, attention, learning, motivation and reward. Recently a fair bit of research has been focused on the role of dopamine in addictive behavior - in particular, defects in dopamine perception can play a role in drug and alcohol abuse. One line of reasoning is that dopamine usually acts as a form of positive reinforcement - when one makes a pleasurable decision, one is rewarded by a spurt of dopamine. If one didn’t respond to that spurt, the positive decision has no rewarding effect. A variation in the dopamine D2 receptor gene (DRD2-TAQ-IA) is correlated with a reduction in the density of dopamine receptors in the brain and thus a reduced perception of the dopamine effect. This mutant allele, known as A1, has been associated with addictive behaviors including alcoholism, compulsive gambling and drug addiction.

Most alcoholics, addicts and compulsive gamblers have at some point gotten into trouble as a result of their obsessions - often on multiple occasions. Many of them, not to mention their loved ones, have wondered why they repeat this behavior - why they don’t learn their lesson. The German group, led by Tilmann Klein and Markus Ullsperger, propose that in some cases it is genetic - that the A1 dopamine receptor mutation can result in a general failure in learning from one’s errors.

In order to test their hypothesis, Klein and his colleagues analyzed the decision making and brain activity of 26 men - 12 of whom carried the A1 allele (the A1+ group) and 14 the “normal” allele (A1-). This is not only a very small sample size -presumably due to either the cost of the fMRI analysis or scarcity of volunteers with the A1 allele - but also sexually biased. Apparently men were used because women’s menstrual cycles affect dopamine levels (insert moody woman joke of choice here). However, it would seem that one could include women in the study with a minimum of extra effort. Regardless of these issues, there were statistically significant differences in the responses of the A1+ group relative to the A1- group. The decision-making test involved showing subjects two symboks. After selecting one, subjects were shown either a positive smiley face or a negative frowning face. One of the symbols resulted in a positive response 80% of the time and the other a negative result at the same rate. The real test is whether the subjects learned to choose the positively biased symbol and avoid the negatively biased. Both sets of subjects learned to choose the positive symbol, but men in the A1+ group failed to learn from negative reinforcement. This result implies that a reduction of the D2 dopamine receptors can lead to a failure to learn from errors.

Further evidence to support this came from the results of the functional MRI scans that were performed. A region of the brain known as the rostral cingulate zone, a part of the posterior medial frontal cortex, was much more active in the “normal” A1- subjects than in the receptor deficient A1+group. This part of the brain is thought to be important in responding to feedback. Therefore the scan results provide support to the idea that

As with many genetic studies of complex human behaviors, things are probably not so cut and dry. As I mentioned above, this is a very small sample size and extremely sex biased. Admittedly, their results are statistically significant, but the addictive tendencies of the test subjects are not addressed. In other words, were all of the A1+ group alcoholics and addicts or none? Were any of the A1- group alcoholic or addicts? There are no controls in place in terms of addictive behavioral patterns.

A second, and likely bigger issue, is that the simple test that they employ - smiley faces and frowny faces - is a massive oversimplification. There is probably little comparison between a disastrous three day drinking binge in which one crashes his car and wakes up somewhere unfamiliar with someone unfamiliar on the one hand and guessing wrong and having a frowny face pop up on a screen. Rarely does a drug-induced robbery gone wrong result from a simple decision between two choices. I believe that their results are reasonably sound, but to draw the conclusion - as they do - that it explains an increased risk of developing addictive behavior in people with the A1 mutant seems a little bit of a a stretch.

Image credits:

Addiction skull

Aftermath

fMRI results

* The Great White song is completely gratuitous, but once I started reading this paper I couldn’t get it out of my head. You have got to love 80’s hair metal.

 

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