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Differentiation of σ ligand‐activated receptor subtypes that modulate NMDA‐evoked [ 3 H]‐noradrenaline release in rat hippocampal slices
Author(s) -
Monnet François P.,
Costa Brian R.,
Bowen Wayne D.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15678.x
Subject(s) - nmda receptor , hippocampal formation , neuroscience , ligand (biochemistry) , receptor , chemistry , hippocampus , pharmacology , biology , biochemistry
1 It is now widely accepted that there are two classes of sigma (σ) binding sites, denoted σ 1 and σ 2 , and recently σ 3 subtype has been proposed. Selective σ 1 and σ 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 σ ligands, the present in vitro series of experiments was carried out on NMDA‐evoked [ 3 H]‐noradrenaline ([ 3 H]‐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 σ 1 agonists, potentiated the NMDA response from 10 nM to 100 nM. This potentiation faded between 100 nM and 1 μ m ligand concentrations. On the other hand, 1,3‐di(2‐tolyl)guanidine (DTG), a mixed σ 1 /σ 2 agonist, at concentrations greater than 100 nM inhibited the NMDA‐evoked [ 3 H]‐NA release. Spiperone, considered as active on putative σ 3 receptors, was without effect on the NMDA response, or on the potentiating effect of BD‐737. 3 The high affinity σ 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 [ 3 H]‐NA release. Whereas haloperidol and BD‐1063, at concentrations < 1 μ m , were inactive on the potentiating effect of BD‐737 (100 nM). 4 4‐(4‐Chlorophenyl)‐α‐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 [ 3 H]‐NA release, failed to reverse the effects of (+)‐pentazocine and DTG, but at concentrations of 30 nM to 1 μ m 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 σ receptor type preferentially sensitive to BD‐737, reduced haloperidol, BD‐1008 and also to NE‐100, that differs from the already identified σ 1 , σ 2 and σ 3 sites.