1992 — 1993 |
Finn, Deborah Ann |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Neurosteroids and Brain Steroidogenesis @ Oregon Health and Science University |
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1996 — 2002 |
Finn, Deborah Ann |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Ethanol Withdrawal and Neuroactive Steroids @ Oregon Health and Science University
The neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20 one (3alpha, 5alpha-P or allopregnanolone) is a potent positive modulator of GABA receptors. Recent results from years 01-04 of the previous Center application suggest that genotypic differences in the modulatory effect of 3alpha,5alpha-P on EtOH withdrawal severity may reflect a balance between the change in sensitivity of the GABAa receptors to 3alpha, 5alpha-P that are occurring concomitantly during EtOH withdrawal. These studies were conducted in two different animal models of ethanol (EtOH) withdrawal severity [i.e., DBA/2 (D2) and C57BL/6(B6) inbred strains and the selectively bred Withdrawal Seizure-Prone and-Resistant lines]. In addition, gene mapping studies in BXD Recombinant Inbred strains found a significant genetic correlation between chronic EtOH withdrawal severity and a region of chromosome 13 (combined p=0.00008) in which the murine gene for the enzyme 5alpha-reductase-1 (Srd5alpha1). Since 5alpha-reductase is the rate-limiting enzyme in the biosynthesis of 3alpha, 5alpha-P, we hypothesize that Srd5a1 represents a candidate gene for differences in EtOH withdrawal severity in mice derived form the B6 and D2 inbred strains. Because male and female mice differ in endogenous levels of 3alpha, 5alpha-P (i.e., female > male) and in EtOH withdrawal severity ( female
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2000 — 2017 |
Finn, Deborah A Rossi, David J (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neurosteroid Modulation of Ethanol Withdrawal Severity @ Oregon Health & Science University
DESCRIPTION (provided by applicant): This competing renewal application builds on our studies in the Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) selected lines and the DBA/2 inbred strain, which suggest that genetic differences in ethanol withdrawal severity are due in part to alterations in the ?-aminobutyric acid (GABA)- modulatory effects of neurosteroids such as allopregnanolone (ALLO), the most potent positive modulator of GABAA receptors. In particular, during ethanol withdrawal, endogenous ALLO levels were reduced, and the anticonvulsant effect of systemically administered ALLO was decreased in WSP and DBA/2 mice, but not in WSR mice. Further, in ethanol withdrawn WSP mice, a reduced sensitivity to ALLO's anticonvulsant effect was also observed when ALLO was infused into specific brain regions within the withdrawal seizure circuit, including the hippocampus. Preliminary electrophysiological experiments in hippocampal slices from ethanol withdrawn WSP mice documented a reduced effect of GABAergic steroids and selective GABAA receptor ligands on GABAA receptor mediated synaptic and tonic currents. Additionally, epileptiform activity in hippocampal slices from ethanol withdrawn WSP mice was reduced by GABAA receptor enhancing ligands. Finally, preliminary experiments with gas chromatography-mass spectrometry (GC-MS) simultaneously quantified hippocampal neurosteroid levels and determined that ethanol injection produced divergent changes in steroids with positive (agonist) and negative (antagonist) effects on GABAA receptor function. Based on these data, the current proposal will adopt a multidisciplinary approach to test the overall hypothesis that a reduction in hippocampal GABAergic function, due to decreased GABAA receptor sensitivity to neurosteroids and a concomitant imbalance in ALLO and related neurosteroids, represents a neurochemical substrate for enhanced susceptibility to ethanol withdrawal severity. Studies will be conducted in WSP and DBA/2 mice, two animal models that are widely used to study genetic liability to ethanol withdrawal in mammals. Aim 1 will use GC-MS to quantify the effect of ethanol withdrawal on multiple endogenous steroid compounds, with agonist and antagonist effects on GABAA receptor function, in the hippocampus at select time points of withdrawal. Aim 2 will use voltage-clamp recording in subregions of hippocampal slices to characterize ethanol withdrawal-induced changes in the pharmacology of synaptic and extrasynaptic GABAA receptors, including alterations in sensitivity to neurosteroids with agonist and antagonist effect and to subunit selective ligands. Aim 3 will integrate information from Aims 1 and 2 and determine if counteracting ethanol withdrawal-induced changes in GABAA receptor properties and in neurosteroid levels rescues the high withdrawal phenotype, measured by epileptiform activity in hippocampal slices and convulsions in vivo. Thus, the proposed experiments will establish the importance of altered hippocampal neurosteroid composition and GABAA receptor pharmacology in mediating ethanol withdrawal severity.
