Lisa M. McFadden, Ph.D. - US grants

Several factors may contribute to major depressive disorder. These include, but are not limited to: 1) smaller hippocampal volumes (Sheline et al., 1999); 2) decreased levels of brain derived neurotrophic factor (BDNF; Dwivedi et al., 2010); and 3) abnormalities in the serotonin transporter (SERT; Caspi et al, 2003). Of note, preclinical studies indicate that administration of selective serotonin reuptake inhibitors, a common treatment for depression in humans, increase hippocampal BDNF levels and decrease depressive symptoms (Sillaber et al., 2008). Similar to major depressive disorder, methamphetamine (METH) abuse in humans is associated with: 1) smaller hippocampal volumes (Thompson et al., 2004); and 2) depressive symptoms in abstinent users (Glasner-Edwards et al., 2009). Further, preclinical studies have shown experimenter-administered METH leads to decreased hippocampal SERT function and serotonin content (Haughey et al., 2000; Cadet et al., 2009). The potential interaction between SERT function, BDNF, hippocampal volumes, and depressive symptoms after METH use has received little attention. Accordingly, the current proposal will test the hypothesis that the self-administration of METH decreases SERT function and, consequently, contributes to decreases in BDNF levels within the hippocampus. These decreases in BDNF, in turn, may lead to decreases in neurogenesis and cell survival, which may contribute to the loss of hippocampal volume, and increases in depressive symptoms. Of note, preliminary data suggest that both decreases in SERT function and BDNF within the hippocampus occur after as little as 5 d of METH self-administration. The results of these studies have the potential to contribute significantly to the understanding of, an potential therapeutic targets for, the treatment of depression associated with METH abuse.

My overall career goal is to work in a university setting where I can pursue my research interests in the neurochemistry underlying addiction and relapse, potential interventions for addiction, and the behavioral consequences of addiction. The K99/R00 Pathways to Independence award is an important step in achieving this goal. The proposed award would allow me to achieve an independent career in academic research through mentoring, collaboration, research and new research skills, and grant writing. The University of Utah can provide the facilities and equipment, mentoring, and collaborative research environment to not only achieve the research proposed for the K99 award, but also launch my career as an independent investigator. The University of Utah has many prominent researchers in the field of methamphetamine (METH) toxicity that are committed to maximizing my potential as a researcher. My mentors, Dr. Fleckenstein and Hanson, have been instrumental in helping me achieve my postdoctoral career goal of enhancing my ability to study the neurochemical changes associated with drug addiction. The support provided by my mentors and mentoring committee (Drs. Bevins & Wilkins), and consultants (Drs. Yamamoto, LaLumiere, Keefe & Wilcox) will allow me to expand my research techniques by learning optogenetics and autoradiography, improve my grant writing and laboratory management skills, and enhance my abilities to teach and mentor future generations. The proposed research will allow me to expand beyond the scope of my mentors' research on the neurochemical effects METH self-administration (SA) in the striatum by investigating the role of neurochemical changes in the frontal cortex in METH SA and reinstatement. Since changes in the frontal cortex have been observed in human METH addicts and are implicated in the cognitive deficits associated with drug abuse, better understanding these changes are important for understanding addiction and relapse. This will be assessed by 1.) identifying the specific serotonergic changes that occur in the frontal cortex following METH SA; 2.) investigating the role of excitatory activity in the medial prefrontal cortex during the reinstatement of METH- seeking; 3.) investigating the role of serotonin and glutamate release and 5HT2A receptor stimulation in the medial prefrontal cortex during the reinstatement of METH-seeking; and 4.) investigating if sex differences in serotonergic function contribute to sex differences in METH-seeking. The current proposal will provide insight into the role of changes in the frontal cortex in the relapse of METH addiction and allow for the targeted development of potential therapeutics. It will also set the foundation to further investigate sex differences in drug abuse. In addition to conducting this important research, this grant will help enable me to submit an R03 grant to pilot data of the behavioral effects of the neurochemical changes following METH SA and R01 grant based on the findings of the proposed studies. The research proposed, in addition to the mentoring described, will enhance my potential to become a successful independent researcher investigating drug addiction.

Project Summary The opportunity for undergraduates to conduct research is a critical element for developing a rigorous program in biomedical education. Specifically, it provides an experiences not normally part of lecture- or laboratory-based course work and it prepares students for post-graduate training or careers in basic research or clinical disciplines. However, opportunities for undergraduate biomedical research experiences are not uniformly available across the United States with both underrepresented minorities and students from primarily rural areas being especially underserved. Many of these undergraduates are first generation college students and attend institutions that less extramural support for biomedical research compared to institutions in more populous states. The Summer Program for Undergraduate Research in Addiction or SPURA at the University of South Dakota (USD) was developed to address this deficit with support from the NIDA and is seeking renewal of this support to continue this work. The specific aims of this program are: (1) To expand undergraduate research opportunities for students in South Dakota, with an emphasis on quality training of first generation college students, students from rural backgrounds, and students who are from underrepresented minorities. (2) To encourage a greater number of South Dakotan students to participate in research and to ultimately pursue post-graduate research careers and/or training in areas related to substance abuse and related mental health issues. (3) To advance the field of substance abuse and related or underlying mental health issues by fostering cross-collaborative student training and research at the University of South Dakota. Each summer, this program will enroll eight students in a multi-disciplinary research experience aimed at providing students with an opportunity to conduct mentored, hypothesis-driven studies in the fields related to drug addiction and underlying mental health issues. The program will incorporate a wide range of experimental approaches including human and animal behavior studies, systems neuroscience, neuropharmacology, and electrophysiology. Faculty involved in this program will include members of the Departments of Biology and Psychology (both part of the School of Arts and Sciences) and Basic Biomedical Sciences (part of the USD Sanford School of Medicine). Over the last four years the SPURA program has been highly successful having supported 36 students, all of whom have either continued their undergraduate studies, enrolled in research- or professional health-based post-graduate education programs, or have become employed.