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Current CTNA Projects:

Project 1

Our studies focus on how precise mechanisms of cortico-striatal circuit activity are altered during alcohol seeking and chronic alcohol-induced decision-making impairments and how the novel mGlu5 negative allosteric modulator mavoglurant modulates these dynamics. We have refined tests of habit-related decision-making, using the novel rodent version of the multi-stage decision-making task and other paradigms to assess cue-associated alcohol-seeking behaviors. Our methods can importantly dissociate habitual from goal-directed decision-making processes based on online trial-by-trial choices.

Project 2

Principal Investigator: Dr. Ismene Petrakis. CTNA will test the central hypothesis that the heritable risk for alcoholism reflects dysfunction of cortico-striatal-midbrain circuitry, mediated by the interplay of glutamate and dopamine, that biases people to respond to drug-like rewards relative to delayed reward/punishments. This bias to respond to drug-like rewards leads to enhanced learning of alcohol-related associations, and facilitation of the development of habitual alcohol consumption. This project will test this hypothesis by assessing alcohol induced dopamine (DA) release in the striatum in at risk subjects and in patients with alcoholism to demonstrate that risk is associated with an increased alcohol-induced DA release in the striatum while the transition from risk to habit is associated with a decreased response. Thus DA dysregulation in ventral striatum influences the propensity to become addicted, and is altered by the process of addiction.

Project 3

Influence of Mavoglurant on Alcohol Craving and Drinking in Heavy Drinkers

Principal Investigator: Dr. Godfrey Pearlson. This project 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.

Project 4

Principal Investigator: Dr. Suchitra Krishnan-Sarin. This protocol examined the influence a Src/Fyn protein tyrosine kinase inhibitor (that modulates NMDA-R signaling via Fyn inhibition), when compared with a matched placebo on alcohol drinking behaviors among heavy drinkers with alcohol use disorder. Alcohol drinking behaviors were assessed using an experimental alcohol drinking paradigm (ADP) which involves exposure to a priming drinking of alcohol and subsequent ad-lib drinking of up to 12 drinks over the three-hour period. Participants completed a baseline ADP and were then randomized to receive active study medication or placebo for a 7-8 day period; participants were seen or contacted daily to observe medication administration and check for adverse events. At the end of this period they completed the second ADP. The primary outcome included the number of drinks consumed, and alcohol craving during the second ADP. Participants also completed a one week follow and one-month follow up appointments.
Director: Dr. Stephanie O'Malley. The Clinical Core has established common methodologies to facilitate cognitive and clinical research domains and allow us to compare and pool data across projects for secondary analyses to help us define issues of vulnerability.
Director: Dr. Joel Gelernter. The goal of the Genetics Core is to support the genetic components of each of the projects participating in this Center to help understand the nature of genetic influences on the phenotypes measured, and to allow for the ascertainment of genetic covariates that might affect those outcomes.
Director:Dr. Kelly S. DeMartini. The CTNA places a high priority on maintaining an efficient flow of information in order to promote the safe and successful completion of proposed studies, to support the initiation of novel pilot studies, to facilitate the career development of trainees and junior faculty affiliated with the Center, and to promote the dissemination of research advances.
Director: Dr. John Krystal. The Pilot Projects Core provides a mechanism to initiate small-scale investigations that implement new technologies or to test important hypotheses associated with the CTNA mission. These projects serve the CTNA by 1) testing hypotheses or addressing methodologic issues central to the CTNA, 2) bringing new investigators into the CTNA and the field of alcoholism research, 3) generating new alcoholism RO1’s, 4) enabling CTNA to rapidly adapt to advances in the field, and 5) guiding the next iteration of the CTNA. Pilot Project Proposals are solicited through an open and public solicitation process. Proposal are developed in collaboration with the CTNA Cores (Data Management and Biostatistics, Clinical, Genetics) and refined with feedback from the Executive Committee.