Memantine, an NMDA receptor antagonist, differentially influences Go/No-Go performance and fMRI activity in individuals with and without a family history of alcoholism

Abstract

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.

Neural Correlates of Impulsivity in Healthy Males and Females with Family Histories of Alcoholism

“…Following 10 out-of-scanner practice trials, participants completed two runs of an fMRI Go/No-Go task (Jamadar et al, 2012;Stevens et al, 2007). Runs each consisted of 246 trials, lasted 7 min 21 s and were separated by an approximately 1-min break.…”

Increased Forebrain Activations in Youths with Family Histories of Alcohol and Other Substance Use Disorders Performing a Go/NoGo Task

“…The most common paradigm used in FH functional imaging studies has been the go/no-go task (Jamadar et al, 2012, Heitzeg et al, 2010, DeVito et al, 2013, Schweinsburg et al, 2004). Go/no-go tasks activate forebrain circuitry that regulates selective attention and inhibitory control by requiring subjects to selectively respond only to appropriate stimuli (“go” cues) and withhold responding to inappropriate stimuli (“no-go” cues) (Eagle et al, 2008).…”

Human Imaging Studies of Brain Circuitry Disrupted by Alcoholism

“…In addition to examining differences in task-activated patterns between alcoholics and controls, fMRI paradigms have been useful in detecting group differences related to preexisting conditions in and predisposing genetic factors to alcoholism occurring in alcoholism (e.g., Cardenas et al, 2005;Claus, Ewing, Filbey, Sabbineni, & Hutchison, 2011;Cservenka & Nagel, 2012;Hill, Terwilliger, & McDermott, 2012;Jamadar et al, 2012;Kareken et al, 2010;Norman et al, 2013;Schuckit et al, 2011;Silveri, Rogowska, McCaffrey, & Yurgelun-Todd, 2011;Villafuerte et al, 2012;Weiland et al, 2013;Wetherill et al, 2012). Regarding responsivity to alcohol cues (Schacht, Anton, & Myrick, 2013;Squeglia, Jacobus, & Tapert, 2014), one fMRI study used a passive viewing paradigm of positive, negative, or neutral words to examine high (vulnerable)-and low (resilient)-drinking late adolescents of alcoholic parents (Heitzeg, Nigg, Yau, Zubieta, & Zucker, 2008).…”