1979 — 1982 |
Geyer, Mark |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Cytofluorimetric Studies of Raphe Neurons @ University of California-San Diego |
1 |
1985 — 1987 |
Geyer, Mark 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. |
Monoamines and Hallucinogens'Effects On Rat Behavior @ University of California San Diego
In order to clarify the involvement of central noradrenergic systems and the nature of the alterations in behavioral responses to environmental stimuli produced acutely by hallucinogenic drugs, we propose to extend our studies of the effects of lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), and 2,5-dimethoxy-4-methylamphetamine (DOM) to include more indoleamine and phenylethylamine hallucinogens, specifically, psilocybin, 2,5-dimethoxy-4-ethylamphetamine (DOET), and mescaline. The behavioral effects of these hallucinogens in male rats will be thoroughly characterized and compared using measures of tactile startle responses and a computerized Behavioral Pattern Monitor that provides detailed information regarding the amount and qualitative patterning of spontaneous activity and investigatory responses to specifiable familiar and novel stimuli in the environment. Rates of habituation of startle and exploration and the animal's sensitivity to novelty will be explicitly measured. The effects of selective neurotoxic lesions of specific noradrenergic pathways in brain will be similarly characterized. The effectiveness and specificity of each lesion will be quantified by both microspectrofluorimetric measures of formaldehyde-induced monoamine fluorescence and high-performance liquid chromatographic assays of regional monoamine levels using electrochemical detection. The possible mediation of the hallucinogen's effects by noradrenergic systems will be examined by testing the hallucinogens in lesioned animals and following pretreatments with selective antagonists or agonists, such as propranolol or clonidine. To minimize the confounding effects on the peripheral sympathetic nervous system, the adrenergic agonists and antagonists will be slowly infused into specific forebrain regions such as the hippocampus concurrently with the behavioral measures. The behavioral effects of these drugs will also be assessed to further delineate the influences of noradrenergic systems on activity, habituation, and responsiveness to exteroceptive stimuli. This work should further our understanding of the basic neural mechanisms mediating the behavioral effects of these drugs of abuse, eventually facilitating the development of antagonists for their effects.
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0.958 |
1985 — 1987 |
Geyer, Mark A |
K02Activity Code Description: Undocumented code - click on the grant title for more information. |
Antidepressants: Behavior and Hippocampal Transmitters @ University of California San Diego
This proposal examines behavioral measures of the functional status of specific transmitter systems in the hippocampi of rats following chronic antidepressants to elucidate the neurochemical substrates of their therapeutic actions. Clinically, most antidepressant drugs take 3 weeks of adminstration to alleviate depression. In animals, chronic antidepressants alter neurochemical, electrophysiological and, most consistently, ligand-binding measures of the functioning of central noradrenergic, serotonergic, and cholinergic systems. To more directly and specifically assess the behavioral relevance of these reported changes, I propose to examine the effects of acute and chronic antidepressants on the behavioral effects of hippocampal microinfusions of norepinephrine, serotonin, and the cholinergic agonist carbachol. Using a new behavioral pattern monitor which reveals quantitative and qualitative changes in locomotor activity and investigation, my laboratory has described dose-dependent behavioral effects specifically reflective of the activation of either beta-adrenergic or muscarinic-cholinergic synapses in the dentate gyrus of the hippocampus. Studies are proposed here to similarly characterize the effects of serotonin infusions with neurotoxin lesions of the raphe nuclei being used to confirm their specificity. The distribution of infusate and the extent of lesions will be assessed with fluorescence histochemistry and liquid chromatography with electrochemical detection. The functional status of the serotonergic, beta-adrenergic, and muscarinic-cholinergic inputs to the hippocampus will be assessed behaviorally after 1 or 21 daily oral treatments with 4 disparate antidepressants: desmethylimipramine; imipramine; tarzodone; and mianserin. Appropriate ligand-binding studies will be done on the hippocampi from the same rats to confirm the expected changes due to the antidepressants. These studies should establish the functional significance at a behavioral level of the ligand-binding changes induced by antidepressants, and increase our understanding of the brain mechanisms responsible for their therapeutic actions in humans.
