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Development of a Cingulate-striatal Addiction Circuit in a Rodent Model of Nicotine Dependence

Principal Investigator: Elliot Stein

Funding Mechanism: Interagency Agreement

ID number: 224-13-9001

Award Date: 12/1/2012

Institution: National Institutes of Health (NIH)

A circuit in the human brain between the dorsal anterior cingulate (dACC) and the ventral striatum (VS, including the nucleus accumbens and extended amygdala) has been linked to nicotine dependence severity; however, it is unclear if changes in the circuit reflect a consequence of neuroplastic changes during the addiction process or if they were pre-existing, thus reflecting intrinsic neuronal processes that predispose an individual to develop nicotine dependence. The goal of this project is to develop a functional magnetic resonance imaging (fMRI) rodent model of nicotine dependence as a biomarker of addiction, and to evaluate the utility of this circuit as a signal that can be used to evaluate potentially addictive constituents of tobacco products. Adult rats will receive intermittent delivery of nicotine (approximating the phasic nicotine delivery that is experienced by human users) via osmotic mini-pumps for seven days. fMRI scans will be conducted prior to, during, and up to 21 days following drug administration. Precipitated nicotine withdrawal will be assessed as a behavioral correlate of circuit strength alterations with nicotine dependence.  Study aims are: (1) to develop a rodent fMRI model of nicotine dependence; (2) to determine the dose range and time to alter the dACC-VS circuit; (3) to determine the relationship between objective behavioral indicators of dependence severity (e.g., precipitated nicotine withdrawal) and circuit strength; and (4) to investigate alterations in the levels of two key neurotransmitters important in addiction, gamma-aminobutyric acid (GABA) and glutamate, in both nodes of the circuit (i.e., dACC and VS). This study may identify biomarkers of addiction that can be used to inform FDA about the abuse liability of tobacco constituents and emerging products.

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