Animal Models of Anxiety and Depression (original) (raw)
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Pharmacology Biochemistry and Behavior, 1982
KATZ, R. J. AND M. SIBEL. Further analysis of the specific'ity of a novel animal model of depression----.effects of an antihistaminic ', antipsychotic, and anxiolytic compound. PHARMAC. BIOCHEM. BEHAV. 16(6) 97%982, 1982.--In previous papers we reported that chronic stress elicited reductions in selected forms of open field activity resembled endogenomorphic depression upon behavioral, motivational, neuroendocrine, and neuropharmacological grounds. In particular, the loss of acute stress elicited activity proved to be exclusively reversible by antidepressant treatments. Insofar as clinically ineffective compounds were tested, the deficit proved refractory to treatment, further suggesting the model reflected just those processes which were disrupted in depression. A number of ineffective compounds are known to yield false positives upon other related tests, but have yet to be examined in the present model. Three such compounds, an antihistamine (tripelennamine), a neuroleptic (haloperidol), and an anxiolytic (oxazepam) were examined for their behavioral and neuroendocrine effects. Although other stress related phenomena were replicated, none of the above compounds was effective in restoring the activation deficit or in eliminating the endocrine abnorm',dity. This suggests the depression model is relatively selective pharmacologically and not critically dependent upon receptor blocking properties of the above drugs.
Kleven and Koek Psychopharmacol 144 1999
Rationale: Although all of the benzodiaze-pines in use for the treatment of anxiety are presumably full agonists, it is conceivable that partial benzodiaze-pine agonists may also be clinically effective on the basis of their effects in preclinical models of anxiety. Objectives: To compare the anxiolytic-like effects of different pharmacological/chemical classes of partial benzodi-azepine agonists in the pigeon conflict procedure. Methods: Anticonflict effects in pigeons whose responding was maintained under a multiple FR30 food:FR30 food+shock schedule were characterized by 1) the magnitude of punished responding or 2) the percentage of pigeons (n=5–7/dose) showing significant increases in punished responding. Results: The partial allosteric mod-ulators bretazenil and imidazenil produced anticonflict effects comparable with or superior to those observed following administration of the relatively full agonist midazolam. In contrast, neither the β-carbolines CGS 9896, ZK 95962 and ZK 91296, nor the imidazopyri-dines, alpidem and zolpidem, produced anticonflict effects comparable to either bretazenil and imidazenil or the relatively full benzodiazepine agonist, midazolam, at the doses examined in this study. Conclusions: Although the β-carboline ZK 95962 produced some anticonflict effects , none of the other compounds had anxiolytic-like effects like those observed with midazolam, bretazenil or imidazenil. However, because bretazenil and imidazenil produced robust anticonflict activity, the results indicate that partial allosteric modulators could have anxiolytic effects similar to those produced by higher efficacy compounds. Altogether, the results indicate that partial ben-zodiazepine agonists differ in their ability to produce robust anticonflict effects in the pigeon.
Kleven and Koek Psychopharmacol 1999 141
Anxiolytic drugs generally produce anticonflict effects in both pigeons and rats, although relatively few anxiolytics have been examined in the pigeon and the procedure has not been as completely validated as the rat model. In this study, we examined the antipunishment effects of a variety of benzodiazepine agonists in pigeons and compared the relationship between their potencies to engender anxiolytic-like effects and their clinical doses in humans. In pigeons whose responding was maintained under a multiple FR30 food :FR30 food+shock schedule, the ben-zodiazepine agonists diazepam, flunitrazepam, alprazo-lam, chlordiazepoxide, lorazepam, flurazepam, bromaze-pam, medazepam, and clorazepate produced dose-related increases in punished responding, and, with the exception of medazepam, decreased unpunished responding at higher doses. Potencies calculated from the percentage of pigeons showing significant increases in punished responding ranged from 0.081 to 11 mg/kg, and these potencies were invariably lower than those for decreases in unpun-ished responding by factors ranging from 2.2 to more than 14. The comparison of relative potencies of benzodiaze-pine receptor agonists in pigeons and humans revealed a high positive correlation (0.90, P<0.005), thus demonstrating the predictive validity of this preclinical animal model for anxiolytic benzodiazepines. The results agree with previous findings of robust anticonflict effects of benzodiazepine receptor agonists and extend further the pharmacological characterization to compounds that have not been examined previously in pigeons.
How valuable are animal models in defining antidepressant activity?
Human Psychopharmacology: Clinical and Experimental, 2001
Animal models of depression have been utilised to screen novel compounds with antidepressant potential although uncertainty lingers concerning their clinical relevance[ In order for a model to be considered of any value\ it must possess predictive validity "does drug action in the model correspond to that in the clinic<#\ face validity "are there phenomenological similarities between the model and the clinic<# and construct validity "does the model possess a strong theoretical rationale<#[ On the one hand\ there are models based on stress such as the learned helplessness model\ the forced swimming test and the chronic mild stress model and\ on the other hand\ models based on neuronal de_cits such as the olfactory bulbectomy model[ To date\ among models more frequently used in depression\ none of them meet all these criteria[ Moreover\ improvements to tests are often poorly validated and estimating time of onset of action of antidepressants remains a major challenge in animal model research[ Finally\ reproducing the tests outside the laboratory of origin continues to be problematic and leads to variability in results[ Although animal models of depression fail to be unequivocally valid\ they represent the best tool to de_ne potential antidepressant activity of drugs\ to investigate their mechanism of action and\ to a greater extent\ explore this complex heterogeneous illness[
Leading compounds for the validation of animal models of psychopathology
Cell and Tissue Research, 2013
Modelling of complex psychiatric disorders, e.g., depression and schizophrenia, in animals is a major challenge, since they are characterized by certain disturbances in functions that are absolutely unique to humans. Furthermore, we still have not identified the genetic and neurobiological mechanisms, nor do we know precisely the circuits in the brain that function abnormally in mood and psychotic disorders. Consequently, the pharmacological treatments used are mostly variations on a theme that was started more than 50 years ago. Thus, progress in novel drug development with improved therapeutic efficacy would benefit greatly from improved animal models. Here, we review the available animal models of depression and schizophrenia and focus on the way that they respond to various types of potential candidate molecules, such as novel antidepressant or antipsychotic drugs, as an index of predictive validity. We conclude that the generation of convincing and useful animal models of mental illnesses could be a bridge to success in drug discovery.