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0.958 |
1986 — 1988 |
Geyer, Mark 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. |
Hippocampal Transmitter Efficacy After Antidepressants @ University of California San Diego
This project seeks to further define profiles of behavioral changes specifically related to the serotonergic, noradrenergic, and cholinergic inputs to the dentate gyrus of the dorsal hippocampus of rats. The transmitter systems will be manipulated by direct microinfusions of agonists and/or antagonists into the dentate gyrus of feely moving rats concurrently with testing in a Behavioral Pattern Monitor (BPM), which provides detailed measures of the frequencies, durations, and sequential patterns of locomotor and investigatory behaviors. Behavioral profiles related to the activation of alpha versus beta adrenergic and serotonin-1 versus serotonin-2 receptors will be characterized. In vivo functional assessments of interactions among the major transmitters in the dentate gyrus will also be studied. Included in these studies will be noradrenergic, serotonergic, cholinergic, and gabaergic manipulations. Neurotoxin-induced depletions of serotonin or norepinephrine will be used to induce supersensitivity of the respective post-synaptic receptors within the dentate gyrus to determine the ability of the microinfusion technique to detect changes in receptor sensitivity and to assess the relevance of the endogenous inputs to the effects produced by the microinfused agonists. Agonists will be administered at three and 14 days after the introduction of lesions in order to distinguish between pre- and post-synaptic mechanisms of supersensitivity. Experiments are also proposed to assess the functional relevance of the changes in beta-adrenergic and serotonin-2 ligand-binding induced by chronic but not acute treatments with antidepressant drugs, including imipramine, desmethy-limpramine, trazadone, and mianserin. The precise distribution of microinfused serotonin will be assessed by microspectrofluorimetric measures of formaldehyde-induced fluorescence. The extent and specificity of neurotoxin-induced lesions will be determined by liquid chromatography with electrochemical detection. This work is intended to further our basic understanding of the behavioral functions of the major neurotransmitters within the hippocampus and to provide a procedure to assess the functional relevance of changes in transmitter-related ligand-binding measures in neuroanatomically specific manner.
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0.958 |
1988 — 1992 |
Geyer, Mark 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. |
Monoamines &Hallucinogens'Effects On Rat Behavior @ University of California San Diego
To clarify the involvement of central serotonergic systems in the behavioral effects of hallucinogens in rats, studies of hallucinogen-induced decreases in startle habituation and increases in behavioral measures of neophobia will be extended to include 3,4-methylenedioxy amphetamine (MDA), 3,4-methylenedioxy-N- methylamphetamine (MDMA, "Ecstasy"), N-ethyl-3,4-methylenedioxy- amphetamine (MDEA, Eve), and their stereoisomers. The behavioral effects of the hallucinogens and related drugs will be thoroughly characterized using measures of acoustic and tactile startle responses and a computerized Behavioral Pattern Monitor that provides detailed information regarding the amount and qualitative patterning of spontaneous activity and investigatory responses to specifiable environmental stimuli. The ability of serotonin releasing agents, such as p-chloroamphetamine (PCA) and fenfluramine, to mimic the effects of the hallucinogens and the ability of serotonin-2 antagonists to block them will be determined. The effects of selective neurotoxic lesions of serotonin in localized protection sites in brain will be similarly characterized. Lesion effectiveness and specificity will be assessed with histofluorescence microscopy and regional monoamine assays using liquid chromatography with electrochemical detection. The hypothesis that specific serotonergic terminal regions are responsible for the acute effects of MDA, MDMA, MDEA, and PCA on startle habituation and the potentiation of neophobia will be tested by examining the effects of these drugs in lesioned animals. Experiments will also test the possibility that neurotoxic lesions or acute administrations of the hallucinogenic amphetamine derivatives lead to long-lasting changes in the behavioral responsiveness of animals to serotonergic agonists. This work should further our understanding of the basic neural mechanisms mediating the behavioral effects of these drugs of abuse. facilitate the development of antagonists for their effects, and begin to clarify the long-term functional consequences of their use.
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0.958 |
1989 — 1993 |
Geyer, Mark A |
K02Activity Code Description: Undocumented code - click on the grant title for more information. |
Limbic Monoamines, Behavior, &Psychopathology @ University of California San Diego
At the basic level, this renewal of a Type II ADAMHA Research Scientist Development Award assesses the involvement of limbic serotonergic and dopaminergic pathways in rats in the modulation of behavioral responsiveness to environmental stimuli. At the preclinical interface, experiments are proposed to clarify deficits in sensorimotor gating and habituation observed in schizophrenic patients and to further develop po- tentially related animal models derived from the basic studies. Schizophrenic patients, exhibit deficits in prepulse inhibition of startle, a measure of sensorimotor gating, and in the habituation of startle. Using electromyographic measures of the blink reflex, the proposed studies will: compare prepulse inhibition and habituation functions in the same patients; assess these deficits using both acoustic and tactile stimuli; examine unmedicated schizophrenics; and test the suggested involvement of dopamine in sensorimotor gating by testing normal subjects after the administration of methylphenidate. In rats, prepulse inhibition of startle is reduced by dopamine agonists, apparently by activating mesolimbic dopamine systems. These effects may provide an animal model of the schizophrenic deficit in sensorimotor gating. The dopamine influences on prepulse inhibition in rats will be clarified by examining dopamine receptor specificity and identifying the relevant anatomical pathways. In rats, startle habituation is decreased by serotonin agonists and increased by serotonin antagonists. Studies using a behavioral pattern monitor which provides a detailed profile of investigatory and locomotor behaviors, reveal that serotonin agonists similarly potentiate other measures of responsiveness to environmental stimuli. These serotonin agonist effects may provide a model of the schizophrenic deficit in habituation. To identify the receptor subtypes and specific pathways involved in this serotonergic modulation of sensorimotor responsivity, rats will be tested in startle and investigatory response paradigms after serotonin agonists, antagonists, releasing drugs, their combinations, or regionally specific serotonergic lesions. The candidate's professional growth will be fostered by participation in graduate within the Department of Psychiatry and direct involvement in research with psychiatric patients.
