C. Radouco-Thomas

The Nuclear-Ribosomal System during Neuronal Differentiation and Development

Electron microscopic investigations on the maturing cytoplasmic organelles and on the growth of neuronal processes were formerly reported in several developing neurons (1, 2, 3, 4, 5, 6, 7). In contrast, the differentiation of the nuclear components in the maturing neuron was little investigated. To the best of the authors’ knowledge, no systematic ultrastructural study on the nuclear maturation is as yet available.

Biological markers in major psychosis and alcoholism: Phenotypic and genotypic markers

Some basic concepts and trends which appear to be essential in the search for biological markers in mental disorders are discussed. Comments related to major psychosis and alcoholism are presented under three headings: (i) heterogeneity of disorders (ii) multifactoriality of disorders and (iii) mental disorders as genetically influenced disorders. Tentative classification and terminology of biological markers are given. Various types of phenotypic markers are discussed and alcoholism is taken as a model for a more detailed discussion of available putative phenotypic markers and of research strategies to be used, namely the pharmacological challenge in high risk subjects (e.g. ethanol and TRH challenge). Some highlights from the field of DNA markers are described, mainly the basic procedures which may be used to investigate genetic aspects of mental disorders by recombinant DNA technology.

Acetaldehyde oxidation in Drosophila melanogaster and Drosophila simulans: Evidence for the presence of an NAD+-dependent dehydrogenase

Abstract 1. 1. An NAD+-dependent oxidation of acetaldehyde has been found in two Drosophila species, D. melanogaster and D. simulans. 2. 2. The enzymatic activity was assessed in partially purified preparations from fly homogenates by monitoring spectrophotometrically NADH production at 340 nm at 25°C. 3. 3. Optimal activity was observed at pH values between 10 and 11 for both species. 4. 4. For both species the affinities ( K m ) for acetaldehyde were in the micromolar range whereas those for NAD+ were in the 100 μM range. 5. 5. Catalytic activity ( V max ) was 2-fold higher in D. melanogaster, a species with high tolerance to ethanol, than in D. simulans, a species with a much lower tolerance to ethanol. 6. 6. Disulfiram proved to inhibit NADH production in preparations of both species. 7. 7. It is concluded that the enzyme involved is an NAD+-dependent aldehyde dehydrogenase (ALDH). Its possible biological significance in ethanol tolerance is discussed.

Experimental narcotic dependence models of primary dependence, abstinence and relapse obtained by intravenous self-administration in rat

Abstract 1. 1. This study evaluated the usefulness of two animal models of morphine dependence, one based on intravenous voluntary self-administration and the other an automated or forced infusion model. 2. 2. The pattern of self-administration observed during primary dependence development in drug-naive rats stabilized after about 14 days with a daily drug intake of 240 mg/kg. 3. 3. On the basis of the self-administration data, a 6-day accelerated model of primary dependence has been produced by passive, automatic administration. In these conditions, animals displayed a similar degree of physical dependence to that observed with self-administration. 4. 4. A triphasic abstinence period is described. The duration, symptoms and propensity to relapse are analysed for each of the three phases: early, intermediate and protracted. 5. 5. The secondary dependence or relapse data obtained in ex-addicted rats allowed to re-administer morphine showed that in comparison with the primary dependence, a higher drug intake was sustained when tested at fixed inter vals between one and six months following morphine removal. 6. 6. Naloxone administered before and in association with morphine during a 7-day period blocked morphine self-administration. This effect was more potent in preventing secondary dependence in ex-addicted animals than the pri mary dependence in drug-naive animals.

Double blind study on the efficacy and safety of tetrabamate and chlordiazepoxide in the treatment of the acute alcohol withdrawal syndrome

1. Efficacy and safety of tetrabamate and chlordiazepoxide in the treatment of the acute or Primary Alcohol Withdrawal Syndrome (PAWS) were assessed during a randomized double blind clinical trial, carried out on sixty male alcoholic in-patients. 2. The two drugs were administered four times a day in double dummy conditions, according to a fixed-flexible decreasing dosage schedule (six days basic regimen). 3. Drug efficacy was measured daily throughout the study period using a battery of standard instruments for collecting quantitative clinical, behavioral, psychopathological and laboratory data. Side effects were daily recorded. 4. Tetrabamate was found to be as efficient as chlordiazepoxide in reducing the intensity of the PAWS, improving sleep and vital signs rapidly and alleviating anxiety progressively. 5. Tetrabamate was found particularly beneficial for severe tremor. Psychomotor and mood scores consistently favored tetrabamate, suggesting psychoanaleptic properties of this compound (increased diurnal vigilance). 6. Side effects were minimal with tetrabamate and generally of weak intensity with chlordiazepoxide. 7. The results of this study indicate that tetrabamate may represent a new alternative drug of choice for the therapy of the acute alcohol withdrawal syndrome.

