Differentiation of sigma ligand-activated receptor subtypes that modulate NMDA-evoked [3H]-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 agonists are known to modulate the neuronal response to N-methyl-D-aspartate (NMDA) in vivo and in vitro. To identify the site of action of a series of recently synthesised high affinity sigma ligands, the present in vitro series of experiments was carried out on NMDA-evoked [3H]-noradrenaline ([3H]-NA) overflow from preloaded hippocampal slices of the rat. 2. The ligands (+)-cis-N-methyl-N-[2,(3,4-dichlorophenyl) ethyl]-2-(1-pyrrolidinyl) cyclohexylamine (BD-737) and (+)-pentazocine, considered as the prototypic sigma(1) agonists, potentiated the NMDA response from 10 nM to 100 nM. This potentiation faded between 100 nM and 1 microM ligand concentrations. On the other hand, 1,3-di(2-tolyl)guanidine (DTG), a mixed sigma(1)/sigma(2) agonist, at concentrations greater than 100 nM inhibited the NMDA-evoked [3H]-NA release. Spiperone, considered as active on putative sigma(3) receptors, was without effect on the NMDA response, or on the potentiating effect of BD-737. 3. The high affinity sigma antagonists haloperidol and 1[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine (BD-1063), inactive by themselves on the NMDA-induced response, at concentrations above 30 nM totally prevented the potentiating effect of (+)-pentazocine (100 nM) as well as the inhibitory effect of DTG (300 nM) on NMDA-evoked [3H]-NA release. Whereas haloperidol and BD-1063, at concentrations < 1 microM, were inactive on the potentiating effect of BD-737 (100 nM). 4. 4-(4-Chlorophenyl)-alpha-4-fluorophenyl-4-hydroxy-1-piperidinebutanol (reduced haloperidol), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (BD-1008), inactive by themselves on the NMDA-evoked [3H]-NA release, failed to reverse the effects of (+)-pentazocine and DTG, but at concentrations of 30 nM to 1 microM antagonised the BD-737-induced potentiation of the NMDA response. Conversely, N,N-dipropyl-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 those 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.