Functional tolerance and physical dependence are thought to involve adaptive changes in the central nervous system (CNS) as compensation for prolonged ethanol-induced depression. An understanding of these mechanisms has been considered to have important implications for the development of a rational therapy of alcoholism. Experimental evidence supports the hypothesis that increased neurotransmission mediated by the inhibitor transmitter, gamma-aminobutyric acid (GABA), is responsible in part for ethanol-induced CNS depression. Conversely, it is also likely that continuous treatment with ethanol causes a compensatory GABAergic hypoactivity to develop. The consequences of this action are believed to be two-fold. Functional tolerance would result from a diminished ability of ethanol to activate GABAergic transmission. Physical dependence and ethanol withdrawal-related, CNS, hyperexcitability would occur due to an imbalance in CNS excitatory-inhibitory activity caused by GABAergic hypodactivity in the absence of ethanol. The present proposal will attempt to evaluate the functional validity oif this hypothesis in three ways. First, the effect of pharacologically activating GABAergic neurotransmission during long-term ethanol treatment will be studied. If the hypothesis is correct then functional tolerance to ethanol and physical dependence should be accelerated. Second, long-term pharmacological activation of GABAergic transmission should result in functional tolerance to ethanol and cause signs similar to ethanol withdrawal if the hypothesis is correct. Finally, rotational behavior caused by unilateral activation of substantia nigra GABA receptors by GABA agonists will be used to evaluate the effects of a single or multiple doses of ethanol on the functional capacity of postsynaptic GABA receptors. These results will determine wehther functionally significant changes in GABA receptors occur, and if these are consistent with both the acute and chronic effecs of ethanol on CNS excitability.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA006322-05
Application #
3109492
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1983-09-01
Project End
1989-02-28
Budget Start
1988-03-01
Budget End
1989-02-28
Support Year
5
Fiscal Year
1988
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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