Blockade by sigma site ligands of N‐methyl‐D‐aspartate‐evoked responses in rat and mouse cultured hippocampal pyramidal neurones

The effects of a range of structurally‐dissimilar compounds which possess affinity for σ binding sites were examined on the responses of cultured hippocampal pyramidal neurones to the excitatory amino acid analogues N‐methyl‐D‐aspartate (NMDA), kainate and (RS)‐α‐ammo‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA). In mouse hippocampal neurones under whole‐cell voltage‐clamp, the compounds tested reversibly attenuated NMDA‐, but not kainate‐ or AMPA‐, evoked currents with a rank order potency (IC₅₀ values in μm): ifenprodil (0.8)>(+)‐N‐allylnormetazocine (1.1)>dextromethorphan (1.8) = haloperidol (1.9)>(+)‐pentazocine (7.2)>1S, 2R‐(−)−cis‐N‐methyl‐N‐[2‐(3, 4‐dichlorophenyl) ethyl]‐2‐(1‐pyrrolidinyl)cyclohexylamine (17) = rimcazole (18)>1,3‐di(2‐tolyl)guanidine (37)>opipramol (96)>caramiphen (110)=carbetapentane (112)> >(+)‐3‐(3‐hydroxyphenyl)‐N‐(1‐propyl)piperidine (485). The attenuation of NMDA‐evoked responses was not mediated through interactions with the agonist, glycine (except haloperidol) or polyamine (except ifenprodil) binding sites on the NMDA receptor‐channel complex but, in the light of the voltage‐ and, in some cases, use‐dependent nature of their antagonism, an interaction with the ion channel appears to be a likely mechanism of action for many of the compounds. Micromolar concentrations of selected σ site ligands also reduced NMDA‐evoked rises in intracellular free calcium concentration in Fura‐2‐loaded cultured hippocampal neurones of the rat with the same rank order potency as observed in the electrophysiological studies. The data indicate that, at micromolar concentrations, the σ site ligands tested act as NMDA receptor antagonists, an action which does not appear to be mediated by high‐affinity σ binding site(s). The functional effects of micromolar concentrations of σ site ligands cannot, therefore, be attributed exclusively to interactions with high‐affinity σ binding sites. 1995 British Pharmacological Society