Functional tolerance and physical dependence appear to involve adaptive changes in the central nervous system (CNS) which compensate for repeated ethanol intoxication. These changes may play an important role in maintaining the pathological consumption of alcoholic beverages. For this reason, an understanding of the cellular mechanisms responsible for functional tolerance and physical dependence could have important implications for the rational development of methods to prevent or treat alcohol abuse or alcoholism. In this regard, increasing experimental evidence suggests that GABAergic neurotransmission and more specifically, GABA receptors are a likely target for ethanol. This proposal will test the hypothesis that: Functional tolerance to and physical dependence on ethanol results in part from GABA receptor down-regulation in response to the initial enhancement of GABA receptor activity during ethanol intoxication. Experiments proposed in this application will characterize the extent of functional down-regulation of GABA-A and GABA-B receptors associated with the development of physical dependence on ethanol modeled in the rat. In addition, the driving forces responsible for adaptive changes in the function of these GABA receptors will be explored to determine whether receptors must exhibit acute ethanol sensitivity in order to undergo functional down-regulation. These questions will be addressed by comparing GABA receptor responses in six distinct populations of anatomically identified neurons using intracellular electrophysiological recording techniques. Measurements will be made in tissue slices prepared from the hippocampus, cerebral cortex, medial and lateral septum which are proposed to possess ethanol sensitive or resistant GABA receptors. The results should help clarify the role of GABA receptors in the neuropharmacology of ethanol.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA006322-10
Application #
3109494
Study Section
Special Emphasis Panel (SRCA (56))
Project Start
1983-09-01
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
10
Fiscal Year
1993
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

Showing the most recent 10 out of 20 publications