The problem with autoreceptors.

Abstract

There are numerous problems with the concept that antagonists enhance transmitter release by blockade of feedback. It was shown that antagonist enhancement of transmitter release does not correlate satisfactorily with the intensity of stimulation or with other indices of biophase transmitter concentration. Wide variations were shown to exist between antagonists in the amount of enhancement of release they induce. Also, antagonists enhance transmitter release or the effector response with a single stimulation pulse, a condition under which no feedback is possible. A study of agonist/antagonist relationships indicates different sites of action, and it was determined that the antagonist effect has negligible or minimal latency and that enhancement by antagonists is maximal under minimal condition of stimulation. Antagonists were shown to enhance release by a direct action, not by passive occupancy of agonist sites. Experiments were described in which acetylcholine and cold selectively antagonized antagonist but not agonist effects. Further, experiments with pulse duration shifts and with veratridine pointed to a direct action of antagonists on Na+ (also Ca++?) channel gating mechanisms, which results in a shift in the voltage dependence of activation. If antagonists, in some particular instances, enhance release by blockade of sites involved in negative feedback this is likely lost or mired in their more prominent direct actions on neurosecretion--and these must be sorted out. The acceptance of the fact that antagonists act directly to alter transmitter release (and not only as passive occupiers of presynaptic receptors), as the present study shows, both in the central nervous system and in the periphery, opens a new area for future investigation, and may be exploitable for therapeutic purposes and to gain an enriched understanding of the mechanism of neurosecretion.