Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride.

Aripiprazole (OPC 14597) is an antipsychotic drug that has high affinity for dopamine D2 and D3 receptors and the dopamine autoreceptor. It is being developed for treatment of patients with schizophrenia. The purpose of this study was to determine whether a dose response following graduated doses of aripiprazole could be quantified and correlated with its occupancy of the D2 and D3 dopamine receptors in the brain of living humans.

Efficacy of a reversible monoamine oxidase-A inhibitor versus imipramine in subgroups of depressed patients.

Two multicentre studies comparing moclobemide with imipramine under similar conditions in patients undergoing a major depressive episode (DSM-III) were combined in the present analysis. A total of 353 patients received moclobemide (300-600 mg/day) and 356 imipramine (100-200 mg/day). In each study, the antidepressant efficacy of the 2 drugs was comparable, and subgroup analysis showed that moclobemide and imipramine were equally effective in endogenous depression.

Efficacy and tolerability of moclobemide compared with imipramine in depressive disorder (DSM-III): an Austrian double-blind, multicentre study.

The antidepressant efficacy, tolerability, and safety of moclobemide, a reversible, monoamine oxidase-A inhibitor, were compared with those of imipramine in parallel groups of patients with a major depressive episode, in a 4-week, multicentre (17 centres), randomised study. A total of 381 patients were randomly allocated to either treatment; they were not required to avoid tyramine-rich foods. Drop-out rates were comparable in both groups at about 17%.

Cholinomimetic activities of minaprine.

The cholinomimetic activities of the antidepressant drug minaprine have been investigated, in vitro and in vivo, in rodents. Minaprine, and its metabolite SR 95070B [3-(2-morpholinoethylamino)-4-methyl-6-(2-hydroxyphenyl) pyridazine hydrochloride] selectively displaced [3H]-pirenzepine from its cortical and hippocampal binding sites, and only weakly inhibited the binding of [3H]-N-methylscopolamine in either the rat cerebellum, heart and salivary glands, or the guinea-pig ileum. In mice, none of these drugs induced the typical cholinergic side-effects up to lethal doses.

Pharmacological characterization of the aminopyridazine SR 95639A, a selective M1 muscarinic agonist.

In order to design a selective M1 muscarinic agonist, we synthesized SR 95639A (morpholinoethylamino-3-benzocyclohepta-(5,6-c)-pyridazine, dihydrochloride), a semi-rigid analogue of the aminopyridazine antidepressant drug minaprine. SR 95639A displaced [3H]pirenzepine from its binding sites in rat hippocampal membranes with an IC50 value of 0.27 microM.

Cerebral-activating (EEG) properties of two inverse agonists and of an antagonist at the benzodiazepine receptor in the rat.

In order to assess the effects of inverse benzodiazepine agonists and antagonists on brain function, computerized EEG (CEEG) analysis was performed in rats following the i.p. administration of SR 95195 (7-phenyl-3-methyl-1,2,4 triazolo-[4,3-b]pyridazine) and CGS 8216 (2-phenylpyrazolo-[4,3c]-quinoline-3-[5H]-one) two benzodiazepine receptor inverse agonists (BRIAGs) and of flumazepil (Ro 15-1788), a benzodiazepine receptor antagonist (BRANT).

3-aminopyridazine derivatives with atypical antidepressant, serotonergic, and dopaminergic activities.

Minaprine [3-[(beta-morpholinoethyl)amino]-4-methyl-6-phenylpyridazine dihydrochloride] is active in most animal models of depression and exhibits in vivo a dual dopaminomimetic and serotoninomimetic activity profile. In an attempt to dissociate these two effects and to characterize the responsible structural requirements, a series of 47 diversely substituted analogues of minaprine were synthesized and tested for their potential antidepressant, serotonergic, and dopaminergic activities. The structure-activity relationships show that dopaminergic and serotonergic activities can be dissociated.

Review of comparative clinical trials. Moclobemide vs tricyclic antidepressants and vs placebo in depressive states.

Moclobemide is a reversible monoamine oxidase inhibitor (MAOI) which preferentially inhibits type-A MAO. In the present communication the results obtained with moclobemide in various clinical trials are reviewed. To this day, the antidepressant efficacy of moclobemide has been compared to that of placebo in four trials.

