1986 — 1994 |
Frye, Gerald D |
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. |
Gabaergic Adaptation in Ethanol Tolerance and Dependence @ Texas a&M University Health Science Ctr
Functional tolerance and physical dependence involve adaptive changes in the central nervous system (CNS) as compensation for repeated ethanol intoxication. Cellular mechanisms underlying these acute and chronic actions of ethanol have important implications for any rational method of prevention or treatment of alcohol abuse or alcoholism. Experimental evidence is consistent with the idea that biphasic stimulant and depressant CNS actions of ethanol involve facilitation of GABAergic hypoactivity. The hypothesis being tested in this proposal is that, "acute or chronic actions of ethanol depend, in part, on increased or decreased efficacy, respectively, of GABA receptors as synaptic transducers". The purpose of this project is to critically test whether changes in GABA receptor efficiency and/or efficacy, alone, play a physiologically significant role in the mechanisms responsible for ethanol intoxication, acute and chronic functional tolerance or physical dependence. A direct test of changes in GABAA or GABAB receptor function is being made using models of GABA pre- and postsynaptic transmission in the peripheral isolated organ (guinea pig ileum), cerebral cortical brain slice, CA1 neurons in the hippocampal slice and subcellular synaptoneurosome which are being evaluated by biochemical, physiological and electrophysiological means. The results should help clarify the role of GABAergic neurotransmission and particularly the role of GABA receptors in the neuropharmacology of ethanol by strengthening or disproving our working hypothesis. This research project is an integral part of Dr. Frye's professional development plan (1 K02 AA00101) under which he is obtaining training in electrophysiological techniques and increasing his efforts in interdisciplinary research collaborations to improve his skills as a basic scientist interested in the biomedical impact or ethanol.
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0.952 |
1987 — 1991 |
Frye, Gerald D |
K02Activity Code Description: Undocumented code - click on the grant title for more information. |
Gabaergic Adaptation in Ethanol Tolerance &Dependence @ Texas a&M University Health Science Ctr
This proposal is a request for an ADAMHA RSDA level II support for Gerald D. Frye, Ph.D. and closely related to R01 AA06322 on which Dr. Frye is the PI. This award will allow Dr. Frye's responsibilities for University and Department service and teaching to be reduced so that he will be able to apply at least 90% of his time to research and professional development. Those departmental resources that are no longer required for Dr. Frye's support will be used to recruit an additional faculty member with biochemical research interests related to alcohol and drug abuse questions. Dr. Frye's research efforts will continue to focus on the role that GABAA and GABAB receptor/transducer complexes play in the genesis of ethanol intoxication, tolerance and physical dependence. The hypothesis being tested is that, "acute or chronic actions of ethanol depend in part on increased or decreased efficacy of GABA receptors, respectively, as synaptic transducers". Studies are designed to evaluate the influence of ethanol treatment on the physiology of model GABAA and GABAB receptor systems. Not only will Dr. Frye continue his research using the guinea pig ileum but he will broaden his research training by learning new neurophysiological techniques in the rat hippocampal slice through an important collaboration with Dr. William Griffith. Additional opportunities for training and new research should come form other planned collaborations in areas where a GABA receptor-ethanol interaction could be an underlying cause of ethanol toxicity. In this regard preliminary collaborations with Dr. Kelly Hester (cardiovascular physiology and hypertension); Dr. Jack Nations (heavy metals toxicity and ethanol preference); and and individual yet to be hired by the Department (ion channel biochemistry). These plans for new training and increased interdisciplinary research collaboration should significantly enhance Dr. Frye's professional development as a basic scientist interested in the biomedical impact of ethanol.
