In CTNA-2, we showed that in a Monetary Incentive Delay (MID) task, FH+ subjects, relative to FH-individuals, had increased engagement of cortico striatal networks when the opportunity for reward presented itself (reward prospect), but reduced activation of this same network when rewards/punishments were delayed (reward anticipation) or when the reward was presented (consummatory reward phase) (see P3). Striatal abnormalities were also seen in FH+ during a Go/No-Go (GNG) task. In CTNA-3, we face the challenge of directly linking the altered cortical-striatal function in FH+ to its underlying neurobiology.
Aim #1 :
The first aim of this project is to determine whether increased NMDA-R function contributes to alterations in cortico-striatal activity associated with FH+ status. Preliminary data (see full project) support the Aim #1's hypothesis by suggesting that memantine 40 mg. p.o. normalizes the deficits in ventral striatal (VS) activation associated with reward anticipation in FH+ individuals but has only modest effects on VS activation in FHN.
Aim#2 :
This aim explores memantine effects on activation of VS and anterior cingulate during GNG.
Aim #3 : The third project aim is critical to linking the pattern of cortico-striatal functional alterations associated with FH+ to the initial step in the addiction process, Pavlovian Conditioning. To that end, FH+ individuals who complete Aim #1 also will complete alcohol cue reactivity testing during fMRI imaging.
Aim #4 : This exploratory aim examines a modification of the MID by inclusion of PIT-related stimuli in FH+ compared to FH- subjects. Lastly, these subjects will be college students who will enter a prospective 2-year follow-up supported by a separate NIAAA grant (the "BARCS" study). This follow-up period will enable CTNA to explore the possibility that reward-related activation (MIDT), alcohol Pavlovian conditioning (cue reactivity), and alcohol PIT (assessed via the Core Battery) predict the intensity of drinking over time. DNA will be collected on all study subjects and the impact of polymorphisms in the genes coding for the proteins in figure 6 will be explored via the Genetics Core.

Public Health Relevance

This proposal will clarify the neurobiology of various forms of impulsivity and disordered reward mechanisms seen in individuals at risk for alcoholism. In particular it will use pharmacologic probes of the NMDA system to explore NMDA/DA interactions in the ventral striatum in a series of fMRI tasks related to reward to assess the relevant circuitry related to the above questions.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Specialized Center (P50)
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Yale University
New Haven
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