Stimulants such as cocaine and amphetamines are popular recreational drugs, which are thought to be used by up to 52 million individuals worldwide (UNODC, 2010). However, despite their high addictive liability, not everyone who uses these drugs develops dependence, though the risk for dependence is significantly increased for people with a family history of addiction. This familial aggregation of drug and alcohol dependence suggests that either genetic factors, a shared family environment, or an interaction of genes and environment underlie the increased risk for addiction in some people. The concept of endophentoypes may offer a useful tool to better understand how a pre-existing vulnerability to addiction might be inherited. Endophenotypes have been described as neurobiological correlates of a disorder, which are thought to be genetically determined and stable over time (Gottesman and Gould, 2003). In other words, abnormalities in brain systems underlying the clinical symptoms of stimulant dependence may not only be observed in individuals who are dependent on stimulant drugs, but also in their non-dependent first-degree relatives. Key symptoms of stimulant dependence, such as the inability to stop using the drug and the loss of control over drug intake, may be underpinned by a general lack of self-control, which may have predated drug-taking.

We assessed a wide range of cognitive and emotional functions as well as personality traits that have previously been associated with drug dependence in three groups of volunteers: 50 adults with stimulant dependence, their non-dependent biological siblings and 50 unrelated healthy volunteers who had neither a personal nor a family history of dependence (Ersche et al, 2012a, 2012b). We identified significant impairments in inhibitory control abilities and abnormally high levels of impulsive and compulsive personality traits in the sibling pairs compared with the unrelated healthy volunteers. The sibling pairs also shared abnormalities in brain regions that have previously been associated with stimulant dependence, such as the inferior frontal gyrus, the amygdale, and the putamen (Chang et al, 2005; Lim et al, 2002). Moreover, their poor performance of behavioral control on the stop-signal task was directly associated with reduced fractional anisotropy in frontal white matter brain fibers, shown in Figure 1.

Figure 1
figure 1

Deficits of motor inhibitory control and white matter organization in stimulant-dependent individuals and their non-dependent siblings. (a) Stop-signal reaction time (SSRT) differed significantly between the three groups (F2,141=9.9, P<0.001). SSRT was significantly prolonged in both the stimulant-dependent individuals and their siblings compared with unrelated healthy volunteers (Bonferroni P0.005, for both comparisons). (b) The skeleton of group differences in mean fractional anisotropy (FA) is colored in blue (F2,141=26.3, P<0.001); on the basis of prior literature, regions of interest were selected within the blue skeleton, which included the inferior frontal gyrus and the pre-supplementary motor area (colored in orange). (c) Scatterplot showing that participants with greater FA in the right inferior frontal gyrus had better inhibitory performance (shorter SSRT) on the stop-signal task (r142=0.24, P<0.005). From Ersche et al (2012a). Reprinted with permission from American Association for the Advancement of Science.

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These findings shed new light on addiction vulnerability and may explain why the risk of becoming addicted to drugs is increased in people with a family history. The observation that abnormalities in brain and behavior may render individuals vulnerable to developing dependence (if resilience factors are absent), opens up new avenues for preventative and therapeutic strategies. For example, preventative approaches may consider strengthening self-control abilities in individuals at risk, while therapeutic interventions could be guided by the successful compensatory strategies used by unaffected siblings to overcome their brain abnormalities in every-day life. The identification of addiction endophenotypes in brain and behavior provide further compelling evidence that drug dependence is a disorder of the brain, with underlying abnormalities that can increase a person’s risk for addiction.