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Biomedical subjects

J L Moreau

Publications and source records attributed to J L Moreau.

At least 19 recordsLinked to original sources
PubMed1995

Control of the IL-2 responsiveness of B lymphocytes by IL-2 and IL-4.

A two-step culture system was used to analyze the parameters involved in the acquisition of IL-2 responsiveness by murine B cells. In the first culture, unstimulated, or resting, B cells prepared from spleen of naive animals were challenged during 48 h with IL-2, IL-4, anti-mu, anti-mu+IL-2, anti-mu+IL4, or anti-mu+IL-2 + IL-4. In a second culture, IL-2 responsiveness was followed by measuring either the cell proliferation or the Ig production. It was found that only B cells stimulated by anti-mu+IL-2 were able to respond. The expression of three chains of the IL-2 receptor (IL-2R alpha, IL-2R beta, and IL-2R gamma) was studied by FACS. IL-2R beta and IL-2R gamma were found to be expressed constitutively on resting B cells. IL-2R alpha was induced by anti-mu and anti-mu+IL-2 treatment. Although B cells treated by anti-mu alone are not able to respond to IL-2, they do express an IL-2 binding capacity comparable with B cells treated by anti-mu+IL-2. This paradoxical result suggests that IL-2 has a direct influence on the acquisition of the IL-2 responsiveness. IL-4 exerts a negative effect on the IL-2 response. At the molecular level, IL-4 was found to reduce selectively the IL-2R beta expression at the B cell surface. This effect was confirmed by Northern blot analysis. Maximum expression of the IL-2R beta mRNA is obtained after anti-mu+IL-2 treatment. In the presence of IL-4, expression of the IL-2R beta mRNA is greatly reduced.

Animals↗
PubMed1995

Dorsal periaqueductal gray-induced aversion as a simulation of panic anxiety: elements of face and predictive validity.

Neurosurgical stimulation of the dorsal periaqueductal gray (dPAG) matter in man induces acute signs of autonomic arousal and feelings of subjective anxiety; those signs have phenomenological similarity with the symptom profile characterizing a panic attack. Animals undergoing dPAG stimulation show comparable physical signs of autonomic activation and sudden fear-suggestive behavioral reactions that can be shaped into operant self-interruption behavior. Drugs known to acutely reduce (alprazolam, clonazepam) or precipitate (yohimbine, caffeine) panic attacks in patients were found to acutely and dose-dependently reduce or enhance, respectively, aversion induced by dPAG stimulation in rats. When considered as an animal model of panic anxiety, the dPAG model simultaneously meets criteria of face validity (symptomatic homology) and predictive validity (pharmacological homology under short-term treatment); aspects of its construct validity (theoretical rationale supporting the model) are discussed. It is suggested that dPAG stimulation-induced aversion may represent a model of some aspects of panic disorders.

Alkaloids↗
PubMed1995

Precipitated withdrawal in squirrel monkeys after repeated daily oral administration of alprazolam, diazepam, flunitrazepam or oxazepam.

The lowest dose of alprazolam, diazepam, flunitrazepam and oxazepam consistently to induce loss of righting reflex in squirrel monkeys or vehicle was orally administered to monkeys on 18 consecutive days: 2 mg/kg alprazolam (n = 4), 30 mg/kg diazepam (n = 4), 1 mg/kg flunitrazepam (n = 4), 280 mg/kg oxazepam (n = 5), or vehicle (n = 4). Tolerance developed rapidly for loss of righting reflex, more slowly for sleep and only minimally for muscle relaxation observed during the period immediately following daily oral administration. Injection of the specific benzodiazepine receptor antagonist flumazenil (10 mg/kg i.v.) 5 h after the ninth daily oral treatment produced signs of precipitated withdrawal (tremor, vomiting and/or convulsions) in one alprazolam-, four diazepam-, one flunitrazepam- and four oxazepam-treated monkeys, but not in the vehicle-treated monkeys. Physiological saline injected intravenously several days later under these same experimental conditions failed to provoke a precipitated withdrawal reaction. When flumazenil-induced precipitated withdrawal was again evaluated after the 18th daily oral treatment, withdrawal signs were observed in all alprazolam- and all diazepam-treated monkeys, as well as in three flunitrazepam- and three oxazepam-treated monkeys, but not in the vehicle-treated monkeys (convulsions were observed in one alprazolam-, two diazepam-, one flunitrazepam- and two oxazepam-treated monkeys). No signs of spontaneous withdrawal were observed in any of the monkeys during a subsequent 3-week drug-free period. Thus, repeated administration of approximately equieffective doses of these four benzodiazepines resulted in a similar development of tolerance and physical dependence (indicated by the occurrence of a precipitated withdrawal reaction).