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0.958 |
1990 — 1992 |
Geyer, Mark 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. |
Drugs of Abuse--Complexity Measures Classify Behavior @ University of California San Diego
The development, adaptation, and application of methods used in nonlinear dynamics to concrete biological data, specifically to analyse rat locomotor paths, is proposed. The long-range goals are first, a theoretical development of an approach to the application of ergodic theory and specifically symbolic dynamics to the characterization of biological systems and, second, a practical demonstration of the potential utility of this approach in the study of the exploratory behavior of rats. Complexity measures developed in the field of ergodic theory will be calculated from data obtained from detailed monitoring of the spatiotemporal patterns of rat locomotor and investigatory behaviors to describe a "phase" of the animals' behavior within a given time frame. The investigation of transitions between phases similar to the study of phase transitions in non-equilibrium thermodynamics will be used to derive descriptors, e.g. critical exponents, appropriate for the construction of predictive models, which will be recruited from abstract dynamical systems with an empirically specified parameter set. Experimentally, drug-induced phase transitions will be studied, focussing on stimulant and "designer" drugs of abuse, which may eventually serve as discriminators and help to constitute new classifiers of different behavioral states. The proposed experiments focus on three major aims: (1) to further develop measures derived from the theory of nonlinear dynamical systems and to sensitively adapt the measures to the particular biological system being studied, i.e. rat locomotor and investigatory behavior under the influence of amphetamine, cocaine, and MDMA (Ecstasy), using existing data from extensive experiments done with a multivariate Behavioral Pattern Monitor; (2) to elucidate dynamical changes of drug-induced behavior in critical dose ranges in order to demonstrate the hypothesized coexistence of several non-equilibrium steady states at the same dose; and (3) to use the complexity measures to assess the stability of the drug-induced states by systematic perturbations in different modalities (acoustical, optical, tactile, drugs, etc.). The resulting models of stability and transition scenarios of drug-induced states should lead to a further understanding of the dynamical aspects of the behavioral effects of drugs of abuse.
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0.958 |
1990 |
Geyer, Mark |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Dynamical Systems in the Neurosciences of Psychiatry @ University of California San Diego |
1 |
1992 — 1994 |
Geyer, Mark A |
F06Activity Code Description: Undocumented code - click on the grant title for more information. |
Prepulse Inhibition in Rats Reared in Isolation @ University of California San Diego |
0.958 |
1993 — 1997 |
Geyer, Mark 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. |
Monoamine and Hallucinogen Effects On Rat Behavior @ University of California San Diego
Studies in rats are proposed to further clarify the involvement of central serotonergic systems in the behavioral effects of acute administrations of both traditional hallucinogens, such as lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4-methylamphetamine (DOM), as well as serotonin releasers such as 3,4-methylenedioxy-N-methylamphetamine (MDMA, "Ecstasy"), N-methyl-l-(l,3-benzodioxol-5-yl)-2-butanamine (MBDB), and N- ethyl-3,4-methylenedioxy-amphetamine (MDEA, "Eve"). The behavioral effects of the hallucinogens, serotonin releasers, and related drugs will be thoroughly characterized using measures of acoustic and tactile startle responses and a computerized Behavioral Pattern Monitor that provides detailed information regarding the amount and patterning of spontaneous activity and investigatory responses to specifiable environmental stimuli. Five specific aims are proposed. Aim l will identify the mechanisms and sites of action subserving the locomotor activating effects of indirect serotonin agonists such as MDMA or MBDB, testing the hypothesis that postsynaptic 5HTIB receptors within the basal ganglia mediate these effects. The second aim will test the hypothesis that indirect serotonin agonists, including MDMA and MBDB, impair the habituation of startle by acting via the release of presynaptic serotonin, which acts in turn upon postsynaptic 5HT1C/2 receptors. The third aim is to characterize the mechanisms underlying the disruptive effects of MDMA-like serotonin releasers on prepulse inhibition of startle, an operational measure of sensori-motor gating. The hypothesis to be tested is that these effects are attributable to the release of presynaptic serotonin. Antagonists will be used to identify the serotonin receptor subtype(s) responsible for these effects. Experiments will also test the hypothesis that the disruption of startle prepulse inhibition produced by LSD is attributable to its actions as a partial agonist at 5HTlA receptors. Aim 4 will clarify the mechanisms by which traditional hallucinogens produce their characteristic effects on exploratory behavior, including the potentiation of both neophobia and agoraphobia. Experiments will use antagonists and combinations of agonists to test the hypotheses that a functional interaction exists between the actions of 5HTlA and 5HT1C/2 receptors and that 5HT1A receptors contribute to the effects of LSD. Aim 5 will use receptor antagonists and cross-tolerance regimens to test the hypothesis that 5HT1A receptors contribute to the effects of LSD on startle habituation. The work should further our understanding of the' basic neural mechanisms mediating the behavioral effects of these drugs of abuse and facilitate the_development of antagonists for their effects.
