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G Chapouthier

Publications and source records attributed to G Chapouthier.

At least 19 recordsLinked to original sources
PubMed1992

Cognitive enhancing properties of beta-CCM infused into the nucleus basalis magnocellularis of the rat.

Peripheral administration of various benzodiazepine derivatives or beta-carbolines (inverse agonists at benzodiazepine receptors), has been shown to affect memory. In this study, the effect of local infusion of a beta-carboline-methyl beta carboline-3-carboxylate (beta-CCM) into the nucleus basalis magnocellularis (NBM) of rats was examined in a two-trial recognition task. The results show that beta-CMM (3 micrograms/0.5 microliter) enhances recognition performance when injected both before or immediately after the acquisition trial. These effects appear to be mediated by a benzodiazepine (BZD) receptor since they were blocked by pretreatment with Ro 15-1788, a BZD receptor antagonist. This study supports the involvement of the NBM in cognitive processes, and demonstrates that these processes can be influenced by alteration of GABAergic neurotransmission.

Animals↗
PubMed1992

Recombinant congenic strains of mice from B10.D2 and DBA/2: their contribution to behavior genetic research and application to audiogenic seizures.

Recombinant congenic strains (RCS) represent a series of related strains, each of which carries a small fraction of the genome of one strain ("donor" strain) on the genetic background of another strain ("background" strain). Recombinant inbred strains (RIS) are commonly used to identify major gene segregation and linkage and associations between behavior and quantitative trait loci, whereas recombinant congenic strains (RCS) open other complementary leads. The variability in the reactivity of RCS to a trait is thus the expression of few minor-effect genes originating from the donor strain, because the probability that major genes are present in any one RCS is low. Unlike RIS in which minor-effect genes are often masked by major genes, RCS enable the effects of minor genes to be studied. With our method, for a given trait, an estimate can be made of the gene strength distribution as well as an estimate of the minimal number of genes involved having a certain strength.

Acoustic Stimulation↗
PubMed1991

Comparisons between patterns of convulsions induced by two beta-carbolines in 10 inbred strains of mice.

The beta-carbolines, methyl-beta-carboline-3-carboxylate (beta-CCM) and 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) are known to have pharmacological properties opposite to those of agonistic benzodiazepines. Convulsions induced by these drugs lead to differential patterns, such as clonus, myoclonic or tonic seizures. In 10 different inbred strains of mice we investigated whether the responsiveness to the two drugs was the same, irrespective of the pattern of convulsions. We found the same ranking in the responsiveness of the strains to both drugs in the case of myoclonic seizures. No such correlation could be found for clonus or tonic seizures. Our conclusion is that the same genetic factors determine myoclonic seizures, whereas a plurality of mechanisms underly the other patterns. Thus, myoclonic seizures seem to be the most appropriate index for evaluating the convulsant action of beta-carbolines in genetic experiments.

Animals↗
PubMed1991

Genetic difference in sensitivity to beta-carboline: evidence for the involvement of brain benzodiazepine receptors.

The convulsive effects of methyl beta-carboline-3-carboxylate (beta-CCM), a benzodiazepine receptor ligand, are different in two inbred strains of mice: BALB/cBy mice are more sensitive to beta-CCM than C57BL/6J mice. In the present article, we report the effects of [3H]flunitrazepam binding in these two strains, which suggest a possible explanation of the differences in their sensitivity to beta-CCM by the involvement of brain benzodiazepine receptors.

Animals↗
PubMed1991

Similar effects of a beta-carboline and of flumazenil in negatively and positively reinforced learning tasks in mice.

Methyl beta-carboline-3-carboxylate (beta-CCM) and flumazenil (Ro15-1788) are known to be respectively an inverse agonist and an antagonist of the central benzodiazepine-receptor. Surprisingly, these two drugs have shown a similar enhancing effect in a negatively reinforced multiple-trial brightness discrimination task in mice. Thus, to evaluate the role of anxiety in this task, the action of these two drugs were compared in the same learning task with a positive or a negative reinforcement. Mice were trained for sessions of ten trials per day for six consecutive days. The sessions during the first three days took place after administration of beta-CCM (0.3 mg/kg), flumazenil (15 mg/kg) or vehicles of these drugs. A negative reinforcement (electric foot-shock) was used in a first experiment, and a positive one (food reward) in a second experiment. Results showed that, whatever the reinforcement, the two drugs enhance learning in a brightness discrimination task. The hypothesis is that flumazenil could have an inverse agonist profile in learning tasks. The question remains as to whether the flumazenil enhancing learning process results from increased arousal and/or anxiogenic factors, or from a negative modulatory influence of endogenous diazepam-like ligands for benzodiazepine receptors.

Animals↗
PubMed1990

Methyl beta-carboline-3-carboxylate enhances performance in a multiple-trial learning task in mice.

