The effects of ethanol exposure on mammalian central nervous system function will be pursued using both extracellular recording of action potential activity from single neurons as well as evoked potentials, and intracellular recording of membrane properties. Recordings will be carried out in vivo in the intact brain in situ, in multiple brain grafts in oculo, and in brain slices as well as in extricated intraocular brain grafts in vitro. In addition to our studies of ethanol effects in rodent brain, we will study ethanol actions on human neurons using in oculo brain xenografts. Studies will focus on genetic variants manifesting differential alcohol-related behaviors as model systems for examining acute ethanol actions as well as for studying ethanol dependence and withdrawal. Our approach is to use genetic and pharmacological techniques to independently manipulate the behavioral effects and neuronal actions of ethanol. We are currently most interested in ethanol interactions with norepinephrine, dopamine, excitatory amino acids, and GABA in locus coeruleus, hippocampus and cerebellum. We propose to extend these studies to the dopaminergic ventral tegmental area and its target areas. The long- term objectives of this research program are three fold. First, electrophysiological and in vivo electrochemical techniques will be used both to characterize acute neuronal responses to ethanol as direct membrane effects, modulatory interactions with synaptic inputs, or alterations in the activity of neuronal pathways. Second, changes in neuronal responses to ethanol, as well as functional changes in neurotransmitter systems, will be determined after induction of ethanol dependence and withdrawal. Finally, using selectively bred and transgenic genetic variants, ethanol- induced electrophysiological responses will be correlated with alcohol- induced behaviors. A greater understanding of how ethanol alters CNS function should furnish new insights into the problems of alcohol intoxication and alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA005915-09
Application #
3109198
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1983-07-01
Project End
1995-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
9
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Freund, R K; Palmer, M R (1997) Beta adrenergic sensitization of gamma-aminobutyric acid receptors to ethanol involves a cyclic AMP/protein kinase A second-messenger mechanism. J Pharmacol Exp Ther 280:1192-200
Lin, A M; Bickford, P C; Palmer, M R et al. (1997) Effects of ethanol and nomifensine on NE clearance in the cerebellum of young and aged Fischer 344 rats. Brain Res 756:287-92
Freund, R K; Palmer, M R (1997) Ethanol depression of cerebellar Purkinje neuron firing involves nicotinic acetylcholine receptors. Exp Neurol 143:319-22
Trok, K; Palmer, M R; Freund, R K et al. (1997) Functional interactions between spinal cord grafts suggest asymmetries dictated by graft maturity. Exp Neurol 145:268-77
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Freund, R K; Palmer, M R (1996) 8-Bromo-cAMP mimics beta-adrenergic sensitization of GABA responses to ethanol in cerebellar Purkinje neurons in vivo. Alcohol Clin Exp Res 20:408-12
Inoue, H K; Henschen, A; Olson, L (1994) Human fetal spinal cord xenografted to the eye of athymic nude rats: survival, ultrastructural differentiation, glial responses and vascular interactions. J Electron Microsc (Tokyo) 43:1-9
Lin, A M; Freund, R K; Hoffer, B J et al. (1994) Ethanol-induced depressions of cerebellar Purkinje neurons are potentiated by beta-adrenergic mechanisms in rat brain. J Pharmacol Exp Ther 271:1175-80
Freund, R K; van Horne, C G; Harlan, T et al. (1993) Electrophysiological interactions of ethanol with GABAergic mechanisms in the rat cerebellum in vivo. Alcohol Clin Exp Res 17:321-8

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