Friday, June 13, 2008
Impulsivity and a Predisposition to Addiction
The improved understanding of addiction that has emerged over the past few decades has transformed the question of whether or not addiction is a choice into a search for predisposing factors that make the risk of addiction much higher for some people than for others. This is a drastic improvement from the times when it was even considered that addiction was a voluntary process—a decision made by degenerates who had no motivation to live a successful life. It has also led to a great deal of research in an attempt to isolate specific genotypes and phenotypes that result in a susceptibility to drug abuse.
Much of that research has focused on two such phenotypes: the sensation or novelty-seeker, and the impulsive personality. Novelty-seeking has been considered a predisposing factor to drug abuse for some time. This was reinforced by studies in the 1980s that found it to be correlated with the acquisition of cocaine self-administration (SA) in rats. Last year, however, a group of researchers at Cambridge found that an impulsive phenotype in rats was more of a predisposing factor to the compulsive use of cocaine that is traditionally associated with addiction.
Novelty-seeking and impulsivity may sound very similar, but there is a distinction between the two types of behavior. In rats, novelty-seekers have a greater tendency to explore a new environment than to stay in one place. Impulsive rats perform poorly on trained responses that will reward them with food, acting too quickly and making premature responses. When it comes to cocaine use, novelty-seeking rats (known as high responders, or HR) have shown a tendency to acquire the SA of cocaine more rapidly. Highly impulsive (HI) rats, on the other hand, don’t acquire SA more quickly, but they are more prone to allow their cocaine use to progress from occasional to compulsive. Thus, HR are more likely to try cocaine, but HI rats are more liable to develop an addiction to it.
Another group of Cambridge researchers (including a few who were also involved in the study mentioned above) published a study in this week’s Science that further explores the difference between HR and HI rats. In order to gain greater relevance to human addiction, they focused on the observation in rats of actual Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria for addiction, specifically 1) an increase in motivation to obtain the drug, 2) an inability to refrain from drug taking, and 3) maintained drug use despite aversive consequences (punishment in this case). Each of the rats was given an overall addiction score based on these criteria (0-3), which corresponded to a score on the Addiction Severity Index (ASI)—a valid, reliable, and widely used addiction assessment tool.
The HI rats were found to have the highest addiction scores, being represented largely in the 2 to 3 point range, whereas low-responder (LR), HR, and low-impulsivity (LI) rats usually had a score of 0 or 1. These results reinforce previous findings that the propensity to use cocaine and the tendency to progress to addiction are influenced by separate (although perhaps overlapping) behavioral traits.
These two patterns of drug use are very distinct in humans as well. The percentage of people who try or experiment with drugs/alcohol is much higher than the percentage who actually become addicted, mirroring the separation in rats between SA and compulsivity. It also makes sense that impulsivity could be more of a negative influence when attempting to stave off the urges of an addiction than novelty-seeking, whereas novelty-seeking could be a primary factor in spurring an initial interest in drug experimentation.
As might be expected, it also seems that different brain regions in the rat control these different types of drug use. Previous studies have found that addiction (in rats and primates) is correlated with lower levels of the availability of a specific dopamine (DA) receptor—the D2/D3 receptor. Cambridge researchers last year found that limited D2/D3 receptor availability in the ventral striatum/nucleus accumbens (NAc) of rats exists before drug use. As other studies have found limited D2 availability throughout the striatum during and after drug addiction, this group suggested that, while NAc D2 deficiencies may predate drug use, the abuse itself (and the excessive DA transmission associated with it) causes downregulation of DA receptors throughout the striatum. Therefore, the reduction in D2 availability in the dorsal striatum may represent more closely the switch to compulsive drug use seen in HI rats. A deficiency in NAc D2 receptors, however, could be a risk factor for the initial use of the drug.
These developments in our understanding of addiction serve several important purposes. They solidify the association that can be made between a predisposition to drug abuse, and addiction itself. As more data indicates that specific phenotypes and genotypes predispose organisms to drug use/abuse, the question of the involvement of choice in addiction will slowly fade into the background as attempts to treat its neurobiological underpinnings become of primary importance. And, as scientists come to more explicitly understand neurobiological influences on drug abuse, social attitudes toward addiction may necessitate revision. Many questions, both philosophical and legal in nature, will have to be examined. For example, should a drug addict be imprisoned for repeated drug possession arrests, when no other crime is involved? How much are they to be held responsible for neurophysiological dissimilarities that made the decision for them to abstain from drugs much more difficult than it is for someone without such deficits?
While the social reverberations may not be felt for some time, however, research will continue into both the genotypes and phenotypes that correlate with addiction, in the hopes of finding improved treatments for the affliction in the near future. Identifying the genes associated with pre-drug decreased D2 receptor density, for example, could lead to the development of a treatment to correct the deficiency (for information on a promising vaccination treatment for addiction, see this post). Already a staggering 1,500 genes that are associated with addiction have been identified, along with eighteen molecular pathways for the disorder, five of which are shared by common drugs of abuse. So, although there is much work to be done, a solid foundation has been laid. And, with each new finding, we come a bit closer to comprehending what was previously one of the most misunderstood brain disorders.
Belin, D., Mar, A.C., Dalley, J.W., Robbins, T.W., Everitt, B.J. (2008). High Impulsivity Predicts the Switch to Compulsive Cocaine-Taking. Science, 320(5881), 1352-1355. DOI: 10.1126/science.1158136