François P. Monnet

N-methyl-D-aspartate-induced neuronal activation is selectively modulated by σ receptors

Abstract The effects of two high-affinity σ ligands, DTG (1,3-di(2-tolyl)guanidine) and haloperidol, on the activation of dorsal hippocampus pyramidal neurons induced by microiontopheretic application of N-methyl-D-aspartate (NMDA) were assessed electrophysiologically. Low doses of DTG (0.5–3 μg/kg i.v.) potentiated the NMDA response. This effect of DTG was blocked by haloperidol (10 μg/kg i.v.), but not by spiperone, a potent dopamine antagonist with low affinity for σ receptors. These results suggest that σ receptors modulate the NMDA-induced neuronal activation.

The effects of sigma ligands and of neuropeptide Y on N-methyl-D-aspartate-induced neuronal activation of CA3 dorsal hippocampus neurones are differentially affected by pertussin toxin.

1 The in vivo effects of the high affinity sigma ligands 1,3‐di(2‐tolyl)guanidine (DTG), (+)‐N‐cyclopropylmethyl‐N‐methyl‐1,4‐diphenyl‐1‐ethyl‐but‐3‐en‐1‐ylamine hydrochloride (JO‐1784), (+)‐pentazocine and haloperidol, as well as of those of neuropeptide Y (NPY), on N‐methyl‐d‐aspartate (NMDA)‐ and quisqualate (Quis)‐induced neuronal activations of CA3 pyramidal neurones were assessed, using extracellular unitary recording, in control rats and in rats pretreated with a local injection of pertussis toxin (PTX), to evaluate the possible involvement of Gi/o proteins in mediating the potentiation of the neuronal response to NMDA by the activation of sigma receptors in the dorsal hippocampus. 2 Microiontophoretic applications as well as intravenous injections of (+)‐pentazocine potentiated selectively the NMDA response in control rats as well as in PTX‐pretreated animals. In contrast, the PTX pretreatment abolished the potentiation of the NMDA response by DTG, JO‐1784 and NPY. Moreover, microiontophoretic applications of DTG induced a reduction of NMDA‐induced neuronal activation. Neither in control nor in PTX‐treated rats, did the sigma ligands and NPY have any effect on Quis‐induced neuronal response. 3 In PTX‐treated rats, the potentiation of the NMDA response induced by (+)‐pentazocine was suppressed by haloperidol, whereas the reduction of the NMDA response by DTG was not affected by haloperidol. 4 This study provides the first in vivo functional evidence that sigma ligands and NPY modulate the NMDA response by acting on distinct receptors, differentiated by their PTX sensitivity.

Neuropeptide Y selectively potentiates N-methyl-D-aspartate-induced neuronal activation.

The present experiments were undertaken to investigate in vivo the effects of NPY on the activation of rat CA 3 dorsal hippocampus pyramidal neurons by microiontophoretic applications of NMDA, quisqualate and kainate

Differential effects of sigma ligands on the N-methyl-d-aspartate response in the CA1 and CA3 regions of the dorsal hippocampus: Effect of Mossy fiber lesioning

In the CA3 region of rat dorsal hippocampus, several sigma ligands, such as 1,3-di(2-tolyl)guanidine (DTG), (+)-pentazocine and (+)-N-cyclopropylmethyl-N-methyl-1, 4-diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride (JO-1784), administered intravenously at low doses, potentiate selectively the pyramidal neuron firing activity induced by microiontophoretic applications of N-methyl-D-aspartate, without affecting those induced by quisqualate, kainate or acetylcholine. A similar potentiation of the N-methyl-D-aspartate response has also been found with microiontophoretic applications of neuropeptide Y, an effect exerted via delta receptors. The present experiments were carried out to determine the effects of these sigma ligands and of neuropeptide Y; in the CA1 and CA3 regions following unilateral destruction by a local injection of colchicine of the mossy fiber system, which is a major afference to CA3 pyramidal neurons. In the CA1 region, DTG, JO-1784 and neuropeptide Y did not potentiate the activation induced by microiontophoretic applications of N-methyl-D-aspartate. However, (+)-pentazocine potentiated the N-methyl-D-aspartate response, similarly to its effect in the CA3 region on the intact side. In the CA3 region, on the intact side, (+)-pentazocine, DTG, JO-1784 and neuropeptide Y induced a selective potentiation of N-methyl-D-aspartate-induced activation, in keeping with previous reports. On the lesioned side, the effect of (+)-pentazocine on the N-methyl-D-aspartate response was still present, but those of DTG, JO-1784 and neuropeptide Y were abolished. These results suggest that (+)-pentazocine, on the one hand, and DTG, JO-1784 and neuropeptide Y, on the other, are not acting on the same subtype of sigma receptors. Since (+)-pentazocine, JO-1784 and neuropeptide Y have been suggested to act on the sigma 1 subtype of receptors, these data suggest the existence of two subtypes of sigma 1 receptors. They also suggest that the receptors on which DTG, JO-1784 and neuropeptide Y are acting are located on the mossy fiber terminals in the CA3 region and are absent in the CA1 region.