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0.958 |
1994 — 1998 |
Geyer, Mark A |
K05Activity Code Description: For the support of a research scientist qualified to pursue independent research which would extend the research program of the sponsoring institution, or to direct an essential part of this research program. |
Limbic Monoamines, Behavior, and Psychopathology @ University of California San Diego
This application for an ADAMHA Research Scientist Award follow,s ten years of NIMH support via the Type II Research Scientist Development Award. At the basic level, the project assesses the involvement of limbic dopaminergic, glutamatergic, and serotonergic systems in rats in the modulation of behavioral responsiveness to environmental stimuli. At the preclinical interface, the proposed experiments will further characterize deficits in sensorimotor gating and habituation observed in schizophrenic patients and extend related animal models derived from the basic studies. Schizophrenic patients exhibit deficits in prepulse inhibition of startle, gating of P3O event-related potentials, and habituation of startle. The proposed studies will: compare prepulse inhibition, P5O gating, and habituation functions in the same patients; relate these deficits to several clinical factors; and examine unmedicated schizophrenics, family members of schizophrenics, and schizotypal patients. In rats, prepulse inhibition of startle is reduced by D2 dopaminergic activation and by related manipulations of neuronal circuitry involving the hippo-campus, nucleus accumbens, ventral pallidum, and pedunculopontine nucleus. Prepulse inhibition is also disrupted by direct and indirect serotonin agonists, non-competitive antagonists at the N-methyl-d-aspartate receptor complex, and isolation rearing. The proposed studies will examine the psychopharmacology and neurobiological substrates relevant to this animal model of the schizophrenic deficit in sensorimotor gating. In rats, startle habituation is deceased by serotonin agonists and increased by serotonin antagonists. These serotonin agonist effects may provide a model of the schizophrenic deficit in habituation. Studies using a behavioral pattern monitor which provides a detailed profile of investigatory and locomotor behaviors, reveals that direct serotonin agonists similarly potentiate other measures of responsiveness to environmental stimuli. The release of presynaptic serotonin by indirect agonists reduces investigatory behavior while increasing locomotor activity. A variety of manipulations of serotonergic systems in rats are proposed to identify the receptor subtypes and, pathways involved in the serotonergic modulation of sensorimotor responsivity and behavioral activity.
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0.958 |
1995 — 2010 |
Geyer, Mark 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. |
Developmental Models of Gating Deficits in Schizophrenia @ University of California San Diego
DESCRIPTION (provided by applicant): Prepulse inhibition (PPI) of the acoustic startle reflex refers to the ability of a weak stimulus preceeding a startling stimulus to inhibit the response to that stimulus. PPI is an operational measure of sensorimotor gating that is amenable to cross-species comparisons. Deficits in PPI have been reported repeatedly in patients with schizophrenia and other psychiatric disorders characterized by abnormalities in sensory, cognitive, or motor gating. Because some forms of schizophrenia appear to be attributable to early developmental insults such as prenatal infection or birth complications, many animal studies have examined the influences of specific developmental manipulations on behaviors and neural circuitry relevant to schizophrenia. Isolation rearing of rats and mice from weaning is a non-pharmacological manipulation that leads to deficits in prepulse inhibition of startle. Similar deficits in PPI are produced in rats'exposed to a prenatal immune challenge. The current proposal will extend and integrate studies of isolation rearing into the broader framework of neurodevelopmental insults, based on the conceptual and empirical connections between social isolation, chronic stress, and immune/inflammatory activation. To clarify the biological underpinnings of this integrated model, the aims of this grant are to examine the mechanistic role of alterations in the endogenous NMDA receptor antagonist, kynurenic acid (KYNA), and the stress-related neuropeptide, corticotropin releasing factor (CRF) in isolation- and immune-mediated developmental models of sensorimotor gating deficits. Recently the endogenous NMDA receptor antagonist kynurenic acid has been shown to disrupt PPI in rats. Hence, Aim 1 studies will assess the contribution of KYNA and its metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) to isolation rearing-induced PPI deficits in rats. Based on the observation that schizophrenia may be associated with a prenatal immune insult (e.g. exposure to a virus), Aim 2 studies will further characterize the effects of prenatal immune challenge on PPI and examine the contribution of KYNA to these immune-related effects on PPI. The anxiety-like phenotype and exaggerated stress responses in isolation-reared rats are consistent with alterations in the brain's CRF system. Hence, Aim 3 studies will test the hypothesized differential roles of specific CRF receptors in mediating isolation rearing-induced deficits in PPI in mice, using CRF-R1 and CRF-R2 null mutant mice.
