Presynaptic Uptake Blockade

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) lightevoked and antidromically stimulated lateral inhibition is enhanced during superfusion of low (1-5 AM) concentrations of LSD and suppressed by higher (5-20 AM) 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 AM). 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.