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G Debonnel

Publications and source records attributed to G Debonnel.

51 records · Page 3Linked to original sources
PubMed1992

Neuropeptide Y potentiates the N-methyl-D-aspartate response in the CA3 dorsal hippocampus. II. Involvement of a subtype of sigma receptor.

In an in vivo electrophysiological paradigm, we have shown in the companion paper that neuropeptide Y (NPY) potentiates N-methyl-D-aspartate (NMDA)-induced neuronal activation via a non-Y1, non-Y2, non-Y3 receptor subtype, in the rat CA3 dorsal hippocampus. Because sigma ligands have also been shown to potentiate NMDA-induced activation and because NPY and peptide YY have been reported to have high affinity for sigma binding sites, the present study was carried out to assess the possibility that the modulation of the NMDA response by NPY might be mediated by a sigma receptor. In the same electrophysiological paradigm, low doses of haloperidol and alpha-(4-fluorophenyl)-4-(5-fluoro-2- pyrimidinyl)-1-piperazine butanol, two antagonists of sigma receptors, reversed the potentiation of the NMDA response induced by NPY, [Leu31, Pro34]NPY or NPY13-36 and blocked the suppressant effect of desamido-NPY on the NMDA response. In contrast, spiperone, which has low affinity for sigma sites, was ineffective in suppressing NPY, as well as desamido-NPY-induced modulation of the NMDA response. In our model, peptide YY, which acts as a NPY antagonist by suppressing the potentiation of the NMDA response induced by NPY, also antagonized the potentiation of the NMDA response induced by the administration of low doses of di(2-tolyl)guanidine and (+)N-cyclopropyl-methyl-N-,methyl-1,4- diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride, two high-affinity sigma agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

In vivo electrophysiological evidence for a selective modulation of N-methyl-D-aspartate-induced neuronal activation in rat CA3 dorsal hippocampus by sigma ligands.

We have reported previously that the high affinity sigma ligand DTG potentiates N-methyl-D-aspartate (NMDA)-induced excitation of pyramidal neurons in the CA3 region of rat dorsal hippocampus. In the present experiments, several selective high affinity sigma ligands have been tested. At low doses, the sigma ligands DTG, JO-1784, JO-1783, AdipG, DnBG, APDQ, BD-737 and (+)-pentazocine dose-dependently enhanced selectively NMDA-induced activation of CA3 pyramidal neurons (with the exception of BD-737 which also presented a late potentiation of the neuronal response to quisqualate). However, at high doses, DTG selectively suppressed the potentiation induced by a low dose of DTG and reduced the NMDA response below base line, presumably due to its low affinity for phencyclidine sites. 2-APHB, a structural analog of DTG devoid of affinity for sigma sites, had no effect on the NMDA response. At low doses that did not by themselves affect the NMDA response, haloperidol, (+)-3-PPP and BMY-14802 reversed DTG- and JO-1784-induced potentiations of the NMDA response. Spiperone, a butyrophenone with very low affinity for sigma sites, was ineffective in this paradigm. The present data suggest that an important function of sigma receptors could be to modulate the NMDA response in this brain region.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1990

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

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

Animals↗
PubMed1990

Neurotoxic effect of domoic acid: mediation by kainate receptor electrophysiological studies in the rat.

