NEURONAL AND NEUROTRANSMITTER ACTIONS OF ETHANOL

本提案将研究神经元和神经递质机制

This proposal will investigate neuronal and neurotransmitter mechanisms underlying the effects of ethanol (ET) intoxication and withdrawal (ETX). ET may act at several brain regions, including inferior colliculus (IC) and pontine reticular formation (PRF), to produce its effects. Rebound activity in these areas may contribute importantly to ETX. An important and potentially dangerous feature of the ETX syndrome is generalized tonic- clonic seizures. The seizures observed in ETX of rats include spontaneous and audiogenic seizures (AGS). Current evidence indicates that ET may enhance GABA's action and decrease the action of excitant amino acids (EAAs). ETX may result from rebound increases in EAA excitation and decreases in GABA inhibition in these pathways. The proposed studies will examine neural mechanisms involved in ET's actions by recording single neuron response patterns in behaving animals and by microinjecting agents affecting GABA and EAA action into IC and PRF. Preliminary studies indicate that microinjection of EAA antagonists, into IC an PRF will block ETX seizures. Preliminary single unit recording studies indicate that auditory responsiveness in IC and PRF neurons in freely moving rats declines during intoxication and hyperresponsiveness during ETX. A dramatic rise in the auditory responses of PRF neurons at high intensity is seen. These changes may involve ET-mediated alterations in GABA and /or EAA actions that govern neuronal responses. Therefore, we propose to compare the effects of iontophoretically applied amino acid neurotransmitters onto IC neurons in animals before, during and after chronic ET administration to observe for ET-induced changes. The IC and PRF are vital for the initiation of AGS exhibited by genetically epilepsy- prone rate (GEPRs). Recent work has delineated neuronal and neurotransmitter mechanisms in AGS in GEPRs which may be relevant to seizures during ETX. Inhibition deficits and abnormal neuronal firing patterns have been observed in IC and PRF of GEPRs which is associated with AGS susceptibility, and our preliminary experiments suggest that similar mechanisms may also be operative during ETX. Alterations in GABA and EAA action in the IC are also observed in GEPRs, and these mechanisms by be similar to changes that occur during ETX. Thus, this proposal seeks to extend our preliminary studies on single unit recording and focal microinfusion studies before and during ET administration and during ETX to improve our understanding of the important public health problem produced by the excessive ET use.