Scanning Sex, Stress and Substance Abuse Susceptibility: Neural Correlates of Vulnerability to Abuse Drugs.

Abstract

Despite decades of research, it is still not understood why some individuals are vulnerable to drug addiction while others are resilient. Susceptibility to use and abuse drugs appears to arise from a complex set of interacting variables. It is known that environmental (e.g. stress exposure), trait (e.g. impulsiveness) and genetic factors all contribute to substance abuse risk, however, the biological mechanisms that underlie this risk are not well understood. Though some research has indicated abnormalities in dopaminergic and opioidergic activity in current and former drug addicts, such as lower D2 receptor availability and higher mu-opioid receptor availability within the ventral striatum, it cannot be determined whether such abnormalities represented predisposing factors to drug use or were a consequence of drug consumption or addiction processes. Studying non-drug using individuals who carry factors that have historically been shown to place them at higher risk for substance use and abuse represents a preferable alternative to studying drug addicts. In these studies, we examined the relationships between several susceptibility factors, specifically exposure to recent life stress, genetic variation at the oxytocin gene (OXT), and trait impulsiveness with measures of dopaminergic and opioidergic functioning in healthy, non-drug using subjects utilizing positron emission tomography (PET). The results of these studies are as follows: First, utilizing mu-opioid receptor agonist radiotracer [11C]carfentanil we observed significantly higher regional mu-opioid receptor concentrations and greater stress-induced endogenous opioid system activation in individuals exhibiting high levels of trait impulsiveness. Second, in scans using the D2/D3 dopamine receptor antagonist radiotracer [11C]raclopride, we observed significant differences in stress-induced dopaminergic activity between men and women throughout the striatum. In addition, we noted a significant interaction between sex and environmental stress in the nucleus accumbens. Finally, we observed that single nucleotide polymorphisms (SNPs) located on chromosome 20 upstream of OXT were associated with dopaminergic and behavioral responses to a stressor, but only in women. The data obtained from these studies are broadly relevant for addiction research and provides original information regarding the mechanisms which may underlie individual risk to use and abuse drugs.