ROLE OF LIGAND-GATED ION CHANNELS IN EHTANOL DISCRIMINAT

The aim of the research project is to assess the contribution of specific
ligand-gated ion channels in mediating the perceptible effects of ethanol
in the CNS. Three of these receptor/channel complexes that are
particularly sensitive to the effects of ethanol in in vitro assays are the
GABAA receptor complex, the NMDA subtype of glutamate receptor complex, and
the 5-HT3 subtype of serotonin receptor. These receptor systems encompass
components of the major inhibitory and excitatory neurotransmitter systems,
and a component of the serotonin system, implicated in many behavioral
effects of ethanol. The interaction of ethanol with these receptor systems
in electrophysiological and biochemical assays occurs at concentrations of
5-50 mM, corresponding to a range of blood ethanol concentrations
associated with mild intoxication to loss of righting reflex. The
sensitivity of these receptor-linked ion channels to ethanol indicates a
specificity to the pharmacological actions of ethanol. The interaction of
ethanol at several different receptor systems can be expected to give rise
to a mixture of internal stimulus effects, composed of distinguishable
component parts. Understanding how ethanol acts at each component receptor
system to produce its discriminable effects will advance our understanding
of ethanol's pharmacological actions and may be helpful in the design of
potential pharmacotherapies to alter and possibly limit excessive ethanol
intake. The proposed studies utilize the drug discrimination procedure to 1)
determine the modulatory sites on the GABAA receptor complex that are
sufficient to produce ethanol-like discriminative effects 2) determine if
antagonism of NMDA transmission by compounds acting at the NMDA, channel,
glycine or polyamine modulatory sites on the NMDA receptor complex results
in similar discriminative stimulus effects as ethanol. 3) Determine the
structural requirements of the 5-HT3 antagonists to block the
discriminative effects of ethanol, and if this blockade can be due to
action of the 5-HT3 antagonists at the nicotinic cholinergic or GABAA
channels. 4) Determine if the dose of ethanol used in training the
discrimination determines the relative contribution of each receptor system
in mediating the discriminative effects of ethanol. 5) Whether a component
of the compound discriminative stimulus effects of ethanol can be isolated
from the action of ethanol at other receptor systems.