The Journal of General Physiology, Vol 82, 245-267, Copyright © 1983 by The Rockefeller University Press
Presynaptic uptake blockade hypothesis for LSD action at the lateral inhibitory synapse in Limulus
L Kass, PH Hartline and AR Adolph
We investigated the action of LSD at the putative indoleaminergic lateral
inhibitory synapse in the lateral eye of Limulus polyphemus. We recorded
extracellular and intracellular voltage responses from eccentric cells
while producing inhibition either by light or by antidromic stimulation of
the optic nerve in the presence of LSD, serotonin (5-HT), chlorimipramine,
or a bathing medium whose high Mg++ and low Ca++ concentrations partially
or completely blocked synaptic transmission. We found (a) light-evoked and
antidromically stimulated lateral inhibition is enhanced during superfusion
of low (1-5 microM) concentrations of LSD and suppressed by higher (5-20
microM) concentrations; (b) these actions of LSD are markedly reduced by
bathing the retina in a medium high in Mg++ and low in Ca++; (c) very low
concentrations of chlorimipramine, a putative uptake blocker of serotonin,
appear to mimic actions of LSD both on eccentric cell firing rate and on
lateral inhibition; (d) superfused 5-HT depresses lateral inhibition at all
superthreshold concentrations (0.1-25 microM). These results suggest that
LSD's action may require an intact inhibitory transmitter release and
postsynaptic response mechanism, whereas serotonin exerts a direct
postsynaptic effect. We propose that LSD blocks presynaptic uptake of
transmitter at the lateral inhibitory synapse. The concentration dependence
of LSD's action can be accounted for as follows: low concentrations
partially restrict transmitter reuptake, thereby prolonging the lifetime of
the transmitter in the synaptic cleft and thus increasing the magnitude and
duration of postsynaptic inhibition. Higher concentrations cause more
presynaptic uptake sites to be blocked; this causes accumulation of
transmitter in the synaptic cleft, which causes a functional blockade of
the synapse because of postsynaptic desensitization. As an alternative, we
propose a hypothesis based on LSD action at presynaptic autoreceptors.
Similar hypotheses can account for many aspects of LSD's action in
mammalian brain.
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