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0.958 |
1999 — 2015 |
Geyer, Mark 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. |
Monoamine and Hallucinogen Effects On Rodent Behavior @ University of California San Diego
DESCRIPTION (Adapted From The Applicant's Abstract): Rats and genetically altered mice will be used to determine the involvement of serotonergic and other systems in the behavioral effects of hallucinogens, such as lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM), or phencyclidine (PCP); and serotonin (5HT) releasers, such as 3,4- methylenedioxymethamphetamine (MDMA) and alpha-ethyltryptamine (AET). Behavioral effects will be measured using acoustic and tactile startle paradigms to assess habituation and sensorimotor gating (prepulse inhibition-PPI) functions and computerized monitoring of patterns of locomotor and investigatory behavior, using a Behavioral Pattern Monitor in rats and a Video Tracker in mice. Aim 1 will identify the mechanisms and sites of action mediating the locomotor-activating effects of indirect serotonin agonists, such as MDMA or AET, and direct agonists, such as RU24969, by testing the hypothesis that postsynaptic 5HTIB receptors mediate these effects of serotonin-releasing agents. Aim 2 will test the hypotheses that indirect serotonin agonists: [1] disrupt PPI in rats by acting indirectly via 5HTIB and/or 5HT2A receptors; and [2] impair startle habituation in rats by acting indirectly on 5HT2A receptors; and [3] have effects on PPI in mice that depend upon a balance between the opposing influences of indirect activation of postsynaptic 5HTIA receptors versus 5HTIB and/or 5HT2A receptors. Knockouts of 5HTIA and 5HTlB receptors will be studied. Aim 3 will clarify the mechanisms and sites of action by which serotonergic hallucinogens, such as LSD and DOM, and glutamatergic hallucinogens, such as PCP, disrupt startle habituation and PPI. Aim 4 will identify the mechanisms and sites of action mediating the effects of hallucinogens on exploratory behavior, testing the hypothesis that both 5HTlA and 5HT2 receptors contribute to the effects of indoleamine, but not phenalkylamine, hallucinogens. The brain regions involved in a proposed functional interaction between 5HTlA and 5HT2 receptors will be identified, as will the sites of action at which 5HT2 receptors modulate the effects of PCP on locomotor activity. These studies should further our basic understanding of the behavioral functions of serotonergic systems and the mechanisms of action of drugs of abuse such as hallucinogens and serotonin releasers.
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0.958 |
2000 — 2004 |
Geyer, Mark 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. |
Startle Gating and Locomotion in D2-Family Knockout Mice @ University of California San Diego
DESCRIPTION: (Adapted from the Investigator's Abstract) Dopamine neurons that project from the midbrain to cortical and limbic structures modulate attention and information processing functions and contribute to the organization of locomotor behavior. Related behaviors are impaired in patients with schizophrenia and other psychiatric disorders, suggesting that alterations in mesocorticolimbic dopamine signaling have pathophysiological relevance in human diseases. D1-like and D2-like dopamine receptors have been implicated in the normal activity of these dopaminergic circuits. The functional distinctions among the 3 cloned members of the D2-like subfamily (D2, D3, and D4) remain elusive, in part because of the limited specificity of pharmacological ligands. Strains of gene knockout mice that lack either the D2, D3, or D4 receptors have been generated as genetic models to understand the functions, at a systems level, of these multiple independent genes. Initial characterizations reveal that the individual receptor knockout strains have many unique behavioral phenotypes, including changes in locomotor behavior and startle response measures of sensorimotor gating deficits seen in schizophrenia. The general hypothesis to be tested is that the D2-like receptor subtypes have selective functional roles in the dopaminergic modulation of information processing, locomotor activity, and the sequential organization of behavior. The specific aims to address this hypothesis are: (1) generate congenic C57BL/6 strains of mutant mice with individual D2, D3, or D4 dopamine receptor knockouts and all permutations of double and triple receptor mutations; (2) characterize the phenotype of each strain of homozygous and heterozygous mice using measures of the amount and patterns of locomotor activity, the response to a novel object, and startle reactivity, habituation, and prepulse inhibition; (3) characterize the effects of amphetamine and selected direct dopamine agonists on the same measures; (4) characterize the effects of amphetamine and selected direct dopamine agonists on patterns of locomotor and exploratory behavior in each of the mutant strains; and (5) characterize the effects of amphetamine and selected direct dopamine agonists on startle reactivity, habituation, and prepulse inhibition in each of the mutant strains of mice. These phenotypic and pharmacological comparisons of D2-subtype knockouts in congenic strains having a common genetic background will provide fundamental information regarding the specific functional roles of D2-like receptors in the regulation of unconditioned behaviors that have particular relevance to both psychotic disorders and psychostimulant abuse. This information will have important implications for the further development of therapeutic approaches to the treatment of both schizophrenia and drug abuse.