Comparative study in mice of tetrazepam and other centrally active skeletal muscle relaxants.

Tetrazepam is a 1,4 benzodiazepine (BZD) clinically used in France and Germany as a muscle relaxant. The activity of tetrazepam was compared to that of diazepam, baclofen, mephenesin and chlormezanone in mice, in pharmacological models which are predictive of muscle relaxant and sedative properties. Tetrazepam was active in all the 6 tests of muscle relaxation (traction, chimney, inclined screen, grip force, horizontal grid and morphine-induced Straub tail).

Specific modulation of social memory in rats by cholinomimetic and nootropic drugs, by benzodiazepine inverse agonists, but not by psychostimulants.

The recognition of an unfamiliar juvenile rat by an adult rat has been shown to imply short-term memory processes. In this study the effect of various psychotropic drugs on this investigatory behaviour was examined. The procedure was as follows: an unfamiliar juvenile rat was placed in the home cage of an adult rat for 5 min.

Sodium diethyldithiocarbamate protects against the MPTP-induced inhibition of immune responses in mice.

The effects of 1-methyl-4-phenyl - 1,2,3,6-tetrahydropyridine (MPTP) on immune parameters, and the restorative influence of sodium diethyldithiocarbamate (DTC) or deprenyl were evaluated in mice. The concentrations of dopamine (DA), 3-methoxytyramine (3-MT), 3-4-dihydroxyphenyl acetic acid (DOPAC), and homovanillic acid (HVA), were concomitantly measured in the striatum. MPTP depressed T-cell responses.

Tetrazepam: a benzodiazepine which dissociates sedation from other benzodiazepine activities. II. In vitro and in vivo interactions with benzodiazepine binding sites.

Tetrazepam is a 1,4-benzodiazepine (BZD) derivative which, in rodents, appears to have very little sedative and ataxic effects. In an attempt to identify the molecular mechanisms underlying this particular pharmacological profile we examined the interaction of tetrazepam with BZD binding sites. Tetrazepam interacted competitively with "central" and "peripheral" BZD binding sites and exhibited comparable affinities for both sites.

Tetrazepam: a benzodiazepine which dissociates sedation from other benzodiazepine activities. I. Psychopharmacological profile in rodents.

In the 1,4-benzodiazepine (BZD) series the nature of the C(5) substituent is critical for activity. In tetrazepam this substituent is a cyclohexenyl ring, in all other clinically effective 1,4-BZD derivatives it is a phenyl ring. The activities of tetrazepam and diazepam, whose chemical structures differ only by the nature of the C(5) substituent, were compared in rodent models which are predictive of anticonvulsant, anxiolytic, muscle relaxant and sedative effects.

Monoamine oxidase-inhibiting properties of SR 95191, a new pyridazine derivative, in the rat: evidence for selective and reversible inhibition of monoamine oxidase type A in vivo but not in vitro.

In rodents, SR 95191 [3-(2-morpholinoethylamino)-4-cyano-6-phenylpyridazine] has been shown to be active in animal models of depression. The profile of activity of SR 95191 suggests that the compound is a selective and short-acting type A monoamine oxidase (MAO) inhibitor (MAOI) in vivo. In the present study, the interaction of SR 95191 with MAO-A and MAO-B activity was further examined in vivo and in vitro.

Characterization of the scopolamine stimulus in rats.

The discriminative stimulus properties of scopolamine, a potent antagonist at muscarinic receptors, were used for testing the discriminative effects of drugs known to act on cholinergic transmission. Rats were trained in a standard two-bar operant conditioning procedure with food as the reinforcer, according to a FR10 schedule. The training dose of scopolamine was progressively reduced from 0.

Brain neocortex and imuthiol regulate the expression of MHC antigens on mouse T lymphocytes.

The induction of T-cell responses involves the recognition of extrinsic antigens in association with antigens of the major histocompatibility complex (MHC). The present results demonstrate that the lateralized control exerted by the brain neocortex on T-cell activities extends to the expression of MHC antigens, yet differently on spleen or lymph node T cells. This study also shows that the neocortex influences the changes induced by an immunopotentiator, sodium diethyldithiocarbamate (imuthiol), on the MHC antigen content on mouse T cell-surface.

