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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA006322-07
Application #
3109493
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1983-09-01
Project End
1992-02-28
Budget Start
1990-03-01
Budget End
1991-02-28
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Texas A&M University
Department
Type
Schools of Medicine
DUNS #
City
College Station
State
TX
Country
United States
Zip Code
77845
Grover, C A; Jasek, M C; Frye, G D et al. (1997) Ethanol inhibition of reduced frequency-dependent rundown of calcium currents in acutely dissociated MS/nDB neurons from chronic in vivo lead-exposed adult rats. Neurotoxicology 18:179-90
Frye, G D; Fincher, A (1996) Sensitivity of postsynaptic GABAB receptors on hippocampal CA1 and CA3 pyramidal neurons to ethanol. Brain Res 735:239-48
Lau, A H; Frye, G D (1996) Acute and chronic actions of ethanol on CA1 hippocampal responses to serotonin. Brain Res 731:12-20
Frye, G D; Fincher, A S; Grover, C A et al. (1996) Lanthanum and zinc sensitivity of GABAA-activated currents in adult medial septum/diagonal band neurons from ethanol dependent rats. Brain Res 720:101-10
Grover, C A; Frye, G D (1996) Ethanol effects on synaptic neurotransmission and tetanus-induced synaptic plasticity in hippocampal slices of chronic in vivo lead-exposed adult rats. Brain Res 734:61-71
Frye, G D; Taylor, L; Grover, C A et al. (1995) Acute ethanol dependence or long-term ethanol treatment and abstinence do not reduce hippocampal responses to carbachol. Alcohol 12:29-36
Frye, G D; Fincher, A S; Grover, C A et al. (1994) Interaction of ethanol and allosteric modulators with GABAA-activated currents in adult medial septum/diagonal band neurons. Brain Res 635:283-92
Grover, C A; Frye, G D; Griffith, W H (1994) Acute tolerance to ethanol inhibition of NMDA-mediated EPSPs in the CA1 region of the rat hippocampus. Brain Res 642:70-6
Frye, G D; Mathew, J; Trzeciakowski, J P (1991) Effect of ethanol dependence on GABAA antagonist-induced seizures and agonist-stimulated chloride uptake. Alcohol 8:453-9
Frye, G D; Taylor, L; Trzeciakowski, J P et al. (1991) Effects of acute and chronic ethanol treatment on pre- and postsynaptic responses to baclofen in rat hippocampus. Brain Res 560:84-91

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