Experimental Disease Models

Drug discovery in depression has been hampered by the lack of a universally accepted animal model(s) that can be used to screen NCEs for antidepressant effects. Although there are several animal models that reproduce some features of depression in the context of stress and/or separation, it is questionable as to whether these are relevant to the human disorder MDD or BPAD. The advantages and disadvantages of animal models for depression are summarized in Table 6. In all cases, the behavioral features can be reversed by conventional antidepressant drug treatment. However, despite their intrinsic limitations, the full potential of these models has not yet been realized and they represent an under-explored opportunity. The heuristic value and the knowledge gain from behavioral animal models in psychopharmacology is, explicitly or implicitly, the central preoccupation of psychopharmacolo-gists.24 There are a number of compelling reasons to believe in the legitimacy of animal models in the development of

Table 6 Animal models of major depression

Model

Rationale

Description

Part 1

Uncontrollable stress models:

• Learned helplessness model (LHM)

• Behavioral despair/ forced swim test (BD/FST)

• Tail suspension test (TST)

Reward models:

• Intracranial self-stimulation (ICSS)

• Sucrose preference

• Place preference

Olfactory bulbectomy

Exposure to uncontrollable stress produces performance deficits in learning tasks that are not subsequently seen in subjects exposed to identical stressors that are under the subjects' control

Stress induces abnormalities in reward processes. These paradigms are not considered models of an entire syndrome, but rather provide operational measures of anhedonia, a core feature of depression and a negative symptom of schizophrenia

Olfactory bulbs are extensions of the rostral telencephalon and constitute 4% of the total brain mass in adult rats. Extensive connections with the limbic and higher brain centres implicate this model in wide-ranging effects other than anosmia

LHM: rats or mice exposed to uncontrollable stress, for example uncontrollable foot shock. BD is a variant of LHM: rats or mice are forced to swim in a confined environment. TST is theoretically similar to BD: mice are suspended by their tails for 6 min; the amount of time they spend immobile is recorded

ICSS: brief electrical self-stimulation of specific brain sites, which is very reinforcing. In reward models, the rate of responding and/or the psycho-physically defined threshold(s) can be used to measure the reward value of the stimulation. The effects of stress are used to change the animal response to reward models; for example, sucrose preference is decreased by chronic stress models, the decrement in sucrose ingestion being a measure of anhedonia. Amphetamine withdrawal seems to be a suitable substrate for inducing depression-like symptoms in rodents

Bilateral removal of olfactory bulbs of rodents (mainly rats)

Phenotype reproduced

Predictive validity

Loss of appetite and weight, decreased locomotor activity and poor performance in both appetitively and aversively motivated tasks

Anhedonia is the markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day

Pharmacological treatments clinically effective in depression are effective in reducing the behavioral and 'physical' abnormalities seen in animals exposed to uncontrollable stress. These models have a high degree of predictive validity in terms of pharmacological isomorphism Stress-induced alterations in ICSS behavior were reversed by antidepressant treatment. Anhedonic effect of stress was reversed by antidepressant treatment, but not by antipsychotic, anxiolytic, amphetamine or morphine treatment, indicating good predictive validity in terms of pharmacological isomorphism

Behavioral, neurochemical, neuroendocrine and neuroimmune alterations seem comparable to changes in depression

Reliable prediction of response to antidepressants in rats

Chronic mild stress (CMS)

Part 2

Drug withdrawal Manual deprivation

Neonatal clomipramine

Drosophila melanogaster

Caenorhabditis elegans

Zebrafish (Danio rerio)

Exposure to mild, unpredictable stressors induces long-term changes resembling those found in depressed patients

CMS has two major readouts: CMS depresses the consumption of sucrose solutions and it also decreases brain reward function (see above)

Withdrawal from drugs of abuse reduces brain reward function

Development of stress-responsive systems is maternally regulated. Separating mother and pups results in activation of stress systems Clomipramine increases monoaminergic availability at the synaptic level and suppresses REM sleep Basis for further dissection of the genetic components of vesicular monoamine transporters (VMATs)

C. elegans expresses both the vesicular acetylcholine transporter and the vesicular monoamine transporter

Linking genes to brain, behavior and neurological diseases

Amphetamine withdrawal seems to be a substrate for inducing depressionlike phenotypes. Readouts can be ICSS, sucrose preference, BD, TST or LHM Litters are separated from their mother for the neonatal period and are subsequently tested

Rat pups are treated from postnatal day 5 to 21 with clomipramine 15 mg per kg subcutaneously twice daily

Genetic analysis of vesicular transporter function and regulation in the Drosophila homolog of the vesicular monoamine transporter (dVMAT)

C. elegans contains monoamine and tyramine receptors, that individual isoforms may differ significantly in their sensitivity to other physiologically relevant biogenic amines

Comparison of dopaminergic (DA) and serotonergic (5HT) neurons in larval and adult zebrafish, both wild type and mutants and their relationship to human neurons

