NEUROPROTECTIVE SIGMA-LIGANDS ATTENUATE NMDA AND TRANS-ACPD-INDUCED CALCIUM SIGNALING IN RAT PRIMARY NEURONS

The effect of neuroprotective sigma ligands possessing a range of rela tive selectivity for sigma and phencyclidine (PCP) binding sites on N- methyl-D-aspartate (NMDA) and (+/-)-1-aminocyclopentane-trans-1,3-dica rboxylic acid (trans-ACPD)-stimulated calcium flux was studied in 12-1 5-day-old primary cultures of rat cortical neurons. In approximately 8 0% of the neurons tested, NMDA (80 mu M) caused a sustained increase i n intracellular calcium ([Ca2+](i)). With the exception of R-(+)-3-(3- hydroxyphenyl)-N-propylpiperidine hydrochloride ((+)-3-PPP) (previousl y shown not to be neuroprotective) all of the sigma ligands studied si gnificantly altered NMDA-induced calcium dynamics. The primary effect of dextromethorphan, (+)-pentazocine, (+)-cyclazocine, (+)-SKF10047, c arbetapentane, 1,3-di(2-tolyl) guanidine (DTG), and haloperidol was to shift the NMDA response from a sustained, to either a biphasic or a t ransient, calcium event. In contrast to NMDA, the primary response obs erved in 62% of the neurons treated with trans-ACPD (100 mu M) was a t ransient elevation in [Ca2+](i). Here, however, only the highly select ive neuroprotective sigma ligands (i.e., those lacking substantial PCP binding affinity) significantly decreased the number of transient res ponses elicited by trans-ACPD whereas the PCP-related sigma ligands su ch as dextromethorphan, (+)-SKF10047 and (+)-cyclazocine were ineffect ive. Unexpectedly, (+)-3-PPP potentiated trans-ACPD activity. These re sults demonstrating attenuating effects of sigma ligands on NMDA-stimu lated neuronal calcium responses agree with earlier studies using glut amate and KCl and identify a sigma receptor modulation of functional N MDA responsiveness. Furthermore, the ability of sigma ligands to atten uate NMDA-, trans-ACPD- and KCl-evoked neuronal calcium dynamics indic ates that the receptor mechanisms mediating sigma neuroprotection comp rise complex interactions involving ionotropic, metabotropic, and even voltage-gated calcium signaling processes.