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2001 — 2005 |
Finn, Deborah Ann |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Excessive Alcohol Intake Induced by Withdrawal @ Oregon Health and Science University
To date, existing genetic animal models do not self-administer alcohol uncontrollably. The present proposal will use a combination of genetic and environmental manipulations to demonstrate excessive alcohol intake induced by withdrawal with the goal of producing an animal model that is easily exported to other laboratories within and beyond the INIA. The data will be made available to the Informatics Core of the INIA to suggest targets for molecular studies (Gene Array Core) as well as physiological studies (Neurocircuitry subgroup and Imaging Core). This project also will make extensive use of the Genetic Animal Models Core. Studies related to Specific Aim 1 will provide important information on the existence of genotypes with high ethanol consumption and whether these animals consume intoxicating doses of ethanol. Studies related to Specific Aim 2 will provide critical background information for an optimal paradigm to be used in the selective breeding aim (i.e., Specific Aim 3), the goal of which is to produce one or more reliable genetic animal model(s) of excessive drinking. The model should be genetically fairly stable at genes not important for the selection response (i.e., drift should be minimized) and replications of the experiment will be generated to eliminate false- positive estimates of genetic correlation. Since we are proposing to produce 2-3 independent replicate lines for excessive alcohol intake, any parallelism between the directly selected and correlated responses will offer very strong evidence for genetic codetermination of the phenotype. The studies related to Specific Aim 4 will give a clearer idea of the role of withdrawal-related and preference-related genes to the excessive alcohol intake phenotype, since additional genetic animal models as well as genotypes from other INIA sites will be tested. Collectively, the proposed studies will address a long term goal of our consortium which is to determine the neurobiological mechanisms underlying the excessive alcohol intake phenotype. Not only will this information help in furthering our understanding of the interaction between ethanol intake and withdrawal, but it also would aid in the development of new strategies for the treatment of alcoholism.
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2008 — 2012 |
Finn, Deborah A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neurochemical Manipulation of Withdrawal-Induced Drinking @ Oregon Health & Science University
Project Summary We have been using a combination of genetic and environmental manipulations to induce high ethanol intake in mice, defined as alcohol intake leading to a blood ethanol concentration (BEC) greater than 100 mg%. We determined that exposure to intermittent ethanol vapor and multiple withdrawal episodes (i.e., MW group) produced high ethanol consumption and withdrawal symptoms that were consistent with the development of physical dependence in these animals. This procedure has been termed Withdrawal-Induced Drinking (WID) and is thought to be one behavioral model of the increased alcohol consumption in dependent animals (also termed dependence-induced drinking). Preliminary data indicate that acamprosate (complex glutamatergic modulator), but not naltrexone (opioid receptor antagonist), significantly decreased the expression of WID. Subsequent studies determined that systemic administration of baclofen (GABAB receptor agonist), MPEP (mGluR5 antagonist), and NBI 27914 (CRF1 receptor antagonist) significantly decreased the expression of WID. Finally, intra amygdala administration of the CRF receptor antagonist D-Phe-CRF(12-41) also selectively decreased the high alcohol intake in the MW group without altering ethanol intake in the Control group. The present proposal will continue this line of inquiry with the WID model to determine the key neurotransmitters and neuropeptides that modulate the expression of WID and begin to discern neural sites that are important for the expression of WID. We hypothesize that neuroadaptations in the central nucleus of the amygdala (CeA) and lateral septum are important for the expression of WID. Aim 1 will pharmacologically manipulate the neurochemical environment of the lateral septum, whereas Aim 2 will manipulate the neurochemical environment of the CeA, to determine the neurotransmitters and neuropeptides that are important for the high alcohol intake and expression of WID in mice. Proposed studies will use a brain site- specific microinjection technique to manipulate the GABAergic, glutamatergic, and CRF peptide environment of the lateral septum and CeA. Microinjection of receptor agonists and antagonists will allow us to determine whether the MW and Control groups are differentially sensitive to these neurochemical manipulations of the CeA and lateral septum, and whether the manipulations are sufficient to modulate the expression of WID. Collectively, the proposed research will examine the neurobiological mechanisms underlying the high alcohol consumption WID phenotype. Not only will this information help in furthering our understanding of the mechanisms underlying dependence-induced drinking, but it also will aid in the development of new strategies for the treatment of alcoholism. Project Narrative The proposed research will examine the neurobiological mechanisms underlying high alcohol consumption in dependent animals. Studies will use a brain site-specific microinjection technique to determine the key neurotransmitters and neuropeptides that modulate the increased alcohol consumption in dependent animals and begin to discern neural sites that are important for this increased alcohol intake. Not only will this information help in furthering our understanding of the mechanisms underlying dependence-induced drinking, but it also will aid in the development of new strategies for the treatment of alcoholism.