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0.958 |
2006 |
Geyer, Mark A |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Serotonin Club Iuphar Satellite Meeting @ University of California San Diego
[unreadable] DESCRIPTION (provided by applicant): The Serotonin Club is an international organization of about 650 biomedical scientists interested in research on serotonin (5-hydroxytryptamine). The Serotonin Club is an authorized affiliate of the International Union of Basic and Clinical Pharmacological Societies (IUPHAR) and sponsors satellite meetings to the IUPHAR Congresses every 4 years. The next meeting will be held at Hokkaido University in Sapporo Japan June 27-30, 2006 as an official satellite of the 2006 World Congress of IUPHAR to be held in Beijing China. The overall goal of this program is to conduct an international meeting on serotonin research that will be of the highest possible scientific quality in order to attract and educate both young and senior investigators. The primary specific aim of this application is to provide financial support to young investigators to enable them to attend and participate in the Serotonin Club Meeting and thereby foster their careers in serotonin research. This year, 16 symposia including four speakers each will cover the full range of new findings regarding serotonin. Serotonin research is very relevant to human health, being germane to substance abuse, pain, cardiovascular systems, and digestive processes, and especially mental health. It is striking that serotonergic drugs are central to treatments of depression, schizophrenia, OCD, mania, anxiety, eating disorders, panic, and PTSD. Nevertheless, additional opportunities exist for novel therapeutics based on compounds having selective actions at specific serotonin receptors and that are only now being explored with new pharmacological tools. Serotonin Club meetings are typically the first place that leading scientists present their newest findings relevant to novel drug discovery and target validations involving serotonergic mechanisms. Accordingly, attendance and participation in the IUPHAR Serotonin Satellite meetings are often singular opportunities in the early careers of young investigators working on serotonin-related problems. Hence, support that would enable neuroscientists-in-training to attend the forthcoming Serotonin Meeting in Sapporo will have a positive influence on young investigators and in turn will have a lasting impact on the field. The Serotonin Club, an international organization of biomedical scientists interested in research on the neurotransmitter serotonin, organizes scientific meetings every other year. This application seeks support to enable young investigators to participate in the 2006 Serotonin Club Meeting. Serotonin research is important to substance abuse, pain, cardiovascular systems, digestive processes, and especially mental health. Serotonergic drugs are used to treat depression, schizophrenia, mania, anxiety, eating disorders, panic, and PTSD. Serotonin Club meetings are typically the first place that scientists present their newest discoveries about novel serotonergic drugs. Hence, helping neuroscientists-in-training attend the meeting will have a positive influence on trainees and a lasting impact on the field. [unreadable] [unreadable] [unreadable]
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0.958 |
2006 — 2009 |
Geyer, Mark 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. |
Sp4 Pathway in Hippocampus Modulates Sensorimotor Gating @ University of California San Diego
[unreadable] DESCRIPTION (provided by applicant): Hippocampal abnormalities are important susceptibility factors for several human psychiatric disorders. Sensorimotor gating, assessed by prepulse inhibition of startle, is reduced in and provides a cross-species endophenotype for a group of psychiatric gating disorders, including schizophrenia, bipolar disorder, autism, and ADHD. In preliminary work, hypomorphic Sp4 mutant mice displayed vacuolization in the hippocampal dentate gyrus, reduced expression of the Grk4 gene in the hippocampus and cortex, robust deficits in sensorimotor gating and contextual memory, and decreased exploration of novel environments. The molecular, hippocampal, and behavioral abnormalities of the Sp4 mutant mice mimic several phenotypes for neuropsychiatric gating disorders. Specific Aim 1 will assess the cell autonomous roles of the Sp4 gene in the vacuolization of dentate gyrus, and the associated deficits in sensorimotor gating and contextual memory. A mouse line will be created with an inducible cre-ERT2 gene fused within the 3' UTR of the endogenous Desmoplakin (Dsp) gene by internal ribosome entry site without knocking-out Dsp expression. Tamoxifen will be used to activate the ere that in turn will reactivate or ablate the Sp4 expression in dentate granule cells. Hippocampal structural and functional abnormalities will be assessed in these rescue or conditional knockout mice. Specific Aim 2 will identify Sp4-mediated genetic pathways in the hippocampus that subserve novel object exploration. Studies will (a) further analyze the defective novelty exploration of the hypomorphic Sp4 mice in established paradigms; (b) examine whether the restoration or ablation of Sp4 expression in the dentate granule cells (Aim 1) can rescue or cause the defective novelty response. Specific Aim 3 will examine the role of the Grk4-mediated signaling pathway in the modulation of sensorimotor gating in Sp4 hypomorphic mice, using both pharmacological and genetic approaches. Cell culture experiments will examine Grk4-mediated desensitization of both dopamine D1 and mGluRI receptors in the Sp4 mutant hippocampal cells. Antagonists of dopamine D1 and mGluRI receptors will be administered to the hypomorphic Sp4 mutant mice to test for reversal of the prepulse inhibition deficit. To evaluate the disruption of Grk4-mediated GPCR signaling pathway in the modulation of sensorimotor gating and hippocampal vacuolization, double knockout mice combining the Sp4 deletion with either dopamine D1 or mGluRI receptor genes will be generated. These experiments will yield novel insights into genetic pathways within the hippocampus that underlie behavioral abnormalities relevant to several psychiatric disorders. [unreadable] [unreadable]