Animal models of psychiatric disorders are usually discussed with regard to three criteria first elaborated by Willner; face, predictive and construct validity. Here, we draw the history of these concepts and then try to redraw and refine these criteria, using the framework of the diathesis model of depression that has been proposed by several authors. We thus propose a set of five major criteria (with sub-categories for some of them); homological validity (including species validity and strain validity), pathogenic validity (including ontopathogenic validity and triggering validity), mechanistic validity, face validity (including ethological and biomarker validity) and predictive validity (including induction and remission validity). Homological validity requires that an adequate species and strain be chosen: considering species validity, primates will be considered to have a higher score than drosophila, and considering strains, a high stress reactivity in a strain scores higher than a low stress reactivity in another strain. Pathological validity corresponds to the fact that, in order to shape pathological characteristics, the organism has been manipulated both during the developmental period (for example, maternal separation: ontopathogenic validity) and during adulthood (for example, stress: triggering validity). Mechanistic validity corresponds to the fact that the cognitive (for example, cognitive bias) or biological mechanisms (such as dysfunction of the hormonal stress axis regulation) underlying the disorder are identical in both humans and animals. Face validity corresponds to the observable behavioral (ethological validity) or biological (biomarker validity) outcomes: for example anhedonic behavior (ethological validity) or elevated corticosterone (biomarker validity). Finally, predictive validity corresponds to the identity of the relationship between the triggering factor and the outcome (induction validity) and between the effects of the treatments on the two organisms (remission validity). The relevance of this framework is then discussed regarding various animal models of depression.
Screening of antipsychotic drugs in animal models
Drug Development Research, 2000
Behavioral models of antipsychotic drug (APD) action in the rat are widely used for the screening and developing APDs. Valid models are not only required to be selective and specific for APDs, but also to be able to dissociate between typical and atypical APDs. In recent years, newer models have been developed that are claimed to model processes impaired in schizophrenic patients. However, these models depend on previous administration of propsychotic drugs for revealing the effects of APDs, raising the possibility that the "model" of APD action is not the specific behavior assessed but the administration of the propsychotic drug. A valid behavioral model of APD action should posses the following characteristics: 1) The behavior assessed in the model has relevance to the clinical condition; 2) The behavioral paradigm used to index the action of APDs can be used in rats and humans. 3) The model is selective and specific to APDs differing in their in vitro and in vivo pharmacology. 4) The model can dissociate between typical and atypical APDs. and 5) The model does not require previous pharmacological manipulations to manifest the behavioral index of antipsychotic activity. In this overview, data are summarized showing that the latent inhibition (LI) model of APD action, which measures a cognitive process known to be impaired in schizophrenia, namely, the ability to ignore stimuli that had been inconsequential in the past, fulfills all of the above criteria. The utility of the LI model can be further extended when it is combined with the forced swim test (FST) model, which is sensitive to the antidepressant-like activity of the atypical APDs, such that the combined LI-FST model can dissociate between typical APDs, atypical APDs, and antidepressants. Finally, the use of the LI model alone or in combination with FST in rats that sustain lesions or other physiological manipulations (e.g., stimulation) to specific brain regions may provide clues as to the relationship between the effects of these drugs and the site of brain damage, and possibly reveal differential effects of typical and atypical APDs, depending on the site of the damage. Drug Dev. Res. 50:235-249, 2000.
Drug discrimination models in anxiety and depression
Pharmacology & Therapeutics, 1990
Drug discrimination is a technique for investigating the stimulus properties of centrally active drugs. Although many studies have employed animals to investigate the stimulus properties of substances used clinically for the treatment of anxiety and depression, it would be a mistake to consider the internal discriminative stimuli as being related specifically to the anxiolytic or antidepressant properties of these drugs. Rather drug cues are better considered as relating to the pharmacological action of classes of compounds. Thus, benzodiazepine cues generalize to other compounds acting at benzodiazepine receptors, but not to substances (anxiolytic or otherwise) acting at 5-HTtA receptors. Similarly, antidepressants with different pharmacological properties, for example the tricyclic imipramine, or the phenylaminoketone buproprion produce distinct, unrelated discriminative stimuli. For this reason, the limits of drug discrimination techniques for investigating novel anxiolytic or antidepressant drugs should be clearly recognized. Attempts to identify an anxiogenic discriminative stimulus using pentylenetetrazole have also been misguided. In this technique it has proven difficult to separate unequivocally the pharmacological proconvulsant effects of the drug from the psychological construct anxiety. Nevertheless, drug discrimination remains a valuable technique for investigating pharmacological interactions in animals and man. CONTENTS I. Introduction 267 2. Anxiolytic Cues 268 2. I. Benzodiazepine cues 268 2.2. Nonbenzodiazepine benzodiazepine receptor ligands 269 2.3. Serotonin cues 271 2.4. Excitatory amino acids 272 3. Anxiogenic cues 273 3.1. Pentylenetetrazole cue 273 3.2. FG 7142 cue 275 4. Antidepressant cues 276 5. Summary and Conclusions 276 References 277