Biomedical subjects
Publications and source records attributed to L Valzelli.
According to the method described earlier (1), the effect of some anxiolytics on memory retention in "good" and "poor" learning mice was studied. While the classical benzodiazepine (diazepam) significantly improves performance of both sub-populations of mice, non-benzodiazepine anxiolytics worsen that of poor learners and triazolobenzodiazepines increase performance.
To avoid the danger of an increasing gap between clinical and animal studies and to assure a constant progression of knowledge, psychiatric researchers need to find a common ground of convergence. Such common ground might be found in searching for human and animal models of disturbed behavior, conceptually comprehensive of the variables which may concur in the determination of the behavioral syndromes.
A new and easy method to demonstrate different degrees of facility for learning and retention within the same strain of laboratory mice is described. According to this method, it is possible to divide the general population into given percentage of "good learners" and "poor learners". These two subpopulations react differently to the influence of several psychoactive drugs. In this study it is shown that pyritinol contributes to retention of the learned task in poor learners and has no effect on good learners.
The evidence suggests that stimulation of brain noradrenergic neurons plays an inhibitory role in rat mouse-killing (muricidal) aggression. Anxiolytic benzodiazepines inhibit locus coeruleus activity and previous data showed that chlordiazepoxide was capable of antagonizing the locus coeruleus-mediated suppression of muricidal aggression. The present experiments showed that this effect is common to new anxiolytic triazolobenzodiazepines and to other non-benzodiazepine derivatives with anxiolytic activity. In this framework, 10 mg/kg of buspirone, of 1-pyrimidine-piperazine and of MJ-13805 proved to be as active as 2.5 mg/kg of alprazolam and as 5 mg/kg of chlordiazepoxide in inhibiting the locus coeruleus-mediated suppression of muricidal aggression.
Several studies have shown that isolation-induced aggressive behavior in rodents may involve alterations in brain serotonin metabolism. The modified response, in isolated, aggressive mice, to several agents specific to serotonin receptors in the brain suggests an altered receptor availability for serotonin-like ligands. In the present study, isolated, aggressive mice showed a significant reduction in the number of serotonin binding sites in three major brain regions, and the effect of amphetamine sulfate varies according to the changes of receptors in differentially housed mice.
During six learning sessions in a shuttle-box avoidance situation, male Sprague-Dawley rats show two kinds of learning efficiency which allow for dividing them in the subgroups of high-responding (HR) and low-responding (LR) animals. The effect of phosphatidylserine, a pharmacologically active phospholipid obtained from bovine brain, has been studied on the relearning phase of these two populations of rats. Chronic administration of phosphatidylserine (15 mg/kg i.p. for 30 days) significantly increased the avoidance performances of LR animals, without changing those of HR rats. The results obtained suggest that the different behavioral response to the phosphatidylserine treatment may depend on the pre-drug baseline of avoidance learning capability and on the effect that the drug exerts on some brain neurotransmitter metabolism.
Antidepressant drugs reportedly counteract mouse-killing activity by rats. There is evidence that antidepressant derivatives exert their anti-muricidal activity through both noradrenergic and serotonergic neurons. The experiments were performed in two types of muricidal aggression with three antidepressants characterized by different neurochemical activity. No major differences in the antimuricidal efficacy of the drug-employed were found, even though spontaneous muricidal animals resulted on the whole less sensitive to antidepressants than p-CPA-induced muricidal rats. In these last animals nomifensine proved to be more potent than desipramine and fluoxetine.
On the basis of the already proposed distinction between "normal" and "pathological" aggression in laboratory animals, it is essayed an integration of the experimental findings derived from a specific animal model of aggression with the available clinical information on human violent behavior. The too disregarded importance of the role played by the inhibitory control of brain functions, appears instead reportedly essential in the regulation of emotions and behavior, and is of great relevance in explaining the behavioral changes that follow induced or spontaneous impairment of the serotonergic system of the brain. As a matter of fact, the numerous evidences indicate that genetic predisposition and induced or acquired defects of serotonergic inhibitory control greatly concur to precipitate anomalous strong aggression. Interestingly, the cluster of symptoms presented by laboratory rats in consequence of the serotonergic discontrol, has many unexpected similarities with several pathological conditions of man. This fact confers to laboratory experiments the value of a tool aimed at a better understanding of the biological mechanisms which underlie corresponding alterations of human conduct, with special reference to pathological aggression and violence. In this line, some specific nutrient defects and/or malabsorption conditions can be important in the facilitation or elicitation of mental illness including human aggression. In addition, the efficacy and neurochemical action of those substances capable to partially or completely block or prevent experimental aggression, will likely assume equal relevance in the management or prevention of human violent behavior.
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p-Chlorophenylalanine is known to selectively decrease brain serotonin and to induce muricidal aggression in previously docile rats. With regard to the substance's relatively time-limited effect on brain serotonergic system, the neurochemical activity of p-CPA on tryptophan, serotonin and 5-hydroxyindoleacetic acid on seven discrete areas of the rat brain is studied in parallel to the time-course of muricidal aggression induced by the drug. Evidence indicates that, following the disruption of brain serotonergic inhibitory control, muricidal aggression becomes a stable behavior, probably on account of its self-reinforcing property.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Surgical, pharmacological or environmental manipulation are widely employed to induce muricidal behavior in naive laboratory male rats. The genetic predisposition of an animal strain to kill mice remains, however, an important factor to obtain the muricidal reaction. Data from the pertinent literature suggest that muricidal behavior may possibly be sustained by increased dopaminergic or catecholaminergic activity in the presence of reduced serotoninergic activity. The results here presented indicate, instead, that complete abolition of brain serotoninergic control, i.e., maximal depletion of brain serotonin, is just enough per se to induce muricidal activity. Further, this chemically-induced muricidal activity goes well beyond any pre-existing strain predisposition to kill mice or not.
p-Chlorophenylalanine (pCPA), a potent inhibitor of serotonin synthesis, specifically depletes brain serotonin in a dose-dependent manner. The resulting impairment of serotonergic inhibitory control of the brain is considered responsible for the consequent muricidal aggression that arises in pCPA-treated rats independent of their strain-dependent genetic predisposition and sex propensity to display this behavior. Judging from the data obtained, the minimal impairment of serotonergic inhibitory control required to induce consistent muricidal aggression in rats of both sexes of the strains considered, corresponds to a brain serotonin depletion of about 55-60%.
Aggression is not a single unitary behavioral entity, then it is impossible to find a single drug showing "specific' and "universal' antiaggressive efficacy and potency. Furthermore, spontaneous aggression is essential to the self-and species preservation, and plays an important role in the process of evolution. In contrast, aggressiveness induced by prolonged socioenvironmental deprivation or isolation, raises the feature of anomalous behavior. The effect of drugs on aggressive behavior must therefore be considered in the light of this distinction, that accounts for discrepancies between the results of literature on "antiaggressive' properties and potency of psychoactive drugs. In addition, and impaired inhibitory control of the brain may be responsible for violent aggression and drugs capable of restoring such control may prove useful in managing the pathology of aggressiveness.