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0.958 |
2006 — 2008 |
Geyer, Mark 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. |
Stress and Crf System Effects On Information Processing @ University of California San Diego
[unreadable] DESCRIPTION (provided by applicant): The goal of this project is to use murine models to elucidate the mechanisms underlying the effects of stress and the neuropeptide corticotropin releasing factor (CRF) on information processing and response inhibition. Across species, presentation of a neutral, non-startling "prepulse" 30-300 ms before a startling stimulus reduces startle magnitude, termed prepulse inhibition (PPI), theoretically by requiring the organism to allocate attentional resources to process the prepulse and hence filter or "gate" the subsequent startling stimulus. PPI is used clinically as an operational measure of sensorimotor gating that is deficient in a number of neuropsychiatric disorders. Certain anxiety disorders, post-traumatic stress disorder (PTSD) and panic disorder (PD), exhibit deficits in PPI. These disorders also appear to exhibit pathology in the CRF system, either CRF hypersecretion or increased receptor signaling. CRF is a neuropeptide that coordinates many behavioral and neuroendocrine responses to stress via activation of 2 known receptor subtypes, CRF-R1 and CRF-R2. Over-expression of CRF or exogenous administration of CRF in rodents reduces PPI, mimicking the PPI deficits observed in PTSD and PD patients. CRF-induced deficits in PPI in mice appear to be mediated via CRF-R1 receptors while CRF-R2 receptors have opposing effects. To guide future clinical studies of the roles of CRF systems in PTSD and PD, experiments in mice are proposed to elucidate the role of CRF receptors in stress-induced deficits in PPI, and to clarify how these receptors modulate PPI when chronically activated. This project tests hypotheses based on a novel model of relative CRF-R1 and CRF-R2 receptor signaling processes in response to normal and pathological CRF release. Aim 1 identifies the respective contributions of CRF and dopamine receptors in CRF effects on PPI. Aim 2 identifies the CRF receptor mechanisms underlying shock stress effects on startle and PPI. Aim 3 assesses the contribution of CRF-R2 receptors and endogenous ligands to the maintenance of and recovery from CRF-induced deficits in PPI. Aim 4 assesses the neuroanatomical substrates contributing to both acute CRF and chronic CRF effects on information processing. These studies are critical for our basic understanding of the mechanisms of stress effects on information processing and response inhibition, and will elucidate new receptor targets for pharmacotherapeutic intervention in anxiety disorder patients exhibiting information processing deficits. [unreadable] [unreadable] [unreadable]
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0.958 |
2010 — 2014 |
Geyer, Mark A Perry, William |
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. |
Inhibitory Deficits in Human and Animal Models of Bipolar Disorder @ University of California San Diego
DESCRIPTION (provided by applicant): Bipolar Disorder (BD) is a severe psychiatric illness that is hallmarked by manic and depressive states. Inhibitory deficits are characteristic of BD and occur throughout the various phases of the illness. Problems with inhibition in people with BD may result in increased risk-taking behavior as well as difficulties in completing important tasks of daily living and complying with treatment. Consequently, studying profiles of disinhibition throughout the BD spectrum may elucidate traits of the disease that are present regardless of symptomatology. Furthermore, inhibitory deficits can be studied in both humans and animals using parallel methodology, thus contributing to the development of much-needed animal models of BD mania. During the past funding period, a novel technology was developed to study inhibitory deficits in humans (the human Behavioral Pattern Monitor: hBPM). Manic BD patients exhibited a "signature" pattern of inhibitory deficits that distinguished them from schizophrenia and nonpatient subjects. Furthermore, selective manipulation of the dopamine transporter in mice, either genetically (knockdown mice) or pharmacologically (GBR12909 administration), uniquely matched the inhibitory profile of manic BD patients. The present application seeks to test whether the inhibitory profile found among manic BD patients is specific to the manic state or persists during the other phases of BD, i.e., euthymic, depressed, and hypomanic states. Additionally, this investigation will examine multiple aspects of cognitive inhibition in a cross-species fashion. BD participants in various phases of their illness will be tested