In contrast to diazepam, a benzodiazepine receptor (BZ-R) ligand, which impairs memory processing, methyl beta-carboline-3-carboxylate (beta-CCM), another BZ-R ligand, administered before a training session, enhances performance in a retention test. This action, however, has only been demonstrated in single trial or single session learning protocols. The present report extends these results to a multiple-trial learning procedure in mice (brightness discrimination in a T-maze with negative reinforcement). The animals were trained for sessions of ten trials per day for six consecutive days. In a first experiment, the sessions during the first three days took place after administration of beta-CCM (0.3 mg/kg), diazepam (2.5 mg/kg) or saline. In a second experiment, especially designed to study the effects of beta-CCM, during the first three days animals received beta-CCM (0.3 mg/kg), Ro 15-1788 (15 mg/kg), beta-CCM + Ro 15-1788, vehicles of these drugs or saline. In the first experiment, performance was improved by beta-CCM and impaired by diazepam in the first three sessions as well as in the final three. In the second experiment, beta-CCM alone, as well as Ro 15-1788 improved performance, and the simultaneous administration of the two drugs suppressed these effects. These results suggest that the performance enhancing effects of beta-CCM observed in single trial learning protocols, during the retention test, can already be observed during drug treatment. They confirm that beta-CCM has an action on acquisition (learning). As the effects of beta-CCM are suppressed by the simultaneous administration of Ro 15-1788, our results could suggest a role for benzodiazepine receptors in learning. This question is discussed.

Animals↗
PubMed1989

beta-Carboline-induced seizures in mice: genetic analysis.

The inbred mouse strains BALB/cBy (C) and C57BL/6By (B6) differed significantly in their susceptibility to seizures induced by the benzodiazepine inverse agonist methyl beta-carboline-3-carboxylate (beta-CCM). Following a 5 mg/kg injection of beta-CCM, 74% of C (n = 35) and 13% of B6 (n = 40) mice exhibited a convulsion. No sex difference was found. Analysis of the reciprocal F1s failed to show either maternal environmental and/or heterosomal effects. A genetic analysis of the strain difference in susceptibility to beta-CCM-induced seizures using recombinant inbred strains (RIS) was performed. The strain distribution for the RIS showed a two group partition. Statistical analysis showed that, although a one-segregating-unit model could not be rejected to explain the strain difference in beta-CCM-induced seizures, some of the evidence weakened the one-segregating-unit hypothesis.

Animals↗
PubMed1989

Synthesis and benzodiazepine receptor affinities of rigid analogues of 3-carboxy-beta-carbolines: demonstration that the benzodiazepine receptor recognizes preferentially the s-cis conformation of the 3-carboxy group.

1H-Indolo[3',2':4,5]pyrido[3,2-b]-2-penten-5-olide (6) and 1H,5H-indolo[3',2'-c]-6,7-dihydro-2-pyridone (7), rigid analogues of methyl 4-ethyl-beta-carboline-3-carboxylate (8) and N-methyl-4-ethyl-beta-carboline-3-carboxamide (9), respectively, were synthesized and their in vitro binding affinities to the central type benzodiazepine receptors were compared. The IC50 values of 6 and 8 were approximately equivalent (42 and 27 nM, respectively). The amide derivative 9, for which theoretical energy calculations indicate that the s-trans carbonyl conformation is the preferred one, displayed very low affinity (IC50 greater than 10(4) nM). However, when the carbonyl group of 9 was forced to adopt the s-cis conformation as in lactam 7, binding to the benzodiazepine receptor was largely restored (IC50 = 150 nM), indicating that the s-cis carboxy conformation at C-3 of beta-carbolines is preferentially recognized by this receptor. In vivo, compound 6 showed neither convulsant, proconvulsant, nor anticonvulsant activity in mice. Moreover, 6 did not antagonize methyl beta-carboline-3-carboxylate induced convulsions in mice. This lack of activity of 6 was attributed to its inability to cross the blood-brain barrier since no significant displacement of [3H]Ro 15-1788 from mouse brain benzodiazepine receptors by 6 could be observed in vivo.

Animals↗
PubMed1989

The search for a biochemistry of memory.

The search for a biochemistry of memory may be divided into two consecutive periods: the search for molecular memory coding in the brain (1960-1975), and the ongoing search for biochemical correlates of learning or memory. During the first period, three main methods were used: chemical analysis of macromolecules after learning, studying the effects on learning of compounds (antibiotics) impairing macromolecule synthesis, and attempting chemical transfer of information items acquired by the brain ("memory transfers"). None of the three methods succeeded in clearly demonstrating that memory is chemically encoded. Subsequent modern work has focused on the search for correlates between brain chemical mechanisms and memory processes: the role of protein synthesis in memorization, peptide modulation of learning, and the role of the main neurotransmitter systems (particularly acetylcholine, catecholamines, GABA and glutamic acid). The correlates, which are to be interpreted with caution, are based on both pharmacological results in animals and clinical data in man.

Acetylcholine↗
PubMed1988

Demonstration of the partial agonist profiles of Ro 16-6028 and Ro 17-1812 in mice in vivo.

