Project Details


Ethanol (EtOH) is an effective brain depressant and an additive drug.
Emerging evidence suggests that glycine receptor/channels (GlyRs) are
sensitive to pharmacologically relevant concentrations of EtOH. Since
glycine inhibits neuronal activity, potentiation of GlyR function would
be expected to enhance neuronal inhibition and perhaps contribute to the
neuronal depressant effects of EtOH. Therefore, we propose to examine
the effects of EtOH on glycine-induced responses of dopaminergic neurons
from the ventral tegmental area (VTA) of the brain, the reward center
for drug abuse. The overall objective of this study is to investigate
the mechanisms by which EtOH alteration of GlyR function contributes to
the central nervous system (CNS) consequences of alcohol in vivo. To
achieve this objective the following three hypotheses will be tested.
HYPOTHESIS I is that EtOH interacts with the GlyR. EtOH regulates the
excitability of dopaminergic neurons by altering functions of GlyRs.
HYPOTHESIS II is that EtOH interactions with the GlyR are modulated by
the protein phosphorylation status of the GlyR, the intracellular
activity of PKA, PKC and G-proteins. HYPOTHESIS III is that GlyR
structure, intracellular C1-concentration of dopaminergic neurons and,
consequently, glycine-induced responses and their response to EtOH
change with development. These hypotheses will be tested on VTA neurons
freshly isolated from both neonatal and mature rats. Whole-cell patch-
clamp technique (especially gramicidin perforated patch technique) will
be used to record glycine-induced responses, including membrane current,
potential and the alteration of spontaneous firing in the absence and
presence of EtOH. Specific activators and inhibitors of protein kinases
A and C and of G-proteins will be used to identify the enzyme pathways
involved in any effects, of EtOH on GlyRs. These studies will
significantly advance our understanding of the effects of EtOH on CNS
GlyRs at the molecular and cellular levels. A better knowledge of the
actions of EtOH in the brain will improve our understanding of related
reinforcement mechanisms, which will, in turn, facilitate the
identification of strategies which might be of value in the treatment
of alcohol abuse and fetal alcohol syndrome.
Effective start/end date4/1/993/31/07


  • Psychiatry and Mental health


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