Jacques Bruhwyler

Nitric-oxide - a New Messenger in the Brain

The important role played by nitric oxide (NO) in the central nervous system has largely been emphasized in the recent literature. It can originate at least from four different sources: the endothelium of cerebral vessels, the immunostimulated microglia and astrocytes, the nonadrenergic noncholinergic nerve, and the glutamate neuron. NO has been implicated in a large number of pathologies (such as neurotoxicity in Alzheimers disease and Huntingtons disease, cerebral ischemia, stroke, and anxiety) and also in normal physiological functions (such as memory and learning, regulation of the cerebrovascular system, modulation of the wakefulness, mediation of nociception, olfaction, food intake and drinking, regulation of noradrenaline, and dopamine release). The aim of this paper is to review and to integrate the most recent advances in our understanding of the roles of NO in the brain.

Clozapine: An atypical neuroleptic

Since it was synthesized in 1960, much has been written about clozapine. Although a number of its properties are those of a neuroleptic, it displays marked differences from classical antipsychotics to the extent that it is currently listed as an atypical neuroleptic. A classical neuroleptic has been defined in man according to its antipsychotic properties, accompanied by extrapyramidal effects, and in animals according to its cataleptic properties, its ability to antagonize apomorphine and amphetamine stereotypies and to suppress the conditioned avoidance response. Moreover, the classical neuroleptic exerted depressive and anhedonic effects in most conditioning schedules. With clozapine, most of these properties are no longer strictly in force to the point that they call in question the validity of the tests carried out to detect the potential of neuroleptics. This article attempts to compare the characteristics of clozapine with those of classical neuroleptics from a toxicological, neuropharmacological, psychopharmacological and clinical point of view.

Double-blind randomized controlled study of the efficacy and tolerability of two reversible monoamine oxidase A inhibitors, pirlindole and moclobemide, in the treatment of depression

The aim of this double‐blind randomized study was to compare the efficacy and the tolerability of moclobemide (300‐600 mg daily) and pirlindole (150‐300 mg daily), two reversible inhibitors of MAO‐A (RIMAs), in the treatment of depression. In total 116 patients were included in the trial, 111 patients (52 patients on pirlindole and 59 patients on moclobemide) were evaluable for efficacy and safety, and 77 patients completed the whole study (42 days of administration). Both treatments produced highly significant improvements in the Hamilton Depression Rating Scale (HDRS) score, the Hamilton Anxiety Rating Scale (HARS) score and the Montgomery‐Asberg Rating Scale (MADRS) score from day 7 to day 42. The pattern of development of the three scores in the two groups did not differ significantly. After 42 days of treatment, an improvement of ≥50% in the HDRS score was noted in 80% and 67% of patients in the pirlindole and moclobemide groups, respectively. A total of 30 (58%) patients on pirlindole and 33 (56%) patients on moclobemide experienced side‐effects that were considered to be possibly or probably related to the medication. The differences between the two drugs were non‐significant for all types of side‐effect, with the exception of dry mouth and tachycardia, which were significantly more frequent with moclobemide.

Modulation of the clozapine structure increases its selectivity for the dopamine D4 receptor

Clozapine has a more marked affinity for the recently cloned dopamine D4 receptor than for the dopamine D2 receptor. In the search for a selective ligand for the dopamine D4 receptor, useful as a pharmacological tool or as a potent atypical antipsychotic, a pyridobenzodiazepine derivative bioisoster of clozapine, JL 18, 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido [2,3-b][1,4]benzodiazepine, was found to be the most dopamine D4-selective ligand belonging to the diarylazepine class. Indeed, JL 18 binds to the dopamine D4 receptor with affinity up to 25 times superior to that for the dopamine D2 receptor and presents reduced affinities for other receptors.

Anxiolytic potential of a microgram dose of chlordiazepoxide in the open-field test

Diazepam, when administered in very low doses (100 micrograms/kg), can induce a specific inhibition of coarse and ambulation activities in the rat, suggesting a novel mechanism of action occurring in the microgram dose range. This study fails to reproduce the same effects with chlordiazepoxide. On the contrary, greater stimulant and anxiolytic effects were measured with the lowest dose tested (0.1 mg/kg). These results demonstrate that the familiar effects of benzodiazepines should not be extrapolated uncritically to lower dose ranges without empirical testing.

