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Sunday, November 23, 2008

Totally Addicted to Genes

Why do some people get addicted to things? As with most things in life, there are lots of causes, most of which have little, if anything, to do with genes or the brain. Getting high or drunk all day may be an appealing and even reasonable life choice if you're poor, bored and unemployed. It's less so if you've got a steady job, a mortgage and a family to look after.

On the other hand, substance addiction is a biological process, and it would be surprising if genetics did not play a part. There could be many routes from DNA to dependence. Last year a study reported that two genes, TAS2R38 and TAS2R16, were associated with problem drinking. These genes code for some of the tongue's bitterness taste receptor proteins - presumably, carriers of some variants of these genes find alcoholic drinks less bitter, more drinkable and more appealing. Yet most people are more excited by the idea of genes which somehow "directly" affect the brain and predispose to addiction. Are there any? The answer is yes, probably, but they do lots of other things beside cause addiction.

A report just published in the American Journal of Medical Genetics by Argawal et. al. (2008), found an association between a certain variant in the CNR1 gene, rs806380, and the risk of cannabis dependence. They looked at a sample of 1923 white European American adults from six cities across the U.S, and found that the rs806380 "A" allele (variant) was more common in people with self-reported cannabis dependence than in those who denied having such a problem. A couple of other variants in the same gene were also associated, but less strongly.

As with all behavioural genetics, there are caveats. (I've warned about this before.) The people in this study were originally recruited as part of an alcoholism project,COGA. In fact, all of the participants were either alcohol dependent or had relatives who were. Most of the cannabis-dependent people were also dependent on alcohol. However, this is true of the real world as well, where dependence on more than one substance is common.

The sample size of nearly 2000 people is pretty good, but the authors investigated a total of eleven different variants of the CNR1 gene. This raises the problem of multiple comparisons, and they don't mention how they corrected for this, so we have to assume that they didn't. The main finding does corroborate earlier studies, however. So, assuming that this result is robust, and it's at least as robust as most work in this field, does this mean that a true "addiction gene" has been discovered?

Well, the gene CNR1 codes for the cannabinoid type 1 (CB1) receptor protein, the most common cannabinoid receptor in the brain. Endocannabinoids, and the chemicals in smoked cannabis, activate it. Your brain is full of endocannabinoids, molecules similiar to the active compounds found in cannabis. Although they were discovered just 20 short years ago, they've already been found to be involved in just about everything that goes on in the brain, acting as a feedback system which keeps other neurotransmitters under control.

So, what Argawal et. al. found is that the cannabinoid receptor gene is associated with cannabis dependence. Is this a common-sense result - doesn't it just mean that people whose receptors are less affected by cannabis are less likely to want to use it? Probably not, because what's interesting is that the same variant in the CNR1 gene, rs806380, has been found to be associated with obesity and dependence on cocaine and opioids. Other variants in the same gene have shown similar associations, although there have been several studies finding no effect, as always.

What makes me believe that CNR1 probably is associated with addiction is that a drug which blocks the CB1 receptor, rimonabant, causes people to lose weight, and is also probably effective in helping people stop smoking and quit drinking (weaker evidence). Give it to mice and they become little rodent Puritans - they lose interest in sweet foods, and recreational drugs including alcohol, nicotine, cocaine and heroin. Only the simple things in life for mice on rimonabant. (No-one's yet checked whether rimonabant makes mice lose interest in sex, but I'd bet money that it does.)

So it looks as though the CB1 receptor is necessary for pleasurable or motivational responses to a whole range of things - maybe everything. If so, it's not surprising that variants in the gene coding for CB1 are associated with substance dependence, and with body weight - maybe these variants determine how susceptible people are to the lures of life's pleasures, whether it be a chocolate muffin or a straight vodka. (This is speculation, although it's informed speculation, and I know that many experts are thinking along these lines.)

What if we all took rimonabant to make us less prone to such vices? Wouldn't that be a good thing? It depends on whether you think people enjoying themselves is evidence of a public health problem, but it's worth noting that rimonabant was recently taken of the European market, despite being really pretty good at causing weight loss, because it causes depression in a significant minority of users. Does rimonabant just rob the world of joy, making everything else less fun? That would make anyone miserable. Except for neuroscientists, who would look forward to being able to learn more about the biology of mood and motivation by studying such side effects.

ResearchBlogging.orgArpana Agrawal, Leah Wetherill, Danielle M. Dick, Xiaoling Xuei, Anthony Hinrichs, Victor Hesselbrock, John Kramer, John I. Nurnberger, Marc Schuckit, Laura J. Bierut, Howard J. Edenberg, Tatiana Foroud (2008). Evidence for association between polymorphisms in the cannabinoid receptor 1 (CNR1) gene and cannabis dependence American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 9999B DOI: 10.1002/ajmg.b.30881

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