Aldehyde dehydrogenase in drosophila: Developmental and functional aspects

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activities were determined in adult flies from several Drosophila species endowed with widely different tolerance to ethanol (ETOH). Plotting ALDH against ADH activities resulted in a high correlation coefficient (r = 0.966). This finding was confirmed in developmental studies. From early larval stage up to late adult life, ADH and ALDH activities demonstrated almost parallel profiles. In the highly ETOH tolerant species D. melanogaster (D.m.), ADH and ALDH profiles were U-shaped: high activities in larvae, low activities in pupae and high activities in adults. In D. simulans (D.s.), a species less tolerant to ETOH, the profiles were L-shaped: high activities in larvae but low activities in both pupae and adults. Interestingly, similar activities (ADH and ALDH) were observed in the larvae of both species. Subcellular distribution studies of larval ALDH in both species revealed that the total ALDH activity is largely contributed by a mitochondrial high affinity enzyme. ALDH activity, clearly distinguishable from aldehyde oxidase (ALDOX), was visualized through analytical isoelectric focusing of the subcellular fractions. The estimated pIs for D.m. and D.s. were 4.9 and 5.2 respectively, thus different from those of ADH. The key biological role initially attributed to Drosophila ALDH is further supported by the present data. In addition the Drosophila developmental model opens new avenues for research on the study of genetic regulation of ADH and ALDH expression.

Effects of trichothecenes (T-2-toxin) on protein synthesis in vitro by brain polysomes and messenger RNA

The effects of T-2 toxin on protein synthesis were tested in two reticulocyte lysate in vitro systems pretreated with micrococcal nuclease. One of the test systems contained purified globin mRNA and was initiation dependent. The other contained rat brain polysomes and incorporated amino acids by an elongation dependent process. T-2 toxin inhibited the translation of globin mRNA at all concentrations tested, from 10(-8) M to 10(-4) M. Rat brain polysomes were much less sensitive to T-2 toxin than globin mRNA. While high concentrations of the toxin (10(-4) M) led to partial inhibition of protein synthesis by polysomes, low concentrations (10(-8) M and 10(-6) M) stimulated protein synthesis. Comparison of the above results with those obtained by other workers suggest that the T-2 toxin may inhibit not only the initiation step of translation, but also elongation and termination, depending upon the concentration of the toxin and the nature of the translation system. A similar mechanism may operate for all the trichothecene toxins that exert their effect through binding to ribosomal peptidyl transferase.

Anti-inflammatory effect of trihydroxyethylrutoside assessed in the granuloma pouch

Abstract A comparative study of the anti-inflammatory activity of two non-addictive analgesics and of the flavonoid Trihydroxyethylrutoside was carried out using the Granuloma Pouch Technique. The antiphlogistic effect of Phenylbutazone and Acetylsalicylic acid was confirmed. A similar significant anti-inflammatory effect, proportional to the dose and free of untoward effects, was produced by Trihydroxyethylrutoside.

NAD+-dependent acetaldehyde oxidation in Drosophila☆

Abstract 1. 1. NAD + -dependent acetaldehyde oxidation was measured spectrophotometrically in homogenates of flies Drosophila melanogaster. 2. 2. The reaction was specifically triggered by addition of acetaldehyde and proceeded linearily over five minutes. 3. 3. At low acetaldehyde concentrations the reaction rate was rapidly maximal whereas higher acetaldehyde concentrations proved to be inhibitary. 4. 4. Enzyme activity in regard to NAD + concentration followed classical Michaelis kinetics. The apparent Km for NAD + was 0.05 mM. 5. 5. These data provide evidence for the presence of a NAD + -dependent aldehyde dehydrogenase. It is suggested that this enzyme is involved in the oxidation of acetaldehyde in Drosophila. 6. 6. The biochemical and biological significance of this enzyme in regard to ethanol metabolism and ethanol tolerance is discussed.

Genetic epidemiology and the prevention of functional mental disorders and alcoholism: Family study and biological predictors

1. This review intends to present some theoretical and practical considerations which appear essential for the development of rational research strategies in the field of primary and secondary prevention of mental disorders and alcoholism. 2. The various advances and trends regarding the nosology and diagnosis of these disorders are discussed. Integrative epidemiological models for relating the multifactorial causation and the heterogeneity (multidimensionality) of these disorders are presented. 3. It is emphasized that alcoholism and the functional mental disorders occur in families as shown by (i) the increased incidence of these disorders among relatives and (ii) the existence of various clinical categories genetically associated. 4. Current methodology in clinical diagnosis and genetic epidemiology represent powerful procedures for typing and subtyping of these disorders. Family studies could identify more homogeneous subgroups and generate hypotheses as to the mode of transmission of mental disorders and alcoholism. 5. Real progress could be made in prevention only if the search for predictors is carried out in homogeneous subgroups. 6. There is a lack of knowledge regarding biological predictors. An urgent need for association studies and linkage analysis should be carried out in order to identify genetic markers (causal relationship) and chromosomal markers. These could provide for the specification of a constellation of markers and the development of appropriate tests to identify subjects at risk likely to develop alcoholism and mental disorders. 7. The immediate issues in secondary prevention and the later outcomes in primary prevention are outlined.