Previous data from our group have shown that selective sigma ([sigma ]) ligands, e.g. JO-1784 [(+) N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-ylamine, hydrochloride] potentiated, whereas DTG [1,3-di(2-tolyl)guanidine] reduced, both concentration-dependently, the N-methyl-D-aspartate(NMDA)-evoked [ 3 H]norepinephrine ([ 3 H]NE) overflow from rat preloaded hippocampal slices. Haloperidol, which binds with high affinity to [sigma ] sites, but not spiperone, another butyrophenone devoid of such affinity, antagonized the effects of both JO-1784 and DTG (1). Otherwise, using an in vivo electrophysiological paradigm of unitary extracellular recordings of rat hippocampal pyramidal neurons, we have shown that, conversely to all other selective and high affinity [sigma ] ligands tested, BD-737 [(+)-cis-N-methyl-N-[2-(3,4-dichlorophenyl) ethyl]-2-(1-pyrrolidinyl) cyclohexylamine] potentiated both NMDA- and non-NMDA-induced neuronal excitability, suggesting that BD-737 may interact with an atypical [sigma ] receptor subtype.The present in vitro studies were thus undertaken to evaluate more precisely the putative involvement of atypical [sigma ] ligands in the modulation of the NMDA response, by using an already established model of release of [ 3 H]NE evoked by NMDA from preloaded rat hippocampal slices.Hippocampal slices from spayed Sprague-Dawley rats were incubated with 0.1 [mu ]mol/l [ 3 H]NE for 30 min and superfused continuously with Mg 2 + -free Krebs' solution containing one of the selective and high affinity a agonists DTG, (+)pentazocine or BD-737, in the presence or absence of haloperidol, reduced haloperidol or BD-1063 [1[2-(3,4-dichlorophenyl)ethyl]-4-methyl piperazine]. 40 min later, the [ 3 H]NE overflow was evoked by NMDA (200 [mu ]M). (+)Pentazocine and BD-737 potentiated the effect in a bell-shaped manner (between 10 nM and 1 [mu ]M), while DTG concentration-dependently (between 10 nM and 1 [mu ]M) reduced the NMDA response. Haloperidol and BD-1063, concentration-dependently (between 30 nM and 1 [mu ]M) suppressed both effects of (+)pentazocine and DTG, being much less effective in reducing BD-737-induced potentiation of NMDA-evoked [ 3 H]NE overflow. Conversely, reduced haloperidol reversed the effect of BD-737, without substantially affecting the effects of (+)pentazocine and DTG.The present results constitute the first functional evidence for the existence of [sigma ] receptors insensitive to haloperidol that also modulate the NMDA response.F.P.M. is recipient of a AHR Fellowship.