Hyperbaric pressure antagonizes the anesthetic effects of anesthetic agents (pressure reversal of anesthesia). In the past, this project has used high pressure to probe the site(s) of anesthetic action in nerve cells, a strategy derived from two linked hypotheses. The first hypothesis is that pressure directly antagonizes anesthetic effects at the molecular and cellular levels; the second, that anesthesia by all agents is fundamentally a unitary phenomenon, with a single site at which all agents act. We have developed evidence against the hypothesis of direct pressure-anesthetic antagonism. Pressure reversal of anesthesia appears to be primarily indirect, and to depend on the activity- dependent synaptic processes of potentiation and facilitation. We now propose to test the unitary hypothesis of anesthesia by examining the extent to which both intravenous and inhalation anesthetic agents modify activity-dependent synaptic interactions. Intracellular studies will be continued on a simple model synapse, a crustacean neuromuscular junction, to confirm that some agents enhance the predominantly presynaptic properties of facilitation and potentiation. Field potential studies in rat hippocampal cortical slice will be carried out to conform and extend our preliminary observation of agent-specific anesthetic effects on facilitation and long-term potentiation. The majority of the proposed studies will use intracellular recording in hippocampal slice CA1 neurons to compare effects of anesthetic agents on the properties which determine the output of this cell type in response to excitatory synaptic input, emphasizing depolarization-spike initiation coupling, GABA-mediated inhibition, activity-dependent after potentials, and synaptic potentiation. In view of evidence linking anesthesia and adrenergic neurotransmission, the interaction between adrenergic agents and anesthetic effects will be examined. The results will test the extent to which a unitary hypothesis of anesthetic action can still be supported, or alternatively supply a cellular substrate for a multisite hypothesis, using a preparation form a part of mammalian brain important in arousal, waking behavior, and memory formation. The results will also provide information on the nearly explored interaction between anesthetics and activity patterns in a synaptic network. Finally, the results may account for observed differences among agents in what have been considered side effects, but which may be an integral part of their anesthetic action.