Nicole Petersen, Ph.D. - US grants

? DESCRIPTION (provided by applicant): The goal of this investigation is to test the hypothesis that circulating estrogen and striatal dopamine (DA) receptor availability interact with one another to influence self-control. Specifically, we predict that increased circulating estrogen wil decrease DA D2-type receptor availability, and this decrease in DA receptor availability will decrease performance on two self-control tasks, the Stop-Signal Task and an emotion regulation task. Self-control tasks have previously been shown to be influenced by DA signaling in both animals and humans, and a smaller number of studies have shown a relationship between estrogen levels and performance on self-control tasks. Therefore, we will test our hypothesis first by measuring DA D2 receptor availability in the brain using Positron Emission Tomography (PET) imaging and measuring estrogen levels in blood serum (Aim 1). Next, participants will complete two self-control tasks that share a common neural substrate: the Stop Signal Task, a measurement of impulsive action (Aim 2) and cognitive reappraisal of emotions (Aim 3). We will enter the results of each behavioral experiment into a statistical model with serum estrogen levels and striatal DA D2 receptor availability measured by BPND to test our hypothesis that circulating estrogen decreases DA D2 receptor availability, and this decrease in receptor availability decreases self-control. If the data support this hypothesis, our findings wil suggest that hormone state is an important factor to consider in experiments that involve self-control tasks and, more importantly, when attempting to modify behaviors that depend on self-control, in particular, addiction.

ABSTRACT Smoking remains the leading preventable cause of death in the United States and worldwide, causing nearly one in ten deaths worldwide. The majority (70%) of smokers want to quit, yet most are unsuccessful. Therefore, new approaches to help people quit are urgently needed, and may differ in efficacy between men and women, in whom a number of brain differences have been documented. At the receptor level, smoking induces dopamine release in the ventral striatum in men, but the dorsal striatum in women, and is also linked to decreased striatal dopamine D2-type receptor availability in men, and increased midbrain dopamine D2-type receptor availability in women. At the network level, preliminary data from our laboratory has linked the relief of cigarette craving to the extent of coupling between large-scale networks in women, but not men, in whom smoking instead is linked to changes in insula connectivity. This application builds on these recent findings to test the efficacy of a novel potential smoking cessation aid, repetitive transcranial magnetic stimulation (rTMS), a noninvasive brain stimulation technique, with special attention to sex as a biological variable. This includes two complementary objectives: To test the effect of rTMS on clinical features of smoking separately in men and women, and in so doing, provide additional training that will facilitate the transition to independence as a researcher specializing in brain differences in male and female smokers. This will be achieved through two experiments. In the first experiment (K99 phase) male and female smokers will receive rTMS stimulation targeting the dorsolateral prefrontal cortex (dlPFC), supplementary motor area (SMA), posterior parietal cortex (PPC), or sham, and the effect of rTMS to each region on craving, withdrawal, and affect will be evaluated. The best of these targets (i.e., where stimulation produced the greatest decrease in craving, withdrawal, and negative affect) will be selected for Experiment 2 (R00 phase), in which 13 sessions of rTMS will be performed. Craving, withdrawal, affect, cigarettes per day, and level of dependence will be evaluated seven days before, daily throughout, and daily for six weeks following rTMS. Resting state functional connectivity will be evaluated before and after rTMS to provide mechanistic information regarding the basis of rTMS efficacy in male and female smokers. The K99 phase will take place at UCLA with support and training from the director of the Neuromodulation Division, a collaborator on this project, and two other collaborators with expertise in smoking research. This team of collaborators will provide training with respect to rTMS and smoking research. A separate team will provide professional development feedback and guidance in addition to the faculty mentor through quarterly meetings. Together, this approach will achieve the project's specific aims to: 1. Develop expertise in rTMS as a therapeutic intervention; 2. Measure the effect of rTMS targeting the SMA, PPC, and dlPFC on craving, withdrawal, and affect; 3. Measure the effect of rTMS on RSFC with fMRI; and 4. Measure effects of rTMS on subsequent smoking and dependence.