DIFFERENTIATION OF SIGMA-LIGAND-ACTIVATED RECEPTOR SUBTYPES THAT MODULATE NMDA-EVOKED [H-3] NORADRENALINE RELEASE IN RAT HIPPOCAMPAL SLICES

1 It is now widely accepted that there are two classes of sigma (sigma ) binding sites, denoted sigma(1) and sigma(2), and recently sigma(3) subtype has been proposed. Selective sigma(1) and sigma(2) receptor ag onists are known to modulate the neuronal response to N-methyl-D-aspar tate (NMDA) in vivo and in vitro. To identify the site of action of a series of recently synthesised high affinity sigma ligands, the presen t in vitro series of experiments was carried out on NMDA-evoked [H-3]- noradrenaline ([H-3]-NA) overflow from preloaded hippocampal slices of the rat. 2 The ligands N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidi nyl) cyclohexylamine (BD-737) and (+)-pentazocine, considered as the p rototypic sigma(1) agonists, potentiated the NMDA response from 10 nM to 100 nM. This potentiation faded between 100 nM and 1 mu M ligand co ncentrations. On the other hand, 1,3-di(2-tolyl)guanidine (DTG), a mix ed sigma(1)/sigma(2) agonist, at concentrations greater than 100 nM in hibited the NMDA-evoked [H-3]-NA release. Spiperone, considered as act ive on putative sigma(3) receptors, was without effect on the NMDA res ponse, or on the potentiating effect of BD-737. 3 The high affinity si gma antagonists haloperidol and 1[2-(3,4-dichlorophenyl)ethyl]-4-methy lpiperazine (BD-1063), inactive by themselves on the NMDA-induced resp onse, at concentrations above 30 nM totally prevented the potentiating effect of (+)-pentazocine (100 nM) as well as the inhibitory effect o f DTG (300 nM) on NMDA-evoked [H-3]-NA release. Whereas haloperidol an d BD-1063, at concentrations <1 mu M, were inactive on the potentiatin g effect of BD-737 (100 nM). 4 alpha-4-fluorophenyl-4-hydroxy-1-piperi dinebutanol (reduced haloperidol), henyl)ethyl]-N-methyl-2-(1-pyrrolid inyl)ethylamine (BD-1008), inactive by themselves on the NMDA-evoked [ H-3]-NA release, failed to reverse the effects of (+)-pentazocine and DTG, but at concentrations of 30 nM to 1 mu M antagonised the BD-737-i nduced potentiation of the NMDA response. Conversely, -2-[4-methoxy-3- (2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100) blocked the effects of (+)-pentazocine as well as those of BD-737, but not tho se of DTG. 5 The present results provide in vitro functional evidence for a sigma receptor type preferentially sensitive to BD-737, reduced haloperidol, BD-1008 and also to NE-100, that differs from the already identified sigma(1), sigma(2) and sigma(3) sites.