In recent years high magnetic field strengths

In recent years, high magnetic field strengths and advances in magnetic resonance spectroscopy (MRS) acquisition sequences have permitted investigation of important in vivo neurochemicals implicated in alcohol action, such as glutamate and gamma amino butyric order RVX-208 (GABA) (Meyerhoff et al., 2014; Silveri, 2014). Notably, glutamate (Glu) and glutamine (Gln) can be resolved and quantified separately, particularly at high field (Hu et al., 2007; Jensen et al., 2009), allowing investigation of these amino acids that are vital to protein construction, cellular metabolism, and excitatory neurotransmission (Behar and Rothman, 2001; Patel et al., 2005; Sibson et al., 1998; Yüksel and Öngür, 2010). The ratio of Gln/Glu, thought to reflect Gln-Glu cycling, has been established as a potential index of neurotransmission (Yüksel and Öngür, 2010). Levels of Gln and Glu are of particular interest in alcohol research as alcohol use, dependence, and withdrawal have been shown to be associated with both acute and protracted alterations in glutamatergic systems (Hermann et al., 2012; Krystal et al., 2003; Tsai and Coyle, 1998). To date, however, only one study has used MRS to identify neurochemical correlates of risk for substance abuse in a FH+ population (Moss et al., 1997), in which phosphorous (31P) MRS was applied to study peripubertal FH+ adolescents and a low-risk FH− comparison group, demonstrating lower parietal phosphodiester concentrations in the high-risk adolescents who also presented with behavior disorders. Accordingly, the current study is the first to use proton (1H) MRS to examine the association of age and FH status with markers of glutamatergic neurotransmission in ACC and a control region in parieto-occipital cortex (POC). It also evaluates relationships between ACC Glu/Gln ratios and cognitive and self-report measures of impulsivity in adolescents and emerging adults. It was hypothesized that the FH+ group would exhibit higher Gln/Glu ratios in ACC, but not in POC, compared to FH− counterparts, given increased vulnerability and relevance of the frontal lobe to addiction. Further, higher ACC Gln/Glu ratios were hypothesized to correlate positively with higher behavioral and self-report measures of impulsivity. Positive associations between Gln/Glu, FH+ status and impulsivity were predicted for both adolescent and emerging adult groups.
Materials and methods
Results
Discussion Results of the current study suggest that family history of alcoholism influences normative age-related differences in neurochemistry in the absence of heavy alcohol use. While the low-risk (FH−) adolescent group exhibited significantly lower Gln/Glu ratios than FH− emerging adult counterparts, perhaps reflecting differences in glutamatergic neurotransmission, no such age difference was observed in the high-risk (FH+) group. Inspection of mean values for each group suggests that the difference in age patterns between FH groups resulted not from lower Gln/Glu in FH+ emerging adults, but rather elevated ratios in FH+ adolescents. While high-risk adolescents (FH+) more closely resemble Gln/Glu ratios observed in emerging adults, distinct relationships were evident between Gln/Glu and impulsivity measures. A positive relationship was observed between Gln/Glu and impulsivity in FH− adolescents, which was no longer evident in emerging adults. In contrast, in FH+ participants, no significant relationships were observed in adolescents, but a strong negative relationship was observed between Gln/Glu ratios and Motor Impulsivity in emerging adults. Thus, relationships with glutamatergic neurotransmission in ACC appear to be altered in FH+ participants, following distinct developmental trajectories that vary according to FH status. It is possible that glutamatergic over-excitation elicits greater impulsivity in the healthy FH− adolescent brain but that this association is decoupled as top-down regulatory networks and GABAergic signaling become more prominent as the brain matures toward adulthood. In other words, correlates of this neurochemical signature may differ during stages of development due to reaching age-related milestones in brain maturation. The strong negative association observed between Gln/Glu in ACC and Motor Impulsivity in the FH+ emerging adults may reflect, in part, the low-risk high-risk nature of this subject group. That is, these individuals are genetically and environmentally at an elevated risk for alcohol use disorders given family history status, but have opted to not drink heavily and are light drinkers. Thus, these individuals display high levels of self-regulation, but may not rely on the same neurocircuitry to achieve this as FH− individuals. While typical adolescent brain development allows the control of impulsive actions to become increasingly automatic (Luna et al., 2010), a failure to make this developmental shift may leave FH+ adults relying heavily on recruitment of regulatory regions such as the ACC to actively self-regulate. This possibility is supported by the elevated levels of ACC activation observed during inhibitory control tasks in FH+ versus FH− individuals (DeVito et al., 2013; Hardee et al., 2014; Silveri et al., 2011). Further studies would be needed to confirm the association between glutamatergic transmission, as indexed by Gln/Glu, and activation during fMRI. Nevertheless, the findings of the current study suggest that the behavioral correlates of elevated Gln/Glu are not equivalent across age and risk groups.