Administration, Oral↗
PubMed1995

Aniracetam reverses memory impairment in rats.

The pyrrolidinone derivative aniracetam given orally immediately after acquisition of an inhibitory avoidance response reproducibly ameliorated scopolamine-induced amnesia in female rats in an extensive series of test sessions conducted over a 1-year period. In a dose-response experiment it was demonstrated that 50 mg kg-1 was the lowest oral dose of aniracetam to significantly ameliorate scopolamine-induced amnesia. Combined results from these numerous test sessions demonstrated that 50 mg kg-1 aniracetam administered to scopolamine-treated rats resulted in 53% of the animals exhibiting correct passive avoidance responding in the retention evaluation versus 9% of the scopolamine-treated rats given vehicle (in comparison, 64% of the rats injected with vehicle rather than scopolamine in this experimental situation exhibited correct responding in the retention test). There was minimal variation in this pattern of results over the successive 1-month blocks constituting the complete experimental period. Thus, the nootropic compound aniracetam replicably exhibited memory enhancing effects in this animal model of reduced cholinergic function.

Administration, Oral↗
PubMed1995

Active cyclin B-cdc2 kinase does not inhibit DNA replication and cannot drive prematurely fertilized sea urchin eggs into mitosis.

Feedback mechanisms preventing M phase occurrence before S phase completion are assumed to depend on inhibition of cyclin B-cdc2 kinase activation by unreplicated DNA. In sea urchin, fertilization stimulates protein synthesis and releases eggs from G1 arrest. We found that in the one-cell sea urchin embryo cyclin B-cdc2 kinase undergoes partial activation before S phase, reaching in S phase a level that is sufficient for G2-M phase transition. S phase entry is not inhibited by this level of cyclin B-dependent kinase activity. Inhibition of DNA replication by aphidicolin suppresses nuclear envelope breakdown, yet it does not prevent the microtubule array from being converted from its interphasic to its mitotic state. Moreover, mitotic cytoplasmic events occur at the same time in control and aphidicolin-treated embryos. Thus unreplicated DNA only prevents mitotic nuclear, not cytoplasmic, events from occurring prematurely. These results together show that the inhibition of cyclin B-cdc2 kinase activation is probably not the only mechanism that prevents mitotic nuclear events from occurring as long as DNA replication has not been completed. In contrast, cytoplasmic mitotic events seem to be controlled by a timing mechanism independent of DNA replication, set up at fertilization, that prevents premature opening of a window for mitotic events.

Animals↗
PubMed1995

Comparison of benzodiazepine receptor ligands with partial agonistic, antagonistic or partial inverse agonistic properties in precipitating withdrawal in squirrel monkeys.

Benzodiazepine receptor (BZR) ligands previously characterized as differing in intrinsic efficacy were evaluated first for potency in antagonizing flunitrazepam-induced sleep in monkeys. Data from these experiments were used to define approximately equieffective doses for subsequent use in precipitating withdrawal in diazepam-treated monkeys. It was shown that partial agonists with intermediate intrinsic efficacy (bretazenil, Ro 41-7812) were relatively ineffective in precipitating withdrawal reactions in diazepam-treated squirrel monkeys. The potent and specific BZR antagonist flumazenil, which possesses weak intrinsic efficacy, was more effective in precipitating a withdrawal reaction in diazepam-treated monkeys. In contrast, the highest dose of the BZR antagonist ZK 93426 that could be administered failed to precipitate withdrawal under the same experimental conditions. Finally, the BZR partial inverse agonist sarmazenil was the most effective of these BZR ligands in eliciting a precipitated withdrawal reaction. Thus, the results of the present investigation strongly suggest that BZR ligands differing in intrinsic efficacy differentially precipitate withdrawal in squirrel monkeys treated chronically with diazepam.

Animals↗
PubMed1994

Application of high-performance liquid chromatography to the study of the biological transformation of adiponitrile.

