Animal models of depression

Animal models of depression are research tools used to investigate depression and action of antidepressants as a simulation to investigate the symptomatology and pathophysiology of depressive illness or used to screen novel antidepressants.

Introduction

Depression

Major depressive disorder, also called "clinical depression" or often simply "depression", is a common, long-lasting and diverse psychiatric syndrome that significantly affects a person's thoughts, behavior, feelings and sense of well-being. Symptoms include low mood and aversion to activity. Depressed people may also feel sad, anxious, empty, hopeless, worried, helpless, worthless, guilty, irritable, hurt, or restless. They may lose interest in activities that once were pleasurable, experience loss of appetite or overeating, have problems concentrating, remembering details, or making decisions, and may contemplate or attempt suicide. Insomnia, excessive sleeping, fatigue, loss of energy, or aches, pains, or digestive problems that are resistant to treatment may also be present.[1]

About one in six people in the U.S will succumb to depression at some point during their life span,[2] and according to the World Health Organization, depression is projected to reach second place as leading contributor to the global burden of disease by the year 2020.[3] The current antidepressants have late drug efficacy about 3–6 weeks; besides, many patients’ illness cannot be alleviated.[4]

Modeling depression in animals

It is difficult to develop an animal model that perfectly reproduces the symptoms of depression in patients. Many animals lack self-consciousness, self-reflection, and consideration; moreover, hallmarks of the disorder such as depressed mood, low self-esteem or suicidality are hardly accessible in non-humans. However, depression, as other mental disorders, consists of endophenotypes[5] that can be reproduced independently and evaluated in animals. An ideal animal model offers an opportunity to understand molecular, genetic, and epigenetic factors that may lead to depression. By using animal models, the underlying molecular alterations and the causal relationship between genetic or environmental alterations and depression can be examined, which would afford a better insight into pathology of depression. In addition, animal models of depression are indispensable for identifying novel therapies for depression.

Endophenotypes in animal model of depression

The following endophenotypes have been described:[5]

Criteria for valid animal models of depression

An appropriate animal model of human depression should fulfill the following criteria as much as possible: strong phenomenological similarities and similar pathophysiology (face validity), comparable etiology (construct validity), and common treatment (predictive validity).[6][7][8] Again, depression is a heterogeneous disorder and its many symptoms are hard to be produced in laboratory animals. The question therefore remains whether we can know the animal is "depressed". Actually, few models of depression fully fit these validating criteria, and most models currently used rely on either actions of known antidepressants or responses to stress. It is not necessary for an "ideal" animal model of depression to exhibit all the abnormalities of depression-relevant behaviors, just as not all patients manifest every possible symptom of depression.

Antidepressant screening tests

Antidepressant screening tests, not like the models which can be defined as an [organism] or a particular state of an organism that reproduces aspects of human pathology, provide only an end-point behavioral or physiological measure designed to assess the effect of the genetic, pharmacological, or environmental manipulation.

Despair-based

Forced-swimming test
The advantages of FST are that it is low-costing and is a fast and reliable tool, easy to handle and has proven its reliability across laboratories, for testing potential antidepressants activities with a strong predictive validity. Besides, it allows rapid screening of large numbers of drugs. The major disadvantages of FST are that it has poor face and construct validities. The test is sensitive to acute treatment only, and its validity for non-monoamine antidepressants is uncertain
Tail suspension test
A major advantage of the TST is that it is simple and inexpensive. A major disadvantage of the TST is that it is restricted to mice and limited to strains that do not tend to climb their tail. Besides, like FST, TST is sensitive to acute treatment only, and its validity for non-monoamine antidepressants is uncertain.

Reward-based

Open field

Anxiety-based

Elevated plus maze
Dark/light box

Stress models

Certain types of human depression are precipitated by stressful life events, and vulnerable individuals experiencing these stressors may develop clinical depression. Consequently, the majority of animal models of depression are based on the exposure to various types of acute or chronic stressors.

Adult stress models

An advantage of LH is that the cognitive and other behavioral outcomes seem to be correlated, thus helping to understand the depressive symptomatology in humans. Besides, this model can also be generally used to measure the escape performance of mice with different mutations, in which target genes of depression may affect the vulnerability to develop a depressive-like state. These excellent face and predictive validities make LH an interesting model to explore the pathophysiology of depression. The biggest disadvantage of LH is it requires very strong stressors to induce the behavioral phenotypes, which does raise ethical problems. Also, most of the symptoms do not persist long enough following cessation of the uncontrollable shock.
The advantages of this model are its good predictive validity (behavioral changes are reversed by chronic treatment with a wide variety of antidepressants), face validity (almost all demonstrable symptoms of depression have been reproduced), and construct validity (CMS causes a generalized decrease in responsiveness to rewards). However, there is a common practical difficulty in carrying out CMS experiments, which are labor intensive, demanding of space, and of long duration. Besides, the procedure can be difficult to be established and data can be hardly replicated.
Like CMS, SDS has good predictive validity (behavioral changes are reversed by chronic treatment with a wide variety of antidepressants), face validity (many symptoms of depression have been reproduced), and construct validity(causing a generalized decrease in responsiveness to rewards) and gives another validity that only chronic but not acute antidepressant administration can reverse the social aversion. One disadvantage of SDS model is the long duration. To apply SDS model for studying human depression, the period of it should last at least 20 days otherwise only anxiety symptoms could be induced. Worthy of note, only male rodents can be used for this model, since female rodents do not fight each other in a resident–intruder confrontation.

Early life stress models

Early adverse experiences such as traumatic life events in childhood result in an increased sensitivity to the effects of stress later in life and influence the individual vulnerability to depression.[27] Suitable animal models could provide a basis for understanding potential mechanisms of environmental and developmental factors of individual differences in stress reactivity and vulnerability to disorders. Models of early life stress involve prenatal stress, early postnatal handling and maternal separation. All these treatments have been demonstrated to produce significant effects that last until adulthood.

Other models

See also

References

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