with the hBPM to measure hyperactivity and disinhibited exploration, the Conner's Continuous Performance Test to assess attentional inhibition, the Iowa Gambling Task to assess risk-taking inhibition, and the Wisconsin Card Sorting Task to assess perseverative inhibition. Mice will be tested in an analogous rodent BPM paradigm and in recently developed mouse versions of the three measures of cognitive inhibition listed above. In keeping with this program's cross-species translational approach, in which human studies inform animal investigations and animal studies inform the next logical step in the human work, an additional aim is to test whether pharmacological manipulations in healthy humans can mimic aspects of the manic BD profile. Thus, inhibitory functioning will be assessed in healthy non-patient subjects using dopamine agonist compounds (amphetamine and modafinil) and compared to a non-dopaminergic stimulant (caffeine) and placebo. These drugs will also be tested in the parallel mouse paradigms to examine the predictive validity of the rodent tasks. Finally, the BD mouse models will be tested at baseline and in response to antipsychotic and antimanic treatments using the cognitive and behavioral paradigms mentioned above. Studying human and parallel animal models of BD will facilitate the refinement of translational models, evaluate putative target endophenotypes, and identify behavioral biomarkers for use in proof-of-concept studies assessing the potential efficacy of novel therapeutic interventions for BD. PUBLIC HEALTH RELEVANCE: Individuals with Bipolar Disorder (BD) have significant difficulty in inhibiting their thoughts and behavior, which adversely impacts their ability to carry out daily activities and resume independent functioning, even when they are not actively ill. This application aims to measure inhibition across the multiple phases of BD and also to study human and animal models of the disease in parallel. Completion of this work will assist in understanding the underlying brain dysfunction of BD as well as assist in discovering and developing novel treatments.
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0.958 |
2016 — 2019 |
Geyer, Mark 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. |
Early Postnatal Disruptions to Glutamate and Gaba Systems and Their Contribution to Reward Deficits @ University of California, San Diego
7. Project Summary/Abstract Deficits in reward function, including impaired reward valuation, effort valuation and reward responsiveness, are core features of psychiatric disorders, such as schizophrenia and major depressive disorder. These reward deficits contribute significantly to the functional disability evident in these disorders. These reward processes correspond to approach/motivation constructs within the Positive Valence Domain of the NIMH Research Domain Criteria (RDoC) Program. The neurobiology underlying reward deficits is not completely understood and, as a result, there are currently no therapeutics that effectively alleviate reward deficits in psychiatric disorders. Schizophrenia and depression are both associated with abnormalities in glutamate and GABA neurotransmission. The GABAergic system is essential in regulating correct glutamatergic transmission that maintains optimal cortical balance. Importantly, postnatal glutamate transmission is critical for the normal development of the GABAergic system. The overarching goal of this R01 application is to investigate how disrupting early postnatal glutamate transmission leads to reward deficits in adulthood. To address this experimental question, we will employ translational behavioral procedures in rats, optogenetics and immunohistochemical techniques to identify the role of altered glutamate and/or GABA transmission in brain regions associated with reward processing. Specific Aim 1 will determine whether administering the N-methyl- D-aspartate (NMDA) glutamate receptor antagonist phencyclidine (PCP) during the early postnatal period to male and female rats impairs reward valuation, effort valuation and/or reward responsiveness. Specific Aim 2 will use optogenetics to either increase or decrease glutamate activity in the orbitofrontal cortex (OFC) or anterior cingulate cortex (ACC) to determine whether such changes in glutamate activity impact reward valuation, effort valuation or reward responsiveness. Specifically, we will determine whether increased or decreased glutamate transmission impairs or improves reward processing in saline- or PCP-treated rats. These findings will provide evidence as to how changes in glutamate transmission lead to the regulation of multiple aspects of reward processing mediated by distinct brain regions. Specific Aim 3 will determine whether the reward deficits resulting from neonatal PCP treatment are associated with alterations in parvalbumin (PV)-, somatostatin (SST)- and/or vasoactive intestinal polypeptide (VIP)-positive GABA interneurons, and glutamic acid decarboxylase isoform 67 (GAD67) content, in brain regions critical for reward function (i.e., OFC, prelimbic cortex, anterior cingulate cortex, dorsal striatum and/or ventral striatum). This multidisciplinary project will promote our understanding of how alterations in neurobiology resulting from neonatally disrupted glutamate transmission contribute to deficits in reward function in adulthood. The generated findings may identify mechanisms that could be targeted to attenuate reward deficits in neuropsychiatric disorders.
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0.958 |