James M. Murphy, Ph.D. - US grants

DESCRIPTION: (Adapted from the Investigator's Abstract) The overall goal of the projects in this proposal is to identify CNS sites and receptors involved in mediating ethanol (E) drinking behavior. The primary focus will be on the mesocorticolimbic dopamine (DA) system, emanating from cell bodies in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAC) shell, medial prefrontal cortex (MPC), and ventral pallidum (VP). The dorsal raphe nucleus (DRN) will also be investigated, which sends serotonin (5-HT) projections to the DA system. A general working hypothesis is that the mesocorticolimbic DA system mediates the reinforcing properties of E, and activity within this DA system is regulated by various autoreceptors, and pre- and post-synaptic receptors. It is assumed that hereditary influences can predispose high E drinking behavior through genetic effects on neurobiological substrates within the neurotransmitter systems and receptors being investigated. Thus, to accomplish the overall goal, rats selectively bred for high alcohol intake, the P, HAD1 and HAD2 lines, will be used as models. The strategy will be to conduct experiments in rats of the P line, and then to confirm key findings in the HAD replicate lines. Three experimental techniques will be used. First, the effects on E drinking in a limited access paradigm will be assessed after CNS site-specific microinjections of receptor agents for DA, 5-HT and GABAA receptors. Selected receptor agents for subtypes will be tested at each CNS site; the VTA, NAc, VP, MPC and DRN. Second, microdialysis will be utilized to assess the extracellular levels of DA in the VTA, NAc, VP, and MPC during ongoing E self administration in an operant paradigm. Third, the reinforcing actions of E at three prospective sites, the NAc, VP and MPC, will be investigated by utilizing an intracranial self administration (ICSA) procedure. The findings will further knowledge regarding the role of the mesocorticolimbic DA system in the reinforcing consequences of E ingestion, and should delineate the importance of certain neurotransmitter receptor subtypes regulating this DA system and mediating ethanol self administration.

The majority of people who drink alcohol drink moderate amounts without serious consequences, but for a subset of individuals, drinking becomes excessive, leading to serious medical, social and legal consequences. The medical consequences alone may reduce expected life span by as much as 20 years; the social and legal consequences, including accidents, conflict with family and friends, job loss and arrest, severely decrease the quality of that shortened life. Recently, it has been recognized that individual differences in liability for alcohol abuse and alcoholism are associated with inherited personality traits. In particular, two patterns have been identified, 1) the disinhibited personality in which alcoholism accompanies high novelty-seeking, risk-taking, and indifference to social rewards and 2) the anxious personality, in which alcohol serves to reduce anxiety. In the present proposal, rats genetically selected for high or low levels of voluntary consumption of alcohol will be tested in models of disinhibition and anxiety to identify the precise neurobiological mechanisms that link each of these behaviors with alcohol drinking. Project 1 combines behavioral and physiological measures to assess the relationship between responses to novelty, attention, anxiety and anticipation to alcohol drinking. In project 2, behavioral and neurobiological techniques are combined to assess differences in brain arousal and inhibitory systems in the genetically selected lines. Project 3 explores the role of the mesocorticolimbic dopamine system in responses to novelty and alcohol drinking. By developing a better understanding of the inherited influences alcohol drinking, the basic biological mechanisms that increase individual liability for alcoholism can be better understood, and targeted strategies for prevention and treatment developed.

DESCRIPTION (provided by applicant): Behavioral and biological phenotypes of alcohol abuse and alcoholism have been described, investigated and reported in the literature for decades. In contemporary experimental literature, there has been considerable effort toward discovering hereditary factors that are ultimately expressed phenotypically as predispositions or susceptibilities to alcohol abuse. Knowledge in this arena has been advanced considerably by research both in humans and in animal models of alcohol abuse and alcoholism but, in many cases, it has been difficult to draw meaningful parallels between the findings from human studies and that of animal research. This proposal focuses on an evaluation of the overall premise that the reinforcing effects of alcohol are reflected in, and are mediated partly by, phenotypic responses, and that these phenotypes include behavioral (e.g., locomotor) and autonomic activation. In recent studies, we have investigated heart rate (HR) as an index of autonomic activity that represents some distinctive profiles consequent to alcohol administration and alcohol ingestion (Bell et al., 2002). The proposed experiments seek to extend these findings and to test hypotheses concerning whether, and the extent to which, behavioral and HR reactions to alcohol's reinforcing properties result, at least in part, from hereditary predispositions to excessive alcohol self-administration. Another goal is to assess whether these phenotypic characterizations could prove to be useful, objective measures in evaluating theoretical assumptions on the behavioral and neurobiological substrates of alcohol's reinforcing efficacy, which could assist in pharmacotherapy development. To accomplish these goals, experiments in four Specific Aims will investigate in selectively bred rats (1) behavioral and HR dose-response effects of ethanol administration, (2) behavioral and HR activating effects of self-administered ethanol in free-choice drinking, (3) behavioral and HR activating effects of self-administered ethanol in an operant paradigm designed to evaluate periods of anticipation, extinction, and recovery of responding, and (4) behavioral and HR activating effects of intracranially self-administered ethanol directly into the ventral tegmental area of the brain in order to provide an evaluation of potential neurobiological substrates mediating these behavioral phenotypes. The findings will serve to evaluate, expand and validate the proposed measures as phenotypic associations within animal models of excessive alcohol-seeking behavior and will provide potential empirical parallels of characterized phenotypes in human alcoholics and those who are predisposed to alcohol abuse and alcoholism.

Graduate Teaching Fellows in K-12 Education (GK-12)
Abstract

Proposal #: 0742475
PI: Kathleen Marrs
Institution: Indiana University-Purdue University
Title: The GK-12 Urban Educators Program at IUPUI: Teaching and Learning Science through Research
NSF-supported STEM disciplines: Biology, Chemistry, Physics, Math, Earth Sciences



This project combines the research and teaching strengths of the IUPUI School of Science (SOS) and the Indiana University School of Medicine (IUSM) with requests by local teachers for inquiry-based STEM laboratory experiences for children in grades 6-12. The selected urban partner schools have core competences in medical or environmental education. The fellows will collaborate with a secondary science or math teacher in ongoing professional development to develop grade-appropriate research activities. Innovative aspects include development of layered research projects that build in complexity through several grade levels, with a theme of relevance to student?s lives.

Expected outcomes include enhanced research, teaching, leadership and communication skills of the fellows. Benefits to science teachers include opportunities for professional development, collaboration with GK-12 fellows and university faculty, and opportunities to engage their students in scientific research. Goals for middle and high school students include exposure to mentors and role models, opportunities to experience research, and exposure to science and math as exciting and desirable career options. By designing a collaborative, diverse partnership between STEM graduate researchers, faculty and STEM teachers, this project allows us to integrate research-based activities into the teaching and learning of secondary science and math, broaden the involvement and participation of a diverse inner-city student body in research, and strengthen existing ties between IUPUI and the local community.