Decrements in per pulse release of norepinephrine, antagonist potentiation of release and presynaptic receptor theory.

In recent decades the theory that amine transmitter release at nerve terminals is routinely regulated through negative feedback systems sensing and responding to the instantaneous perineuronal concentration of previously liberated transmitter has assumed pre-eminence. However, observations indicate a major drop off in per pulse transmitter release when only two or four stimulation pulses are administered, reflecting the unexpectedly prompt operation of feedback inhibition. We explored this quandary in our understanding of control of transmitter release by axonal depolarization versus terminal feedback using isotopic norepinephrine and in vitro slices of rabbit hippocampus. A technique of continuous collection of superfusate over a 30min cycle of stimulation utilizing a wide range of intervals between individual stimulation pulses was used. Following simulation with single pulses even 60s apart or pseudo one pulses 150s apart a marked decline in per pulse release was noted. The deficits in per pulse release were not related to the number of pulse delivered at any time over the course of a 30min stimulation period. The pulse decrements were independent of the activity of neuronal uptake and of superfusion flow rate or even individual pulse duration and frequency. Presynaptic receptor antagonists, potentiated efflux near maximally with the second of only two pulses. Potentiations were independent of pulse number, pulse duration, or frequency. No linkage between perineuronal transmitter concentrations and the antagonist potentiation of release was found. However, the decrements in per pulse release with multiple pulses and the potentiation by alpha presynaptic antagonists occurred under the same test conditions. We conclude that the pulse deficit can be looked at as largely attributable to an enhanced efflux with delivery of the first pulse in a train of pulses, rather then to a pattern of progressively declining efflux linked to increasing extracellular transmitter levels as frequency and pulse number increase.