Nicole C. Barbarich-Marsteller, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): [unreadable] The motivation and desire to obtain a reward underlies many behaviors ranging from natural incentives such as the intake of food to the pharmacological modulation of brain circuitry involved with drugs of abuse. Substantial evidence suggests that the mesolimbic dopamine (DA) system plays a key role in modulating the neurochemical circuitry involved in reward pathways. Alterations in DA activity may underlie individual differences in reward sensitivity as well as the propensity to pursue rewarding stimuli despite undesirable consequences. Moreover, recent evidence suggests that a disturbance in one system affecting reward changes the responsiveness of other reward-related systems. Given that DA influences the properties of a reward, the goal of this proposal is to measure the specific behavioral and neurochemical changes that occur following experimental manipulation of food and drug reward pathways. First, I will use conditioned place preference to determine if food restricted rats will select an environment associated with food over an environment associated with cocaine. Second, I will use 11 C-raclopride and microPET, in combination with AMPT, to measure changes in D2 receptor number induced by chronic food restriction and/or cocaine use. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): In this revised application for a K01 Mentored Research Scientist Development Award, Dr. Nicole Barbarich-Marsteller has proposed a comprehensive training and research plan in the translational neurobiology of substance abuse and eating disorders. There is significant comorbidity between these disorders and preclinical studies suggest that food restriction increases the reinforcing effects of psychostimulants; however, we are limited by 2 significant gaps in the literature that inhibit the translation of preclinical research on the effects of food restriction on drug reward into a better understanding of the relationship between clinical eating disorders and substance abuse. First, preclinical research has utilized adult rats, whereas the clinical onset of eating disorders and initial drug use typically occurs during adolescence. Second, preclinical research has focused on males, whereas the overwhelming majority of individuals with eating disorders and a significant proportion of substance abusers are females. The fact that there are sex-dependent changes in the dopamine receptor system during adolescence suggests there may be sex differences in the development of vulnerability to addictive behaviors during adolescence. Thus, the research aims of this grant are to use a multi-dimensional approach (conditioned place preference, self-administration, receptor density, microPET imaging) to identify how food restriction alters the behavioral and neurochemical response to psychostimulants during adolescence and to determine whether these effects are sex-dependent. The training goals for Dr. Barbarich-Marsteller are to: 1) acquire a more comprehensive knowledge of substance abuse and reward mechanisms; 2) gain expertise in sex-dependent, developmental aspects of the dopamine system and how they relate to addictive behaviors; 3) expand expertise in preclinical techniques for studying the dopamine system; 4) increase knowledge of the clinical relationship between substance abuse and eating disorders; and 5) increase proficiency in manuscript and grant writing and ethical issues in research. Overall, this award will ensure Dr. Barbarich-Marsteller's successful transition to an independent investigator. [unreadable] PUBLIC HEALTH RELEVANCE: The onset of substance abuse and eating disorders are increased during adolescence, yet the sex-dependent and neurobiological mechanisms that increase vulnerability during this period are not well understood. These studies will fill critical gaps in our understanding of adolescent reward mechanisms. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Anorexia nervosa (AN) is a psychiatric illness with no accepted pharmacological treatment [1] and with one of the highest mortality rates among the mental illnesses (10-20%) [2-4]. Even if not fatal, AN can cause life-long damages to multiple organ systems, creating an increased burden on the health care system. AN has a stereotypical age of onset at puberty, with 90-95% of cases occurring in females [5]. This developmental pattern suggests that hormonal changes in females associated with puberty may trigger changes in brain connections that increase an individual's vulnerability to stress, anxiety and AN. AN is also associated with frequent relapses[6], suggesting that anorectic behavior during this pivotal, final stage of brain development may cause long-lasting changes in brain connections. The long-term goal of this project is to identify developmental changes at central synapses that are linked to AN vulnerability among females entering puberty and to characterize changes that are induced further by this illness and following recovery. We will test a novel hypothesis - namely, that pubertal females are more vulnerable to AN due to fluctuation in the release of a neurosteroid, THP, that triggers an increased expression of a4b2d GABAA receptors at the plasma membrane of hippocampal pyramidal neurons which, in turn, renders the hippocampus hyper-excitable during stressful events. This THP-GABA hypothesis will be tested by using an animal model of AN, activity-based anorexia (ABA), which captures multiple key features of AN but for which the sex- and age-dependence have not been fully explored. We will first run behavioral tests to determine whether the two key factors that influence the human population - age and sex - also influence ABA vulnerability of rodents. This will be achieved by comparing the behavioral factors related to the development of ABA, recovery from ABA and ABA relapse across 3 developmental stages (prepubertal, pubertal, and adulthood) and 2 sexes (male and female). We will then use biochemical and electron microscopic immunocytochemical approaches to determine whether a4b2d GABAA receptor expressions in certain brain regions (biochemical data) and at synapses (EM data) correlate with ABA vulnerability, development, recovery and relapse. To further test the THP-GABA hypothesis, we will also determine whether ABA vulnerability and EM/Biochemical changes associated with the onset of puberty among females are reduced by pre-treatments that target the THP-GABA system. PUBLIC HEALTH RELEVANCE: Anorexia nervosa (AN) is a psychiatric illness occurring predominately among females entering puberty, with one of the highest mortality rates among mental illnesses (10-20%) and no accepted pharmacological treatment. The aim of this proposal is to test a novel hypothesis - namely, that females entering puberty are more vulnerable to AN because the limbic system of female brains at this stage in development express more of a particular type of neurotransmitter receptor that is sensitive to both GABA (an inhibitory neurotransmitter) and a stress-related hormone, THP (also called allopregnanolone). The results obtained from this study will provide the rationale for exploring a new pharmacologic treatment that targets the site of action of THP upon the GABAergic system within limbic pathways.