Benzodiazepine receptor occupancy by the full agonist, diazepam, and by the two putative partial agonists, Ro 16-6028 and Ro 17-1812, was measured by inhibition of in vivo [3H]Ro 15-1788 binding in mouse brain and was correlated with their pharmacological effects. The anticonvulsant effects of Ro 16-6028, Ro 17-1812 and diazepam (ED50 values) appeared at receptor occupancies of 40, 20 and less than 5%, respectively. Moreover, at the highest measurable receptor occupancy (90-100%), Ro 16-6028 and Ro 17-1812 did not induce any rotarod deficit whereas a complete deficit was observed with diazepam at 35% receptor occupancy.

Animals↗
PubMed1987

Anxiogenic effects of methyl-beta-carboline-3-carboxylate in a light/dark choice situation.

Doses of benzodiazepine, clorazepate, and also of the inverse agonist of the benzodiazepine receptor, beta-CCM, which failed to present sedative or postictal depressive effects, were at first determined in a free exploratory situation. Then, the effects of clorazepate dosed at 1.0, 2.0 and 4.0 mg/kg and beta-CCM dosed at 1.0 and 2.5 mg/kg were studied in the light/dark box choice procedure. Clorazepate tended to produce an increase of the time spent by mice in the lit box as well as of the number of transitions between the two boxes, whereas the dose of 1.0 mg/kg of beta-CCM had opposite effects. The benzodiazepine antagonist RO 15-1788 completely counteracted the anxiolytic effects of clorazepate dosed at 2.0 mg/kg and the anxiogenic effects of beta-CCM.

Animals↗
PubMed1987

Enhancement of performance by methyl beta-carboline-3-carboxylate, in learning and memory tasks.

Benzodiazepines are known to induce a profound anterograde amnesia in man. In this report, it is shown that methyl beta-carboline-3-carboxylate (beta-CCM), an inverse agonist of the benzodiazepine receptor, has the opposite effect; it enhances performance in learning and memory tasks. Three different learning models were used: habituation to a new environment and passive avoidance in mice and imprinting in chicks. The opposite effects of both beta-CCM and the benzodiazepine diazepam were blocked by administration of the benzodiazepine receptor antagonist Ro 15-1788, providing evidence that the benzodiazepine receptor is involved in these effects.

Animals↗
PubMed1986

3-(Methoxycarbonyl)-amino-beta-carboline, a selective antagonist of the sedative effects of benzodiazepines.

We have previously described the synthesis of a novel compound, 3-(methoxycarbonyl)-amino-beta-carboline (beta-CMC), which has a high in vitro affinity for the benzodiazepine receptor. In vivo testing showed that this compound had a restricted pharmacological profile. beta-CMC lacked intrinsic activity but it antagonized the convulsions induced by the methyl ester of beta-carboline-3-carboxylic acid, an inverse agonist of the benzodiazepine receptor. Moreover, beta-CMC selectively antagonized the sedative but not the anxiolytic or anticonvulsant effects of benzodiazepines. The possible mechanisms involved in the selective antagonism of the sedative effects of benzodiazepines by beta-CMC are discussed.

Animals↗
PubMed1986

The benzodiazepine receptor ligand, methyl beta-carboline-3-carboxylate, is both sedative and proconvulsant in chicks.

Certain pharmacological properties of methyl beta-carboline-3-carboxylate (beta-CCM), a benzodiazepine receptor ligand, have been investigated in chicks. Although beta-CCM has been established previously as an "inverse agonist" of benzodiazepine receptors in rodents, having effects opposite to those of benzodiazepines in a variety of tests, in chicks this compound had a different pharmacological profile. Firstly, in contrast to the overt convulsant action of beta-CCM in other species, beta-CCM (0.05-40 mg/kg) did not produce convulsions by itself in chicks, but it was only proconvulsant. Secondly and most surprisingly, beta-CCM, like diazepam, produced in chicks a sedation which could be blocked by the benzodiazepine receptor antagonist Ro 15-1788. Thus it appears that beta-CCM can function both as an agonist and as an inverse agonist in this animal.

Animals↗
PubMed1985

3-Amino-beta-carboline derivatives and the benzodiazepine receptor. Synthesis of a selective antagonist of the sedative action of diazepam.

Seven 3-N-substituted derivatives of 3-amino-beta-carboline were synthesized and their affinities for the benzodiazepine receptor were assessed in vitro. Two compounds, 3-(ethylamino)-beta-carboline and 3-[(methoxycarbonyl)amino]-beta-carboline (beta-CMC), showing IC50 values of 460 and 71 nM, respectively, were selected for in vivo studies. The former compound showed long-lasting proconvulsant activity in Papio papio baboons while beta-CMC was shown in mice to selectively antagonize the sedative effects of diazepam without exhibiting convulsant, proconvulsant, or anxiogenic activity by itself.

Animals↗