Neural Mechanisms Underlying Nicotine and Alcohol Combinations

Overview

Nicotine and alcohol are frequently used together and their combined use contributes to more than half a million deaths each year, with more alcoholics dying from smoking-related diseases than from alcohol-related diseases. Using a new multi-modal MRI approach combined with data fusion, the investigators propose to study how nicotine modulates alcohol-induced changes in the function of brain circuits. The investigators hypotheses are: * functional connectivity (FC) in the reward network, containing components of the mesolimbic dopamine system, will be altered by alcohol, and additional increases in FC will be observed if nicotine is also present (e.g., additive effects). * co-administration of nicotine will counteract the effects of alcohol on FC in multiple brain networks, including visual, sensorimotor and motor brain circuits, that may be associated with the impairing effects of alcohol

Long-term Objectives: Our long-term objective is to bring together non-invasive quantitative functional magnetic resonance imaging (q-fMRI) with a newly developed cutting-edge analysis method to study changes in neuronal metabolism and cerebrovascular function that occurs during psychoactive drug use. Specific Aims: Our first specific aim is to validate the components of the q-fMRI acquisition, which requires several different kinds of fMRI scans (or multimodal measurements). The second aim then applies the q-MRI method to study the functional brain networks that define brain activity when a person is simply resting and not engaged in any activity. These networks each consist of a unique set of regions that spontaneously fluctuate together in order to be "tuned" for future task performance. The effects of nicotine and alcohol and their interaction on these resting state networks are the focus of the application of our new q-fMRI strategy. q-fMRI measurements require several different scans, including making measurements of perfusion and oxygen metabolism, and an integrated analysis of all of these different results will be much more informative than separate analyses of each measurement. However, the analysis method, the linked independent component analysis (linked ICA) approach is very new and has never been applied to q-fMRI measurements or any other measurements of psychoactive drug effects. Thus, the third aim is to apply this novel analysis method to data acquired under different drug conditions to identify patterns of related activity in our multimodal fMRI data. Research Design and Methods: A randomized within-subject study of 23 healthy subjects will be done as follows: fMRI scanning will begin four hours after pre-treatment with either nicotine or placebo patch (randomized). Alcohol will then be consumed by subjects while in the scanner and a second scanning session will be done of the combination of nicotine (placebo) + alcohol to assess changes in resting state functional connectivity due to alcohol and nicotine and their interactions. Significance: Linked ICA with q-fMRI measurements is an innovative strategy for studying brain function that could have a significant impact in the ability of fMRI to give an integrated picture of the spectrum of effects that drugs of abuse may have on brain function, and is thus ideally suited to the goals of the CEBRA mechanism. By applying this technique to study alcohol and nicotine co-use, we also will contribute greatly to the understanding of this significant health problem.