Eighteen animal, models of depression are reviewed in relation to three sets of validating criteria. Of the 18 models, five could only be assessed for predictive, validity, seven could be assessed for predictive and face validity, and six could potentially have predictive, face and construct validity. Some traditional models (reserpine reversal, amphetamine potentiation) are rejected as invalid; the models with the highest overall validity are the intracranial self-stimulation, chronic stress and learned helplessness models in rats, and the primate separation model.

The validity of animal models of depression.

Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publication.

Animal models of depression: an overview.

Marine sponges have been considered as a gold mine during the past 50 years, with respect to the diversity of their secondary metabolites. The biological effects of new metabolites from sponges have been reported in hundreds of scientific papers, and they are reviewed here. Sponges have the potential to provide future drugs against important diseases, such as cancer, a range of viral diseases, malaria, and inflammations. Although the molecular mode of action of most metabolites is still unclear, for a substantial number of compounds the mechanisms by which they interfere with the pathogenesis of a wide range of diseases have been reported. This knowledge is one of the key factors necessary to transform bioactive compounds into medicines. Sponges produce a plethora of chemical compounds with widely varying carbon skeletons, which have been found to interfere with pathogenesis at many different points. The fact that a particular disease can be fought at different points increases the chance of developing selective drugs for specific targets.

/pdf/marine-sponges-as-pharmacy-1k32yowllo.pdf

Marine sponges as pharmacy.

Over the course of the last 50 years many models of major depressive disorder have been developed on the basis of theoretical aspects of this disorder. These models and procedures have been crucial in the discovery and development of clinically-effective drugs. Notwithstanding, there is presently great concern about the discrepancy between positive outcomes of new candidate drugs in animal models and apparent lack of efficacy in humans i.e., the predictive validity of animal models. Some reasons for this concern lie in the over-reliance in the face value of behavioural models, design of clinical trials, placebo responses, genetic variations in response to drugs, species differences in bioavailability and toxicology, and not least, disinterest of pharmaceutical sponsors to continue developing certain drugs. Present model development is focusing on endophenotypic aspects of behaviours rather than trying to model whole syndromes. This essay traces the origins and theoretical bases of our animal models of depression or depressed-like behaviours in humans and indicates how they have evolved from behavioural assays used to measure the potency and efficacy of potential candidate drugs to tools by which endophenotypes of depression may be identified and verified pharmacologically. A cautionary note is included though to indicate that the true predictive validity of our models will not be fully assessed until we can determine the attrition rate of molecules discovered from new drug targets translating into clinically-effective drugs.

Animal models of depression in drug discovery: a historical perspective.

To further test the new hypersensitive postsynaptic serotonin (5-HT) receptor theory of depression bases on or animal model, it was necessary to demonstrate that some of the currently used antidepressive drugs can block D,L-5-hydroxytryptophan (5-HTP) induced depression acting through postsynaptic rather than presynaptic mechanisms. Rats working for milk reinforcement and exhibiting behavioral depression following administration of 5-HTP (IP) were pretreated (1 hour before the 5-HTP injection) with fluoxetine (5 mg/kg IP) or methysergide (5 mg/kg IP) to establish a behavioral basis for distinguishing between pre- and postsynaptic events, respectively. Fluoxetine, a known specific uptake blocker of 5-HT, potentiated the depressive effect of 12.5 mg/kg 5-HTP by 200%. Methysergide, a postsynaptic blocker of 5-HT, almost completely (93%) abolished the depressive effect of 50 mg/kg 5-HTP. Since acute pretreatment with comparable clinical doses of the antidepressive drugs, mianserin, amitriptyline, imipramine, or iprindole, resulted in blockade of the 5-HTP induced depression by 70, 50, 40, and 20% respectively, these drugs can act as antagonists of 5-HT at the postsynaptic serotonin receptor. When these results are viewed in terms of recent data reported from CNS binding studies, the therapeutic effects of some antidepressants may be explained by their postsynaptic rather than presynaptic effects at central serotonergic receptors.

Postsynaptic action by four antidepressive drugs in an animal model of depression.

Rats working on a food-reinforced operant schedule and exhibiting behavioral depression following administration of D,L-5-hydroxytryptophan (5-HTP) were pretreated with one of three drugs: methysergide, fluoxetine, or amitriptyline. The former two drugs were used to establish a basis for distinguishing between pre- and postsynaptic events. We found that methysergide, a known postsynaptic blocker of serotonin, almost completely abolished the depressive effect of 5-HTP, whereas fluoxetine, a known specific uptake blocker of serotonin, potentiated the depressive effect of the 5-hydroxytryptamine (5-HT) precursor. Amitriptyline, one of the commonly prescribed antidepressive drugs, reduced the behavioral depression following 5-HTP by approximately 50%. These data indicate that amitriptyline can act as an antagonist of 5-HT at the postsynaptic receptor. The results of this study, as well as those recently reported from CNS membrane binding studies, suggest that the therapeutic effects of some antidepressive drugs may be explained by their postsynaptic rather than presynaptic properties at central serotonergic receptors. Thus, these studies support the hypothesis that some types of human depression may be primarily due to an excess of free 5-HT acting at postsynaptic receptors.

Pre- and postsynaptic serotonergic manipulations in an animal model of depression☆

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Postsynaptic action by four antidepressive drugs in an animal model of depression.

Pre- and postsynaptic serotonergic manipulations in an animal model of depression☆