Kass L, Hartline P H, Adolph A R
J Gen Physiol. 1983 Aug;82(2):245-67. doi: 10.1085/jgp.82.2.245.
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.
我们研究了麦角酸二乙酰胺（LSD）对美洲鲎侧眼中假定的吲哚胺能性侧向抑制突触的作用。我们记录了偏心细胞的细胞外和细胞内电压反应，同时在存在LSD、血清素（5-羟色胺，5-HT）、氯米帕明或一种高镁离子和低钙离子浓度的灌流介质（其部分或完全阻断突触传递）的情况下，通过光照或对视神经的逆向刺激来产生抑制作用。我们发现：（a）在低浓度（1 - 5微摩尔）的LSD灌流期间，光诱发的和逆向刺激的侧向抑制增强，而在较高浓度（5 - 20微摩尔）时受到抑制；（b）通过将视网膜置于高镁离子和低钙离子的介质中，LSD的这些作用显著减弱；（c）极低浓度的氯米帕明（一种假定的血清素摄取阻断剂）似乎在偏心细胞放电率和侧向抑制方面都模拟了LSD的作用；（d）灌流的5-羟色胺在所有阈上浓度（0.1 - 25微摩尔）下都会抑制侧向抑制。这些结果表明，LSD的作用可能需要完整的抑制性递质释放和突触后反应机制，而血清素则发挥直接的突触后效应。我们提出LSD在侧向抑制突触处阻断递质的突触前摄取。LSD作用的浓度依赖性可以如下解释：低浓度部分限制递质再摄取，从而延长递质在突触间隙中的寿命，进而增加突触后抑制的幅度和持续时间。较高浓度会使更多的突触前摄取位点被阻断；这会导致递质在突触间隙中积累，由于突触后脱敏而导致突触的功能性阻断。作为一种替代方案，我们基于LSD对突触前自身受体的作用提出了一个假说。类似的假说可以解释LSD在哺乳动物大脑中作用的许多方面。
