Signal transduction pathways involved in the acute potentiation of NMDA responses by 1S,3R‐ACPD in rat hippocampal slices

A grease‐gap recording technique has been used to investigate the mechanisms underlying the acute potentiation of N‐methyl‐d‐aspartate (NMDA) responses by aminocyclopentane‐1S,3R‐dicarboxylic acid (1S,3R‐ACPD) in area CA1 of rat hippocampal slices. 1S,3R‐ACPD (10 μm), but not 1R,3S‐ ACPD (10 μm), potentiated submaximal responses to NMDA (dose‐ratio of 0.81 ± 0.02 (mean ± s.e.mean); n = 55), but not to α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA), in a readily reversible manner. Potentiation also occurred in slices treated with 0.2 μm tetrodotoxin, and in slices perfused with Mg²⁺‐free medium. 1S,3R‐ACPD‐induced potentiation was unaffected by the protein kinase inhibitors K‐252b (0.1 μm) and staurosporine (1 μm) and the intracellular Ca²⁺ store depletor, thapsigargin (10 μm). Coapplication of staurosporine and thapsigargin was also without effect. 1S,3R‐ACPD‐induced potentiation was unaffected by inhibitors of arachidonic acid formation, bromophenacyl bromide (50 μm) and RG80267 (100 μm). Arachidonic acid (10–50 μm) depressed reversibly NMDA‐induced responses. The potentiation was unaffected by 8‐bromo cyclic AMP (500 μm) or the PKA inhibitor Rp‐adenosine 3,5‐cyclic monophosphothioate triethylamine (Rp‐cAMPS; 50 μm). 1S,3R‐ACPD‐induced potentiation was abolished in slices perfused with Ca²⁺‐free medium. The potentiation was also blocked by phorbol‐12,13‐diacetate (1 μm), in a staurosporine‐sensitive manner. It is concluded that the potentiation of NMDA responses by 1S,3R‐ACPD is not mediated by protein kinase A or C., by release of Ca²⁺ from intracellular stores or by arachidonic acid. It involves a Ca²⁺‐sensitive process and is negatively regulated by protein kinase C. 1993 British Pharmacological Society