A procedure for the assay of nitrile hydratase and amidase activity by high-performance liquid chromatography is described. The method can be used to assay the intermediate compounds resulting from the hydrolysis of adiponitrile into adipic acid, and to determine the kinetics of the hydrolysis of these compounds using whole cells and enzyme extracts. The precision of the method makes it suitable for the determination of the enzyme parameters: Km and Vm (nitrile hydratase and amidase). Using cyanovaleramide as substrate, Km and Vm were respectively 370 mM and 2060 U/mg for nitrile hydratase and 6.6 mM and 33 U/mg for amidase.

Adipates↗
PubMed1994

Acute and chronic treatment with 5-HT reuptake inhibitors differentially modulate emotional responses in anxiety models in rodents.

This study investigated behavioural effects of very potent 5-HT reuptake inhibitors after acute treatment (cianopramine and citalopram), as well as after chronic treatment (cianopramine), in two behavioural models of anxiety: 1) the light/dark choice procedure in mice and 2) the elevated plus-maze test in rats. In addition, the responses of mice to novelty in a free exploration paradigm were assessed after acute administration of both drugs. A single injection of cianopramine or citalopram increased neophobic reactions in the free exploration test. Furthermore, these drugs increased the avoidance reaction to a brightly illuminated chamber in the light/dark choice procedure as well as to open arms in the elevated plus-maze test. In contrast, after chronic treatment (10 mg/kg IP, once daily for 21 days) of cianopramine, anxiogenic-like effects were no longer produced in the light/dark choice paradigm whereas in the elevated plus-maze test, anxiolytic-like effects appeared. These results shed more light on the 5-HT hypothesis of anxiety, insofar as the increased availability of 5-HT resulting here from reuptake inhibition seems to initially result in an increased emotional reactivity which, however, subsequently disappears during chronic treatment.

Animals↗
PubMed1994

Brain 5-HT1C receptors and antidepressants.

A variety of antidepressants of different chemical classes were tested for their in vivo and in vitro activity at 5-HT1C receptors in the brain. Conventional tricyclic antidepressants (imipramine, desipramine, maprotiline, clomipramine, trimipramine, amitriptyline, nortriptyline, doxepin, amoxapine, oxaprotiline) and two atypical antidepressants (mianserin and trazodone) were found to display affinity for 5-HT1C receptors in the nanomolar range. Antidepressants of other chemical classes and mechanisms of action (serotonin uptake inhibitors: fluoxetine, citalopram, sertraline, fluvoxamine; noradrenaline-dopamine uptake inhibitors: nomifensine, bupropion, amineptine; or monoamine oxidase inhibitors: moclobemide, iproniazid) had affinities in the micromolar range for 5-HT1C receptors, except fluoxetine. When tested in an in vivo functional model revealing agonistic or antagonistic properties at 5-HT1C receptors, all antidepressants displaying high affinity for this receptor type (except fluoxetine, clomipramine, trimipramine and oxaprotiline) were antagonists at 5-HT1C receptors. Antidepressants with lower 5-HT1C receptor affinity (except nomifensine) were inactive in this functional in vivo model. Antagonism at brain 5-HT1C receptors is a component of the antiserotonergic properties of a number of established antidepressants, especially of the tricyclic class.

Animals↗
PubMed1994

Curative effects of the atypical antidepressant mianserin in the chronic mild stress-induced anhedonia model of depression.

This study was designed to validate a novel animal model of depression by testing the curative effects of the atypical antidepressant mianserin. In this paradigm, the hedonic state of rats was assessed using an intracranial self-stimulation (ICSS) procedure. The ICSS threshold was determined before, during and after a 38-day period of exposure to a variety of intermittent, unpredictable, mild stressors. After 11 days of this regimen, the ICSS threshold was significantly higher in the stressed rats, suggesting a gradual decrease of sensitivity to reward. This "anhedonia" lasted throughout the stress regimen and progressively diminished over a 20-day period after stress was terminated. When stressed animals exhibiting anhedonia were treated with mianserin, the stress-induced increase in the ICSS threshold was gradually reversed over ten days of treatment. These results provide further support for the value of this anhedonia paradigm in modelling an important aspect of human depressive disorders.

Animals↗
PubMed1993

Evidence for a role of 5-HT1C receptors in the antiserotonergic properties of some antidepressant drugs.