Behavioral, neurochemical, neuroendocrine and neuroimmune alterations that resemble those seen in depression

Anhedonia is the markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day

H PA axis alterations. Constellation of behavioural changes in the adult rat resembling features of human depressive psychopathology

Behavioural changes in adulthood, circadian disturbances and sexual behaviour alterations

The regulation of mammalian VMAT and the related vesicular acetylcholine transporter (VAChT) has been proposed to involve membrane trafficking, similar to mammalian systems

C. elegans monoaminergic and tyrpaminergic signaling may be important in understanding of the regulation of mammalian systems with regard to trace amines

Zebrafish offer a potentially important source of mutant neurons that will aid understanding of the development as well as the function of forebrain DA and 5HT neurons

Anhedonia-like behaviors are reversed by chronic but not acute antidepressant treatment. Poor reliability of results in rats has limited the utilization of this model

Anhedonia-like behaviors are reversed by chronic but not acute antidepressant treatment

Limited testing of antidepressants has been conducted

Limited testing of antidepressants has been conducted

Similar to mammalian VMAT homologs and are inhibited by reserpine and the environmental toxins

The pharmacological profile of C. elegans VMAT is closer to mammalian VMAT2 than VMAT1

Potential to provide important insights into the relationship between genes, neuronal circuits and behavior in normal as well as diseased states continued

Table 6 Continued

Model

Rationale

Description

Phenotype reproduced

Predictive validity

Part S

Genetic models: selective animal breeding

Transgenics

Other useful tests

Rats are selectively bred for hypo- or hypersensitivity or specific receptor subtypes whose altered function has been thought to be involved in aetiology of depression Transgenic mice (knockout or overexpressers) that exhibit depression or antidepressant-related behavior

These tests may address specific psychiatric behavior/symptoms

Cholinergic-noradrenergic neurotransmitter imbalance (Flinders Sensitive Line rats); the 8-OH-DPAT line of rats Fawn-Hooded (FH/Wjd); Rouen 'depressed' mice

• Norepinephrine (NE) system

• Monoamine oxidase

• Glutamate substance P system

• Immunological intracellular signaling molecules and transcription factors

• Other neurotransmitters or receptors

EEG characterization energy expenditure, nesting behavior, social avoidance or withdrawal swimming, treadmill/running wheel

Attention, spatial memory working memory

Prenatal stress

Novelty suppressed feeding Resident intruder

LPS-induced immunological activation

Animals are more susceptible to stress-induced behavioral disturbances

Phenotype is variable and each model has been accessed by one or more paradigm listed above (such as BD, TST, LHM, and CMS)

Fatigue or loss of energy can be assessed by these tests; social withdrawal can also be a measure of anxiety

Decreased ability to think or concentrate May reproduce stress or conditions that influence behavioral or physiological changes during adulthood May reflect anxiety

May reflect social stress or anxiety

Might reproduce neuroimmume or neuroendocrine changes that occur during stress

Increased immobility in the forced swim test and foot shock response to antidepressants

Phenotypes can be depressionlike or antidepressant

These tests measure changes in signs that are not necessarily specific for depression

Same as above

Same as above

Behavioral effects following chronic treatment Change in agonistic behavior during the course of antidepressant drug treatment Sensitive to tricyclic antidepressants

BD, behavioral despair; CMS, chronic mild stress; EEG, electroencephalogram; GABA, g-amino-butyric acid; HPA, hypothalamic-pituitary-adrenal; LHM, learned helplessness model; LPS, lipopolysaccharide; REM, rapid eye movement; TST, tail suspension test. Modified from Wong and Licinio (2004).25

new improved drugs for the treatment of mental disorders; however, these models need to be based on the following

• Predictive validity: the ability of a model to accurately predict clinical efficacy of a psychoactive pharmacological agent.

• Face validity: the similarity of the model to clinical manifestations of phenomenon/disorder in terms of major behavioral and/or physiological symptoms and etiology.

• Construct validity: the strength of the theoretical rationale upon which the model is based.

Animal models have been defined as experimental preparations developed in one species for the purpose of studying or understanding a phenomenon occurring in another species (e.g., the 5HTsyndrome crosses species). In the case of animal models of human psychopathology, the aim is to develop syndromes that resemble those in humans in order to study selected aspects of psychopathology. The behavioral models are explicitly related to a broader body of theory, as they fulfill a valuable function in forcing the clinician and psychopharmacologists alike to critically examine their assumptions of the manifestations and pathophysiology of depression and bipolar disorders.25

To denigrate animal models of psychiatric disorders seems unwise when various examples can be clearly replicated in animals and in humans, which argues for their validity in creating phenotype models of mental disorders. It is clear that the etiology of psychiatric disorders is still in its infancy; however, a healthy skepticism provides a valuable service in pointing out the many shortcomings when animal models are measured against the complexities of human behavior.29

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