ETHANOL AND NEUROTRANSMITTER INTERACTIONS - FROM MOLECULAR TO INTEGRATIVE EFFECTS

There is extensive evidence that ethanol interacts with a variety of n eurotransmitters. Considerable research indicates that the major actio ns of ethanol involve enhancement of the effects of gamma-aminobutyric acid (GABA) at GABA(A) receptors and blockade of the NMDA subtype of excitatory amino acid (EAA) receptor. Ethanol increases GABA(A) recept or-mediated inhibition, but this does not occur in all brain regions, all cell types in the same region, nor at all GABA(A) receptor sites o n the same neuron, nor across species in the same brain region. The mo lecular basis for the selectivity of the action of ethanol on GABA(A) receptors has been proposed to involve a combination of benzodiazepine subtype, beta 2 subunit, and a splice variant of the gamma 2 subunit, but substantial controversy on this issue currently remains. Chronic ethanol administration results in tolerance, dependence, and an ethano l withdrawal (ETX) syndrome, which are mediated, in part, by desensiti zation and/or down-regulation of GABA(A) receptors. This decrease in e thanol action may involve changes in subunit expression in selected br ain areas, but these data are complex and somewhat contradictory at pr esent. The sensitivity of NMDA receptors to ethanol block is proposed to involve the NMDAR2B subunit in certain brain regions, but this subu nit does not appear to be the sole determinant of this interaction. To lerance to ethanol results in enhanced EAA neurotransmission and NMDA receptor upregulation, which appears to involve selective increases in NMDAR2B subunit levels and other molecular changes in specific brain loci. During ETX a variety of symptoms are seen, including susceptibil ity to seizures. In rodents these seizures are readily triggered by so und (audiogenic seizures). The neuronal network required for these sei zures is contained primarily in certain brain stem structures. Specifi c nuclei appear to play a hierarchical role in generating each stereot ypical behavioral phases of :he convulsion. Thus, the inferior collicu lus acts to initiate these seizures, and a decrease in effectiveness o f GABA-mediated inhibition in these neurons is a major initiation mech anism. The deep layers of superior colliculus are implicated in genera tion of the wild running behavior. The pontine reticular formation, su bstantia nigra and periaqueductal gray are implicated in generation of the tonic-clonic seizure behavior. The mechanisms involved in the rec ruitment of neurons within each network nucleus into the seizure circu it have been proposed to require activation of a critical mass of neur ons. Achievement of critical mass may involve excess EAA-mediated syna ptic neurotransmission due, in part, to upregulation ai; well as other phenomena, including volume (non-synaptic diffusion) neurotransmissio n. Effects of ETX on receptors observed in vitro may undergo amplifica tion in vivo to allow the excess EAA action to be magnified sufficient ly to produce synchronization of neuronal firing, allowing participati on of the nucleus in seizure generation. GABA-mediated inhibition, whi ch normally acts to limit excitation, is diminished in effectiveness d uring ETX, and further intensifies this excitation. (C) 1998 Elsevier Science Ltd. All rights reserved.