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2020 — 2021 |
Finn, Deborah A. Ryabinin, Andrey E (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sensitivity and Resilience to Increased Alcohol Drinking in Males and Females Following Traumatic Stress @ Oregon Health & Science University
Project Summary Post-traumatic stress disorder (PTSD) is twice as prevalent in females as in males, with a proportion of individuals also developing an alcohol use disorder (AUD). Using predator odor stress (PS) as an animal model of PTSD, we determined that two PS exposures significantly increased anxiety-related behavior and neuronal activation in the hippocampus (HC) of male and female C57BL/6J (B6) mice. Notably, intermittent PS significantly increased alcohol (ethanol) intake by 60% (males) and 71% (females), with heterogeneity in the response. Further, ?sensitivity? to PS-enhanced ethanol intake conferred significantly greater corticotropin releasing factor receptor-1 (CRFR1) protein levels in female versus male HC, consistent with evidence for sex differences in CRFR1 signaling following stress. The proposed studies build on the above evidence by testing the hypothesis that comorbidity of PTSD and AUD is due to increased CRFR1 expression in HC neurons projecting to mPFC and that sex differences in CRFR1 induction by PS contribute to this comorbidity. Aim 1 will determine whether sex differences exist in the association between PS-enhanced ethanol drinking and alteration in anxiety, heart rate (HR), and/or compulsive ethanol drinking in B6 mice. We predict that PS-enhanced drinking in ?sensitive? mice will be associated with an increase in anxiety, HR, and compulsive drinking and that there will be sex differences in the pattern of changes. Aim 2 will map changes in CRFR1 expression and neuronal activation by PS and by PS-enhanced drinking in crfr1-gfp mice. We predict that there will be sex differences in brain regional CRFR1-colabelled activity patterns in response to intermittent PS and in the relationship with ethanol intake. Aim 3 will manipulate the activity of CRFR1- expressing neurons using chemogenetic or pharmacologic approaches and determine the impact on PS- enhanced drinking. Two studies will use Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in crfr1-cre mice to test the necessity and sufficiency of CRFR1 in ventral CA1, with inhibitory (Gi) and excitatory (Gq) DREADDs, respectively. We predict that preventing PS-induced activation of ventral CA1 (Gi DREADD) will block PS-enhanced drinking only in ?sensitive? mice, whereas activating the ventral CA1 (Gq DREADD) will enhance ethanol intake in mice drinking ethanol without intermittent PS. A complementary study will determine whether systemic administration of a CRFR1 antagonist will reduce PS-enhanced drinking intake in B6 mice, with the prediction that the antagonist will be most effective in ?sensitive? mice. Aim 4 will determine whether manipulation of the projection from ventral CA1 to mPFC is important for PS-enhanced drinking in B6 mice, by injecting Gi DREADDs into ventral CA1 and clozapine-N-oxide into mPFC. We predict that preventing PS-induced activation of the ventral CA1 to mPFC projection will block PS-enhanced drinking. Collectively, the information will elucidate sex differences in mechanisms underlying sensitivity to PS- enhanced drinking that can be targeted for the treatment of PTSD-induced AUD.
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