Individuals family-history positive (FHP) for alcoholism have increased risk for the disorder, which may be mediated by intermediate behavioral traits such as impulsivity. Given the sex differences in the risk for and clinical presentation of addictive disorders, risk for addiction may be differentially mediated by impulsivity within FHP males and females. FHP (N ¼ 28) and family-history negative (FHN, N ¼ 31) healthy, non-substance-abusing adults completed an fMRI Go/No-Go task and were assessed on impulsivity and alcohol use. Effects of family history and sex were investigated as were associations between neural correlates of impulse control and out-ofscanner measures of impulsivity and alcohol use. FHP individuals showed greater activation in the left anterior insula and inferior frontal gyrus during successful inhibitions, an effect that was driven primarily by FHP males. Higher self-reported impulsivity and behavioral discounting impulsivity, but not alcohol use measures, were associated with greater BOLD signal in the region that differentiated the FHP and FHN groups. Impulsivity factors were associated with alcohol use measures across the FHP and FHN groups. These findings are consistent with increased risk for addiction among FHP individuals being conferred through disrupted function within neural systems important for impulse control. Keywords: impulsivity; family history of alcoholism; insula; inferior frontal gyrus (IFG); addiction; sex differences. INTRODUCTIONAlcohol use disorders (AUDs) are prevalent and associated with detrimental health and societal outcomes (Li, 2008). Individuals with a family history of alcoholism (familyhistory positive (FHP)) have increased risk for alcoholism driven by genetic and environmental factors (Lieb et al, 2002;Slutske et al, 2002). Healthy FHPs model addiction vulnerability without confounding effects of excess alcohol on cognition and brain function.Increased AUD risk among FHPs may be conferred via heritable impulsive tendencies (Dick et al, 2010;Tessner and Hill, 2010). Impulsivity is a multi-factorial construct, where distinct sub-components appear to have differential neural bases and relationships with addiction (de Wit, 2009;Lejuez et al, 2010;Rogers et al, 2010). Aspects of impulsivity may both predispose to and be exacerbated by addictive behaviors. Impulsivity predicts development of AUDs; is higher in FHPs with more alcohol-dependent relatives (ie higher family-history load); and partially mediates the relationship between FHP and alcohol and substance use disorder (for review, see de Wit, 2009;Dick et al, 2010;Lejuez et al, 2010;Verdejo-Garcia et al, 2008). Other less well-studied impulsivity-related constructs (eg, sensationseeking, risk-taking, compulsivity, behavioural activation/ inhibition, reward/punishment sensitivity) have been related to addiction vulnerability, and addictions therefore warrant consideration (eg, Meda et al, 2009).Sex differences are important to consider as they are observable for rates, clinical presentation, and health cons...

Rationale Individuals with a family history of alcoholism (family history positive [FHP]) show higher alcoholism rates and are more impulsive than those without such a family history (family history negative [FHN]), possibly due to altered N-methyl-D-aspartate (NMDA) receptor function. Objectives We investigated whether memantine, an NMDA receptor antagonist, differentially influences impulsivity measures and Go/No-Go behavior and fMRI activity in matched FHP and FHN individuals. Methods On separate days, participants received a single dose of 40 mg memantine or identical-appearing placebo. Results No group performance differences were observed on placebo for Go correct hit or No-Go false alarm reaction time on the Go/No-Go task. During fMRI, right cingulate activation differed for FHP vs. FHN subjects during No-Go correct rejects. Memantine had attenuated effects in FHP vs. FHN subjects: For No-Go false alarms, memantine was associated with limited reduction in subcortical, cingulate, and temporal regions in FHP subjects and reduced activity in fronto-striatal–parietal networks in FHN subjects. For No-Go correct rejects, memantine (relative to placebo) reduced activity in left cingulate and caudate in FHP but not FHN subjects. Conclusions Lower sensitivity to the effects of memantine in FHP subjects is consistent with greater NMDA receptor function in this group.

ABSTRACT. Objective: Enhanced N-methyl-D-aspartate (NMDA) receptor function associated with a positive family history of alcoholism (FHP) has been hypothesized to contribute to the heritable risk for alcoholism. The objective of this study was to evaluate the relationship of alcoholism family history, NMDA receptor function, and cortical information processing by testing acute effects of the NMDA receptor antagonist memantine on event-related potential (ERP). Method: Twenty-two healthy FHP and 20 healthy family history-negative (FHN; no alcoholic relatives) subjects were administered placebo or 40 mg of memantine under double-blind counterbalanced conditions on two separate occasions. Electroencephalogram data were collected from eight channels with eyes open during an auditory oddball discrimination task. We evaluated P3b amplitude, total theta, alpha activity, and fractal dimension from ERP trials. Results: FHP and FHN subjects did not differ in P3b amplitude. A signifi cant Group × Drug interaction was observed in theta, alpha activity, and fractal dimension at the parietal and occipital sites. FHP individuals exhibited signifi cantly higher fractal dimension and lower theta and alpha activity after placebo relative to FHN subjects. Following memantine administration, theta activity decreased in both groups but more markedly for FHN individuals. Alpha activity decreased for FHN subjects and increased for FHP individuals, whereas the fractal dimension decreased for FHP subjects and increased for FHN subjects after memantine.