Is excitation by enkephalins of hippocampal neurones in the rat due to presynaptic facilitation or to disinhibition?

1. Extracellular recordings of postsynaptic potentials (field potentials), population spikes or unitary action potentials and intracellular records of excitatory and inhibitory postsynaptic potentials were obtained from neurons in superfused slices of rat hippocampus, to study the mechanism of the excitatory effect of enkephalins. 2. Most experiments were carried out with a synthetic, stable enkephalin analogue (FK 33-824) administered either by perfusion or by local administration (ionophoresis or pressure application from micropipettes). Comparisons were made when appropriate with metenkephalin, morphine, 4-aminopyridine and bicuculline. 3. The enkephalins caused a small increase in extracellular recordings of e.p.s.p.s and a more marked increase in the amplitude and frequency of population spikes. The effect of 4-aminopyridine on the extracellular e.p.s.p. was more marked than that of enkephalins, indicating that the enkephalins may have an additional effect upon regenerative spike mechanisms in the dendrites, which is not possessed by 4-aminopyridine. The actions of the enkephalins and morphine were blocked by naloxone, which did not block the action of bicuculline or 4-aminopyridine. 4. The increase in extracellularly recorded e.p.s.p. was shown to be due to a marked increase in the e.p.s.p. amplitude recorded intracellularly in CA1 and CA3 neurones and dentate granule cells. The augmented e.p.s.p.s evoked more action potentials. 5. The increase in e.p.s.p. amplitude was not accompanied by any marked change in membrane potential or resistance. 6. The inhibition of background firing by appropriate stimulation and recorded as peristimulus histograms was not reduced by FK 33-824. There was a slight prolongation. 7. Intracellularly recorded i.p.s.p.s were not blocked by FK 33-824. There was a prolongation of the i.p.s.p.s and an apparent increase in latency due to the unmasking and prolongation of e.p.s.p.s. 8. Dendritic excitability, as tested with ionophoresis of DL-homocysteic acid locally to the dendrites was unaffected by FK 33-824. 9. It is concluded that the increase in e.p.s.p.s produced by enkephalins can be explained by an increased release of excitatory transmitter, as occurs with 4-aminopyridine.