Domoic acid, an excitatory amino acid structurally related to kainic acid, has recently been identified as being responsible for the severe intoxication presented, in 1987, by more than 150 people having eaten mussels grown in Prince Edward Island. The present in vivo electrophysiological studies, using unitary extracellular recordings obtained from pyramidal neurons of the CA1 and of the CA3 regions of the rat dorsal hippocampus, were undertaken to study the effect of kainic acid and domoic acid applied by microiontophoresis and compare their potencies to that of agonists of the 2 other subtypes of glutamatergic receptors or neuropeptides. The activation induced by domoic acid and kainate was more than 20-fold more potent in the CA3 than in the CA1 region, whereas no such regional difference could be detected with all the other substances tested. In the CA1 as well as in the CA3 region, domoic acid was about 3 times more potent than kainate. A selective lesion of the mossy fibre system originating from the dentate gyrus and projecting to the CA3 region of the dorsal hippocampus, drastically reduced the excitatory effect of kainic acid and domoic acid in this later area, without affecting the response to the other substances tested. Several class of pharmacological agents were studied in an attempt to find an antagonist of kainate and domoic acid. Only benzodiazepines could selectively suppress the neuronal activation induced by kainate, however, with a lower efficacy in the CA3 than in the CA1 region. These results demonstrate that domoic acid is a potent agonist of kainate receptors and that, in the CA3 region, it might produce its neurotoxic effects through activation of kainate receptors located on mossy fibre terminals. Finally, in the event of a new wave of intoxication, our results suggest that a rapid treatment with high doses of benzodiazepines could possibly prevent the important and irreversible hippocampal damage.

Acetylcholine↗
PubMed1990

Effects of long-term haloperidol treatment on the responsiveness of accumbens neurons to cholecystokinin and dopamine: electrophysiological and radioligand binding studies in the rat.

Cholecystokinin (CCK) and dopamine (DA) coexist in a subpopulation of neurons of the ventral tegmental area projecting to the nucleus accumbens. The present experiments were undertaken to determine the effect of acute and long-term administration of haloperidol on the responsiveness of accumbens neurons to microiontophoretic applications of the sulfated cholecystokinin octapeptide (CCK-8S), kainate (KA), and DA and on the density of CCK, D1, and D2 receptors determined by radioautography. Acute administration of haloperidol (1 mg/kg, i.v.) did not modify the neuronal responsiveness to DA and KA but increased that to CCK-8S. Long-term treatment with haloperidol decanoate (4 mg/kg/week, i.m., for 3-5 weeks) induced a marked increase in the responsiveness to CCK-8S, without noticeable change of that to DA and KA. After a 5 week treatment, significant increases in the amounts of CCK and D2 binding were found in the nucleus accumbens, whereas D1 binding parameters remained unchanged. Since long-term haloperidol treatment results in a depolarization inactivation of A10 dopaminergic neurons, these results suggest that, despite the reduced firing activity of mesolimbic dopaminergic neurons induced by the long-term haloperidol treatment, dopamine is still released in an amount sufficient to maintain a normal neuronal responsiveness of postsynaptic accumbens neurons to DA, whereas the release of CCK is possibly decreased to a greater extent, resulting in an enhanced responsiveness of the neurons to this peptide.

Animals↗
PubMed1990

Hippocampal mossy fiber denervation induces a supersensitivity to cholecystokinin of CA3 pyramidal neurons in the guinea pig but not in the rat.

Immunohistochemical studies have revealed the presence of cholecystokinin (CCK) in the guinea pig hippocampal mossy fiber projections, but this peptide appears to be absent in this system in the rat. However, in both species the mossy fiber system shows a strong opiate-like immunoreactivity. The present electrophysiological studies were undertaken to determine, in the two species, the effect of a unilateral colchicine-induced mossy fiber denervation, by comparing the responsiveness of target pyramidal neurons to Met-enkephalin, CCK and the nonpeptidic excitatory agents acetylcholine, kainate, quisqualate and ibotenate, on the intact and on the lesioned side. In both species, the colchicine lesion induced an increased responsiveness to Metenkephalin in the CA1 area, whereas no change was found in the neuronal responsiveness to the other excitatory agents tested. In the rat, the responsiveness of CA3 pyramidal neurons to kainate was reduced by 90%, those to the other excitatory agents were unchanged. In the guinea pig, the mossy fiber denervation induced a 10-fold increase of the responsiveness of CA3 pyramidal neurons to CCK, but did not modify their response to Met-enkephalin, kainate, quisqualate, ibotenate and acetylcholine. These results are consistent with the lack of CCK-like immunoreactivity in the mossy fiber projection to the CA3 region of the rat and with previous reports suggesting the presynaptic location of kainate receptors in this region. They provide novel evidence for the physiological role of CCK in the hippocampal mossy fiber projection in the guinea pig.