A variety of antidepressants of different chemical classes were tested for their in vivo and in vitro activity at 5-HT1C receptors in the brain. Conventional tricyclic antidepressants (imipramine, desipramine, maprotiline, clomipramine, trimipramine, amitriptyline, nortriptyline, doxepin, amoxapine) as well as mianserin and trazodone were found to display high to low nanomolar affinity for 5-HT1C receptors. Antidepressants of other chemical classes and with other mechanisms of action (affecting amine uptake systems: fluoxetine, citalopram, sertraline, fluvoxamine, nomifensine, amineptine; or monoamine oxidase inhibitors: moclobemide, iproniazid) had negligible affinities (micromolar range) for 5-HT1C receptors, except fluoxetine. When tested in an in vivo rat model thought to reveal functional agonistic or antagonistic properties at 5-HT1C receptors, all antidepressants displaying high affinity for this receptor type (except clomipramine and trimipramine) were antagonists at 5-HT1C receptors. Antidepressants with a lower affinity for 5-HT1C receptors (except nomifensine) were inactive in this functional in vivo model. Taken together, these results suggest that antagonism at brain 5-HT1C receptors is a component of the antiserotonergic properties of a number of established antidepressants. In addition, the study confirmed that 5-HT1A receptors functionally interact with 5-HT1C receptors, which suggests that some degree of activity at 5-HT1A receptors may also be an important property for antidepressant activity.

Animals↗
PubMed1993

Effects of repeated mild stress and two antidepressant treatments on the behavioral response to 5HT1C receptor activation in rats.

This study investigated the possible involvement of 5HT1C receptors in the development of depressive states and in the mode of action of antidepressants. The effects of repeated unpredictable mild stress (a regimen known to induce an anhedonic state in the rat) and of chronic administration of either of two recognized antidepressant treatments (sleep deprivation or inhibition of monoamine oxidase type A) in rats were studied on a 5HT1C receptor initiated response, i.e. mCPP-induced penile erection. A 3-week period of repeated, but unpredictable exposure to mild stressors induced a shift to the left of the dose-response curve for mCPP-induced penile erection. In contrast, 72-h REM sleep deprivation resulted in a shift to the right of the mCPP dose-response curve and 10-day administration of the monoamine oxidase type A inhibitor moclobemide (20 mg/kg IP bid) also resulted in a decreased number of mCPP-induced penile erections. These findings support the hypothesis that neuronal activities initiated via 5HT1C receptor stimulation may play a role in the pathophysiology and treatment of depression.

Animals↗
PubMed1993

Pharmacological characterization of benzodiazepine receptor ligands with intrinsic efficacies ranging from high to zero.

Several benzodiazepine receptor ligands were pharmacologically characterized in a battery of functional tests after oral administration in mice, rats, and monkeys. Previous experiments have consistently demonstrated that diazepam exhibits high intrinsic efficacy, bretazenil exhibits intermediate intrinsic efficacy, Ro 42-8773 and Ro 41-7812 both show low intrinsic efficacy, and flumazenil exhibits virtually zero intrinsic efficacy. In the test battery used here it appears that nearly full intrinsic efficacy is required for clear anterograde amnesia or rotarod impairment. In contrast, full protection in the pentetetrazol test was achieved with intermediate-to-high intrinsic efficacy and nearly full protection with lower intrinsic efficacy. In the audiogenic seizure test full anticonvulsant effects were produced with intrinsic efficacy ranging from low to high. Clear inhibition of punished operant responding was observed for all test compounds except for Ro 41-7812 and flumazenil, which exhibit the lowest intrinsic efficacies. All of the test compounds enhanced palatable food consumption, with even those having low intrinsic efficacy producing maximum effects approximating that of diazepam. By additionally taking into consideration the degree of receptor occupancy required to obtain pharmacological activity in each of the tests in this battery it is possible to order the compounds with respect to intrinsic efficacy: diazepam > bretazenil > Ro 42-8773 > Ro 41-7812 > flumazenil. The latter four compounds all exhibited a maximum antagonistic activity in tests involving reversal of meclonazepam- or flunitrazepam-induced central nervous system depression. Thus, using these tests appears to permit the accurate ordinal classification of benzodiazepine receptor ligands for intrinsic efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMed1993

Acute and chronic administration of buspirone fails to yield anxiolytic-like effects in a mouse operant punishment paradigm.