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0.952 |
1999 — 2002 |
Frye, Gerald D |
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. |
Cns Development, Gabaars and Vunerability to Ethanol @ Texas a&M University Health Science Ctr
Children with fetal alcohol syndrome (FAS), suffer mental deficits that handicap them for life. Understanding how ethanol exerts its neuroteratogenic action at a cellular and molecular level may offer insights into the design of interventions to improve CNS functional outcomes for these individuals. In this regard, it is now clear that GABA/ARs are predominantly "excitatory/neurotrophic" transducers in developing brain and take on the better known, classical inhibitory role as the brain matures. Early GABA/ARs depolarize immature neurons, activating voltage-dependent Ca/2+ entry and stimulating neurogenesis, neuronal differentiation, migration as well as synaptogenesis. Currently, little is known about the impact of ethanol on the function or expression of "excitatory" GABA/ARs in the immature CNS. If ethanol distorts the normal developmental pattern of GABA/AR activity, this could contribute to neurological deficits in FAS. We have recently identified a delay in the postnatal evolution of GABA/ARs in rat medial septal/diagonal band (MS/DB) neurons one week after moderate "binge- like" postnatal ethanol exposure. Basic GABA/AR function recovers bu 4-5 weeks of life, but subtle longer-lasting changes in Zn/2+ inhibition remain. Impairment of early postnatal GABA/AR function in the MS/DB could distort appropriate synapse formation and contribute to attention deficits characteristic of individuals with FAS. This project will use well-established in vivo rodent models of FAS, in vitro primary neuronal culture systems, immunocytochemistry, stereology and in vitro electrophysiological recordings in individual neurons and brain slices to determine the impact of prenatal ethanol exposure on MS/DB functional development. These studies will test the hypothesis that: "Perinatal ethanol exposure inhibits excitatory GABA/ARs which interferes with normal patterns of neuronal development."
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0.952 |
2007 — 2011 |
Frye, Gerald D |
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. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Cns Development, Gabaars and Vulnerability to Ethanol @ Texas a&M University Health Science Ctr
DESCRIPTION (provided by applicant): Children who suffer cognitive deficits after in utero ethanol intoxication are severely handicapped and struggle to succeed in our complex world. Sadly, there are no treatments to prevent or reverse this injury. Our long- term goal is to rationally identify / test therapies that could protect developing neurocircuits from ethanol injury and preserve cognitive functioning. We have identified a defect in GABA signaling caused when ethanol distorts newly forming synapses. Resulting changes in GABA tone could skew information processing in cognitive neurocircuits causing learning and memory deficits. Synaptic defects could be present even when alcohol-induced neuronal loss does not occur. During a period equivalent to human 3rd trimester brain development, binge-like intoxication in rat pups distorts maturation of GABA miniature postsynaptic currents in medial septum / diagonal band neurons in brain slices. This action seems to be faithfully modeled in primary septal cultures and surprisingly, in cultures, it is largely prevented by finasteride, a drug that blocks formation of 51-reduced neurosteroids. If GABAergic synaptic dysfunction permanently skews inhibitory input to medial septum / diagonal band neurons, then neurocircuit activity essential for cognitive performance could be compromised. In fact, performance in spatial learning and memory tasks is impaired both in children suffering from fetal alcohol exposure and in rats after early postnatal intoxication, suggesting that septal-hippocampal circuits could be dysfunctional. Here we test the hypothesis that 3rd trimester equivalent ethanol intoxication distorts maturation of GABA synapses in the medial septum / diagonal band and disrupts associated cognitive functioning. Whether an intervention such as finasteride can occlude ethanol-induced deficits also will be studied using an established in vivo rodent model of binge ethanol exposure, whole cell electrophysiology, receptor pharmacology and behavioral assessment. If successful, this work could provide a model for testing treatments aimed at offering hope for preventing or limiting cognitive injury. PUBLIC HEALTH RELEVANCE Children who suffer cognitive deficits from ethanol intoxication during pregnancy can be severely handicapped and struggle to succeed in our complex world. Sadly, there are no treatments to prevent or reverse this injury. The long-term goal of this project is to rationally identify and test therapies that could protect the developing brain from ethanol injury and preserve cognitive functioning in children at risk for fetal alcohol spectrum disorders.
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0.952 |