The sensitivity of gamma-aminobutyric acid antagonists to thiocyanate is related to the absence of a functional anionic group in their structure.

Pyridazinyl derivatives of gamma-aminobutyric acid (GABA) have recently been shown to be selective, reversible and competitive GABAA antagonists. Unlike what is observed with all other GABAA antagonists, the affinity of these compounds for the GABAA receptor is not modified by thiocyanate. The chemical structure of these pyridazinyl-GABA derivatives differs from that of other GABAA antagonists by the presence of a free carboxylic group in their structure.

Effects of intracerebroventricular pirenzepine on muscarinic discriminations in rats.

In rats, mixed M1/M2 muscarinic ligands induce a discrimination which is of central origin and selectively mediated by either one or both muscarinic receptor subtypes. In the present study we examined the effects of intracerebroventricular (i.c.

Behavioural evidence for a selective GABA-A antagonistic activity of SR 95103 and SR 42641 after intrastriatal injection in mice.

Two pyridazinyl GABA derivatives, SR 95103 and SR 42641 have recently been described as selective GABAA receptor antagonists. We have now investigated the behavioural effects of SR 95103 and SR 42641 after intrastriatal injection in mice. When injected into the right striatum, SR 95103 (0.

Characterization of the binding of [3H]SR 95531, a GABAA antagonist, to rat brain membranes.

A synthetic derivative of gamma-aminobutyric acid (GABA), SR 95531 [2-(3'-carboxy-2'-propyl)-3-amino-6-p-methoxyphenylpyridazinium bromide], has recently been reported, on the basis of biochemical and in vivo microiontophoretic studies, to be a potent, selective, competitive, and reversible GABAA antagonist. In the present study, the binding of [3H]SR 95531 to washed, frozen, and thawed rat brain membranes was characterized. Specific binding was linear with tissue concentrations, had a pH optimum at neutrality, and was maximal at 4 degrees C after 30 min of incubation.

Minaprine and imipramine in the treatment of major depressive disorders. A comparative double-blind study.

Minaprine dihydrochloride is an aminopyridazine derivative which is chemically unrelated to other known psychotropic drugs. In rodents minaprine is active in most models of depression and is thought to exert this activity by enhancing serotonergic and dopaminergic transmission. In humans minaprine has been shown to be more effective than placebo in the treatment of major depressive episodes as defined by the DSM-III.

[Animal models of epilepsy and experimental seizures].

Animal models of epilepsy are essential for the search of new effective antiepileptic drugs. Moreover they may lead to the discovery of the basic neuronal dysfunction(s) which underlies human epilepsies. Animal epilepsies as well as experimental seizures are usually considered as valid models of human epilepsies when, and only when, the drugs which are effective in human epilepsies prevent seizures in animals.

SR 95191, a selective inhibitor of type A monoamine oxidase with dopaminergic properties. II. Biochemical characterization of monoamine oxidase inhibition.

SR 95191 [3-(2-morpholino-ethyl-amino)-4-cyano-6-phenylpyridazine] is a novel psychotropic drug which possesses the pharmacological properties of a selective, reversible type A monoamine oxidase inhibitor (MAOI). The MAOI activity of SR 95191 was examined in the rat brain, liver and duodenum and compared to that of clorgyline, harmaline, l-deprenyl, moclobemide and cimoxatone. In vitro, SR 95191 selectively inhibited MAO-A and was less potent than cimoxatone, clorgyline and harmaline, but was more potent than moclobemide.

SR 95191, a selective inhibitor of type A monoamine oxidase with dopaminergic properties. I. Psychopharmacological profile in rodents.

SR 95191 [3-(2-morpholino-ethyl-amino)-4-cyano-6-phenyl-pyridazine], a novel compound, has been shown in preliminary experiments to inhibit type A monoamine oxidase (MAO). This report describes the activities of SR 95191 in behavioral experiments in mice and rats and shows that SR 95191 has the profile of a selective type A MAO inhibitor (MAOI). Moreover, SR 95191 also possesses dopamine (DA) stimulant properties.