Drug-naive mice failed to exhibit antipunishment effects of ascending doses of buspirone (1-30 mg/kg, PO) in an operant punishment paradigm; however, these same mice subsequently exhibited increased punished responding after diazepam (10 mg/kg, PO). In a separate group of drug-naive mice, diazepam (1-30 mg/kg, PO)produced a robust antipunishment effect under identical experimental conditions, but crossover to buspirone (10 mg/kg, PO) failed to enhance punished responding. In a further experiment using this conflict model, two groups of benzodiazepine-experienced mice received daily oral administration of either vehicle or buspirone (5 mg/kg) for four weeks followed by a test with buspirone; neither group exhibited an antipunishment effect. Two other groups of benzodiazepine-experienced mice received either oral vehicle or diazepam (5 mg/kg) daily for four weeks followed by a test with diazepam; both groups exhibited a clear antipunishment effect. Finally, a group of benzodiazepine-experienced mice given vehicle daily for four weeks followed by a test with vehicle failed to exhibit an antipunishment effect. Thus, despite the attempt to optimize some important experimental conditions in this mouse conflict paradigm, buspirone still failed to produce an antipunishment effect. In contrast, diazepam consistently exhibited a robust anxiolytic-like effect under the same experimental conditions.

Animals↗
PubMed1993

Effects of moclobemide, a new generation reversible Mao-A inhibitor, in a novel animal model of depression.

This study was designed to investigate the predictive validity of a recently described chronic mild-stress-induced anhedonia model of depression. In an intracranial self-stimulation (ICSS) paradigm, rats were allowed to self-stimulate in the ventral tegmental area. Stimulation frequency thresholds for ICSS responses were determined prior to, during, and after a 19-day period of exposure to a variety of mild, intermittent, unpredictable stressors. After nine days of mild stress, stimulation threshold was significantly increased, suggesting a gradual decrease in the rewarding properties of brain stimulation. This anhedonic state lasted throughout the stress period and slowly disappeared over a 10-day period after termination of the stress regimen. This stress-induced increase in ICSS threshold was not observed in rats that were stressed and concomitantly treated with the reversible inhibitor of monoamine oxidase type A (RIMA) moclobemide (20 mg/kg, b.i.d.). In nonstressed animals treated with vehicle or moclobemide, no significant change in ICSS occurred during the course of the experiment. These experimental results reinforce the value of this animal model with respect to its predictive and construct validity.

Animals↗
PubMed1993

Aspects of benzodiazepine receptor structure and function with relevance to drug tolerance and dependence.

Potential development of tolerance to and dependence on benzodiazepine tranquilizers often limit their use for long-term treatment of epilepsy, anxiety and insomnia. Current developments in benzodiazepine receptor pharmacology, i.e. the advent of partial agonists and receptor subtype specific agonists (Fig. 1), however, might eventually overcome these limitations, thus greatly improving therapeutic prospects. The present study demonstrates that subchronic administration of alprazolam (a high-efficacy agonist) results in strong withdrawal reactions upon injection of a benzodiazepine receptor antagonist in mice and monkeys. The partial agonist bretazenil, as well as the benzodiazepine receptor type 1-preferring agonist zolpidem, however, are much less prone to producing such reactions. Neurochemical studies showed that subchronic infusion of lorazepam (a high-efficacy agonist), in contrast to betrazenil, led to benzodiazepine receptor downregulation in vivo and reduced potentiation of gamma-aminobutyric acid (GABA)-stimulated chloride flux by diazepam ex vivo. These findings indicate that partial and receptor subtype 1-selective agonists differ from full, non-selective agonists in their liability to induce drug dependence and tolerance upon chronic administration. It is hypothesized that the neurochemical basis of these adaptive phenomena may be receptor downregulation and/or reduced coupling between GABAA receptor/chloride channel gating and benzodiazepine receptor binding.

Animals↗
PubMed1993

Pharmacology of moclobemide.

Moclobemide is a reversible inhibitor of monoamine oxidase (MAO) with clear preference for the A type (so-called RIMA). The enzyme inhibition shows complex kinetics, and the molecular mechanism of interaction with the enzyme is not yet clear. Moclobemide increases the extracellular concentration of the monoamines in rat brain and decreases the level of their metabolites. Neither a loss nor a cumulation of activity has been observed after chronic treatment. Reversibility of MAO-A inhibition was demonstrated in vitro as well as in vivo. In various animal behavioral models, in particular in a novel model of stress-induced anhedonia, moclobemide was as effective as standard antidepressants. Moclobemide improves cognitive functions that are impaired in experimental situations. A neuroprotective action is seen in rats subjected to transient global ischemia/-hypoxia. Moclobemide lacks anticholinergic and other effects and only slightly increases the pressor effect of orally administered tyramine. Possible links between MAO-A inhibition and the various effects of moclobemide on brain function are discussed.

Animals↗