Animals↗
PubMed1989

Domoic acid, the alleged "mussel toxin," might produce its neurotoxic effect through kainate receptor activation: an electrophysiological study in the dorsal hippocampus.

Domoic acid, an excitatory amino acid structurally related to kainate, was recently identified as being presumably responsible for the recent severe intoxication presented by more than 100 people having eaten mussels grown in Prince Edward Island (Canada). The amino acid kainate has been shown to be highly neurotoxic to the hippocampus, which is the most sensitive structure in the central nervous system. The present in vivo electrophysiological studies were undertaken to determine if domoic acid exerts its neurotoxic effect via kainate receptor activation. Unitary extracellular recordings were obtained from pyramidal neurons of the CA1 and the CA3 regions of the rat dorsal hippocampus. The excitatory effect of domoic acid applied by microiontophoresis was compared with that of agonists of the three subtypes of glutamatergic receptors: kainate, quisqualate, and N-methyl-D-aspartate. In CA1, the activation induced by domoic acid was about threefold greater than that induced by kainate; identical concentrations and similar currents were used. In CA3, domoic acid was also three times more potent than kainate. However, the most striking finding was that domoic acid, similar to kainate, was more than 20-fold more potent in the CA3 than in the CA1 region, whereas no such regional difference could be detected with quisqualate and N-methyl-D-aspartate. As the differential regional response of CA1 and CA3 pyramidal neurons to kainate is attributable to the extremely high density of kainate receptors in the CA3 region, these results provide the first electrophysiological evidence that domoic acid may produce its neurotoxic effects through kainate receptor activation.

Action Potentials↗
PubMed1989

Reduced neuroexcitatory effect of domoic acid following mossy fiber denervation of the rat dorsal hippocampus: further evidence that toxicity of domoic acid involves kainate receptor activation.

Domoic acid, an excitatory amino acid structurally related to kainic acid, has been shown to be responsible for the severe intoxication presented, in 1987, by more than one hundred and fifty people having eaten mussels grown in Prince Edward Island (Canada). Unitary extracellular recordings were obtained from pyramidal neurons of the CA3 region of the rat dorsal hippocampus. The excitatory effects of microiontophoretic applications of domoic acid and of the agonists of the two other subtypes of glutamatergic receptors, quisqualate and N-methyl-D-aspartate, were compared on intact and colchicine-lesioned sides. Similar to what has been previously found for kainate, the colchicine lesion of the mossy fiber projections induced a 95% decrease of the neuronal responsiveness to domoic acid, whereas the effect of quisqualate was unchanged and that of N-methyl-D-aspartate was only slightly decreased. These results provide further electrophysiological evidence that domoic acid is a potent agonist of kainate receptors and that it may produce its neuroexcitatory and neurotoxic effects, in the hippocampal CA3 region, through activation of kainate receptors located on the mossy fiber terminals.

Animals↗
PubMed1988

Increased neuronal responsiveness to cholecystokinin and dopamine induced by lesioning mesolimbic dopaminergic neurons: an electrophysiological study in the rat.