In Vivo Modulation of Sigma Receptor Sites by Calcitonin Gene-related Peptide in the Mouse and Rat Hippocampal Formation: Radioligand Binding and Electrophysiological Studies

Possible interactions between sigma (σ) receptor sites and calcitonin gene‐related peptides (CGRP) were investigated using receptor subtype‐related analogues and fragments in in vivo [3H](+)SKF 10 047/σ binding in the hippocampus, and electrophysiological recording of the N‐methyl‐D‐aspartate (NMDA)‐induced activation of CA3 pyramidal neurons, two well‐established σ assays. In both paradigms, CGRP and the agonist [Cys(ACM)2,7]hCGRPα modulated σ systems. In vivo binding experiments demonstrated that CGRP and [Cys(ACM)2,7]hCGRPα inhibited 25–40% of specific [3H](+)SKF 10 047 labelling in the mouse hippocampal formation while the purported antagonist hCGRP8–37 was inactive. The specificity of this modulation was demonstrated further by the lack of effect of other vasoactive peptides, including the atrial natriuretic peptide, substance P, and its N‐terminal fragment, substance P1–7. In the CA3 subfield of the rat dorsal hippocampus, hCGRPα decreased (up to 61%) the NMDA‐induced activation of the pyramidal neurons. Conversely, the linear analogue [Cys(ACM)2,7]hCGRPα enhanced (by 85%) the NMDA‐induced activation of CA3 pyramidal neurons, while the antagonistic fragment hCGRP8–37 had no effect. Haloperidol, a high‐affinity σ receptor ligand, inhibited by 90% the in vivo [3H](+)SKF 10 047 labelling, and prevented the modulation of the NMDA‐induced activation by hCGRPα and [Cys(ACM)2,7]hCGRPα. It thus appears that CGRP can modulate σ‐related systems in the hippocampal formation.

Steroidal Modulation of Sigma Receptor Function

The term “sigma” (σ) receptor was coined by Martin et al. (1), who identified the unique psychotomimetic effects of N-allylnormetazocine (SKF-10047), a prototypic benzomorphan, and has initially been designated as a subtype of opioid receptors. σ ligands belong to diverse structural classes including (+)-benzomorphans ([+]-SKF 10047, [+]-pentazocine), morphinans (dextrometorphan), guanidines (1,3-di-o-tolylguanidine or DTG), phenothiazines (perphenazine, chlorpromazine), butyrophenones (haloperidol), tricyclic antidepressants (imipramine), monoamine oxydase inhibitors (clorgyline), serotonin uptake inhibitors (sertraline), piperazines (α-[4-fluorophenyl]-4[5-fluoro-2-pyrimidinyl]-1-piperazine butanol or BMY-14802), phenylpiperidines ([+]3-[3-hydroxyphenyl]-N-[1-propyl]piperidine or [+]-3PPP), cytochrome P-450 inhibitors (proadifen), anticonvulsants (phenytoin), addictive drugs (cocaine, amphetamine), polyamines (ifenprodil), and certain steroids (progesterone [PROG], testosterone) (for reviews, see refs. 2 and 3).