Multicentric open-label study of the efficacy and tolerability of citicoline in the treatment of acute cerebral infarction☆☆☆

Citicoline is considered a promoter of neuronal repair. It has been shown in humans to be effective in the treatment of several cerebral pathologic conditions, including acute stroke. The aim of this open-label, uncontrolled study was to assess the efficacy and tolerability of citicoline in the treatment of patients suffering from acute cerebral infarction. Included in the trial, which lasted 10 to 14 days, were 123 patients who had an acute stroke within a maximum of 48 hours of the study. During the first 5 days, citicoline was administered intravenously (2 g per 24 hours). From day 6, it was administered intramuscularly (1 g per 24 hours). Patients were assessed using the Canadian Neurological (CAN) scale (patient alert or drowsy) and side effects were recorded at each visit. Each patient was always assessed by the same neurologist, who was aware of the treatment. The total score on the CAN scale showed a significant evolution over time. Post-hoc paired Students t tests showed that this score had increased significantly after 3 days of citicoline administration and continued to increase to the end of treatment. An end-point analysis (value observed at the last available visit; n = 113) showed that the score decreased in 5.3% of patients and remained the same in 15.9% of patients. The score increased at least 1 point in 71.7% of patients, 3 points in 35.4% of patients, and 5 points in 12.4% of patients. Patients receiving aspirin concomitantly did not show a greater improvement in their neurologic state than patients receiving citicoline only. The frequency of patients showing side effects probably related to the medication was 7.4%. The results of this study are consistent with those already available, which show that citicoline is an effective and well-tolerated treatment for patients suffering from acute cerebral infarction.

Differentiation of haloperidol and clozapine using a complex operant schedule in the dog

This study aimed to differentiate chronically administered typical (haloperidol) and atypical (clozapine) neuroleptics in the dog using a complex temporal regulation schedule combining operant, voluntary, and involuntary motor parameters. Although clozapine and haloperidol showed some characteristics of neuroleptics, justifying their adherence to the same class of compounds, differences have also been highlighted and compared to the clinical observations. Haloperidol induced catalepsy, tremor, dystony, hyperkinesia, and stereotypy. Subjects produced anticipated responses before any stimulus. Incomplete and delayed responses were also produced. An interpretation in terms of akathisia and anhedonia has been suggested. Clozapine induced tremor, exploration, dystony, and hypersalivation. Subjects produced disinhibitory responses to the negative stimulus and incomplete responses but these latter were submitted to tolerance. The simultaneous presence of tranquilizing and disinhibitory effects has been reported on the clinical potential of clozapine both in cases of positive and negative schizophrenic symptomatologies.

Effect of chronic hypoxic treatment on the retention of fixed-interval responding

The present experiments aimed to study the effects of hypoxic treatment (10 min on 3.5% oxygen) on the stabilized performance of rats in a fixed-interval schedule (FI 60 s). The hypoxic treatment was given once a day, for 3 days, immediately after the FI session. The results showed that the operant performance was disturbed from the very first posthypoxia FI session. There was a sharp drop in response rate, and changes in the temporal distribution of responses occurred. The data obtained greatly limit the importance of nonspecific factors in explaining these changes in performance. The results are discussed with reference to the retrieval hypothesis. In particular, it is suggested that the decreases of performance may be due to an effect of hypoxia on the retrieval mechanisms associated with long-term memory.

A double-blind randomized placebo-controlled study of the efficacy and safety of pirlindole, a reversible monoamine oxidase A inhibitor, in the treatment of depression

The efficacy and safety of pirlindole (300 mg/day), a new reversible inhibitor of monoamine oxidase A, have been evaluated in a multicentre placebo‐controlled double‐blind randomized trial in 103 in‐patients suffering from unipolar major depression (DSM‐III‐R 296.2, 296.3) over a 42‐day period after a run‐in placebo period of 6 days. Pirlindole produced a significantly greater decrease than placebo in the Hamilton depression score (from day 28), the Hamilton anxiety score (from day 28) and the Montgomery‐Asberg depression score (on day 42). On day 42, the Hamilton depression score was ≤ 7, ≥8 and ≤15, or ≥16 in 21 %, 45% and 34%, respectively, in the placebo group compared to 72%, 24% and 3.4%, respectively, in the pirlindole group (P < 0.001). The differences between the two groups in terms of tolerance and safety were not statistically significant.

Stimulant effect of the β-carboline FG 7142 in the open-field test

Abstract The anxiogenic activity of N-methyl-β-carboline-3-carboxamide (FG 7142) is sometimes difficult to observe in rats. As the open field has recently been applied successfully to test the anxiogenic potential of n-butyl-β-carboline-3-carboxylate (β-CCB) in mice, a comparable experiment was performed with FG 7142 (1, 5, 10, 30 mg/kg i.p.) in rats. In contrast to the inhibitory effects measured with β-CCB, FG 7142 significantly increased the ambulation and rearing scores and induced aggressivity in some animals. A differential sensitivity of mice and rats to β-carbolines, predominant analeptic properties of FG 7142, and differences in the types of anxiety induced are proposed to account for this discrepancy.