In the rat, cholecystokinin (CCK) and dopamine (DA) coexist in a subpopulation of neurons of the ventral tegmental area (VTA) projecting to the nucleus accumbens. However, in the dorsal hippocampus, dopaminergic projections from the VTA do not contain CCK, the latter neurotransmitter being mainly localized in intrinsic hippocampal neurons. The present experiments were undertaken in order to compare the interactions of CCK and DA and the effects of lesioning VTA dopaminergic neurons in a region where these neurotransmitters coexist and in one where they do not. The effects of microiontophoretic applications of CCK, kainate (KA), glutamate (GLU) and DA were determined in control rats and in rats pretreated with a local injection of 6-hydroxydopamine (6-OHDA) in the VTA. In the nucleus accumbens and in the hippocampus of intact rats, DA exerted a similar depressant effect whether applied during CCK-, KA- or GLU-induced activations. The 6-OHDA lesion enhanced responsiveness of accumbens neurons to KA, GLU and CCK (the responsiveness to this latter peptide being increased by more than 15-fold) and the depressant effect of DA when applied during neuronal activation by KA or GLU but not when the same neurons were activated with CCK. In the dorsal hippocampus, the 6-OHDA lesion enhanced neuronal responsiveness to KA and DA in the CA1, but not in the CA3 region, whereas the responsiveness to CCK remained unchanged in both regions. These results suggest a physiological role for the coexistence of CCK and DA in the nucleus accumbens. The induction of a supersensitivity to DA in the CA1, but not in the CA3, region of the dorsal hippocampus following a VTA lesion is consistent with the regional distribution of the dopaminergic innervation in this structure.

Action Potentials↗
PubMed1987

Pipequaline acts as a partial agonist of benzodiazepine receptors: an electrophysiological study in the hippocampus of the rat.

Pipequaline (PK 8165), a quinoline derivative and a ligand of the benzodiazepine binding site, is a clinically-effective anxiolytic, which is devoid of sedative and anticonvulsant properties. Several biochemical and behavioral studies have indicated that this molecule shares some properties with both agonists and antagonists of benzodiazepine receptors. The present in vivo electrophysiological studies were undertaken to determine the effects of microiontophoretic applications and of intravenous injections of pipequaline on hippocampal pyramidal neurons, activated by kainate, glutamate or acetylcholine and to characterize the effects of pipequaline on the action of benzodiazepines. Intravenously administered pipequaline exerted a partial suppression of activations by kainate, glutamate and acetylcholine. Microiontophoretic applications of pipequaline reduced the neuronal activation by kainate. This effect was blocked by RO 15-1788. In small intravenous doses, pipequaline potentiated the effect of microiontophoretically-applied flurazepam whereas, in larger doses, it suppressed the effects of microiontophoretically-applied flurazepam and of intravenously administered lorazepam on kainate-induced activation. Similarly, microiontophoretic applications of pipequaline blocked the suppressant effect of microiontophoretically-applied flurazepam on kainate-induced activation. These results constitute further evidence that the selective anxiolytic activity of pipequaline might be ascribed to its partial agonistic action on benzodiazepine receptors.

Animals↗
PubMed1984

Cholecystokinin-octapeptide in chronic schizophrenia: a double-blind placebo-controlled study.

Antipsychotic properties of cholecystokinin have been suggested both in laboratory studies and in some open clinical trials, mainly in patients suffering from chronic schizophrenia. Eighteen patients (14 males, 4 females) meeting Research Diagnostic Criteria for schizophrenia had been receiving neuroleptics at a dosage that had not changed for 3 months, and to which the patients were at best only partially responsive. The patients were randomized into groups that received weekly intravenous injections of 10 micrograms of CCK-8 or normal saline over 8 weeks. Neuroleptic medication was unchanged for the study. Baseline and weekly assessments were carried out using the Brief Psychiatric Rating Scale (BPRS) and the Schizophrenia Subscale of the Present State Examination (SS-PSE). Analysis of covariance revealed significant differences between CCK-8 and placebo over the study period on the Thought Disturbance Factor and Total Score of the BPRS, and on the Nuclear Syndrome, Total Delusion Factor, and Total Score of the SS-PSE. No important side effects were noted. It is concluded that CCK-8 has definite antipsychotic properties in patients with chronic schizophrenia. Clinical trials in neuroleptic-free patients are warranted.

Animals↗