Depression Animal Models

Irwin Lucki

Departments of Psychiatry and Pharmacology, university of Pennsylvania, Philadelphia, PA, uSA

Definition

Animal models for ► depression refer to experimental procedures or animal preparations which model the aspects of Major Depressive Disorder (MDD) in humans. These animal models are broadly subdivided into screening models, used primarily for identifying potential therapeutic effects of established and novel compounds, and simulation models, where the emphasis is on understanding the theoretical basis for MDD. General reviews of animal models of depression are available (Cryan et al. 2002; Nestler et al. 2002; Willner and Mitchell 2002a,b) and specific models are described in a special issue of Neuroscience & Biobehavioral Reviews (2005, vol. 29, No. 4-5).

Current Concepts and State of Knowledge Symptoms of MDD

The clinical symptoms required for diagnosis of an episode of MDD are depressed mood, markedly diminished interest or pleasure in activities, significant weight loss or weight gain, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate, and recurrent thoughts of death or suicide (DSM IV) (American Psychiatric Association 1994). The symptoms must be persistent, at least 2 weeks in duration. Some of the clinical symptoms can be modeled directly by behavioral studies in rodents and are marked in the italicized rows of Table 1. These behaviors form the basis for some of the tests and animal models of the predisposition or treatment of mood disorders.

Symptoms outside of the DSM IV criteria, such as anxiety, loss of control, and irritability, may also form the basis for animal models of depressive behavior because they are part of a dimension of similar behavior clusters described for MDD. Symptoms of depressed mood and recurrent thoughts of death and suicide cannot be modeled in rodents because they are internal or private states experienced by the patients.

Behavioral Screening Tests for Antidepressant Treatments

The most common use of animal screening tests for depressive behaviors (Table 2) is to predict the therapeutic

Depression: Animal Models. Table 1. Comparison of DSM IV symptoms of major depressive disorder in humans and behavioural tests in rodents that model those symptoms (italicized area).

Clinical symptoms of depression (humans)

Behavioral model of symptoms in rodents

Markedly diminished interest or pleasure (anhedonia)

Intracranial self-stimulation, operant responding for positive reward, ingestion of sucrose, social withdrawal

Significant changes to appetite or weight gain

Loss in body weight after exposure to chronic stress

Insomnia or excessive sleeping

Abnormal sleep architecture

Psychomotor agitation or retardation

Agitation: irritability on handling; Retardation: reduction of motor activity or speed

Fatigue or loss of energy

Reduced activity in home cage, activity tests, nest building

Indecisiveness or diminished concentration

Deficits in woking or spatial memory, learning, sustained attention

Difficulty in performing even minor tasks, such as personal hygiene

Poor coat condition and impaired grooming

Depression: Animal Models. Table 2. Pharmacological and behavioural screening tests for antidepressant drugs.

Screening tests for antidepressant drugs

Pharmacological tests

Reserpine and tetrabenazine reversal (reversal of catecholamine insufficiency)

5-HTP potentiation (augmentation of serotonin function) Yohimbine potentiation (a2 receptor blockade) Apomorphine (dopamine) and clonidine (a2) autoreceptor antagonism

8-OH-DPAT (5-HT1A autoreceptor) antagonism

Potentiation of apomorphine and clonidine-induced aggressive-defensive behaviour

Cytokine-induced depression or illness

Behavioral tests

Behavioral despair

Forced swim test

Tail suspension test

Hyponeophagia

DRL behaviour

Waiting behavior or delayed discounting effects of novel drugs. The rationale for the prediction is to reproduce the pattern of response of antidepressant drugs that have already been shown to be clinically effective, a criterion of success defined as ► predictive validity. Predictive validity for antidepressant treatments has grown more complex with the introduction of compounds and somatic treatments with a wide array of pharmacological and physiological effects. Initially, ► TCAs and ► MAOIs were the principal classes of antidepressant drugs. Subsequently, other classes of antidepressant drugs were introduced, including ► SSRIs, NRIs, ► SNRIs, and atypical antidepressants. In addition, some effective somatic treatments for depression are in widespread use, including ► electroconvulsive shock, exercise, ► transcranial magnetic stimulation, and stimulation of the vagus nerve. Diffferent antidepressant treatments (SSRIs, SNRIs, novel compounds) may produce similar behavioral effects, though they may produce their effects through different mechanisms.

Pharmacological screening tests may be based on a particular theoretical rationale, but the particular theoretical rationale used in the screen may also limit the range of compounds that can be detected with the test. For example, reversal of the effects of ► reserpine or ► tetrabena-zine ptosis, motor activity or hypothermia is based on the catecholamine hypothesis of affective disorders, because reserpine and tetrabenazine deplete catecholamines and the clinical use of reserpine was reported to cause depression. However, these screening tests cannot be used to detect SSRIs or other compounds that do not involve catecholamine mechanisms. Behavioral screening tests may differ from pharmacological tests because they are not limited to identifying drugs from a particular class. Thus, the forced swim test, based on a theoretical rationale involving ► learned helplessness (LH) as a contributor to the development of depression, can detect all of the major pharmacological and somatic classes of antidepres-sant treatments.

Behavioral tests of depressive behavior are not true animal models of MDD. They do not attempt to reproduce multiple components of depression and they do not induce symptoms for a prolonged duration. Screening tests are usually a behavioral characteristic, or an ► endophenotype, that can be measured quantitatively and is associated with a single dimension of emotional behavior related to depression. Tests of ► behavioral despair involve the reaction of animals to inescapable stress and the loss of control, hyponeophagia involves anxiety associated with novelty, and DRL or waiting behavior are tests of impulse control.

Another important dimension is whether screening tests or models respond to acute or chronic antidepressant treatment. There is a temporal delay between the initiation of clinical treatment and the appearance of full or even partial recovery. Some behavioral and pharmacological effects require chronic treatment to develop and may bear a closer temporal correlation with the time course of clinical treatments. Tests such as the forced swim test, tail suspension test, DRL behavior, and waiting behavior can respond to acute treatment with antidepres-sants, particularly at high doses. However, these tests may respond or demonstrate sensitization upon chronic treatment, particular if lower doses are used that produce plasma levels of drug that are similar to those in humans. Some behaviors, such as reduction of hyponeophagia, are produced only following chronic treatment and are associated with increases in ► brain-derived neurotrophic factor and hippocampal neurogenesis.

Depression Models Based on Environmental Adversity

A number of animal models of depression use environmental stress to produce long-term changes in behaviors associated with depression. The models of environmental adversity are based on the rationale that exposure to stress is a known precipitate of MDD (Table 3).

Learned Helplessness

► Learned Helplessness (LH) is based on an influential theory that exposure to uncontrollable stress leads animals to learn that voluntary actions will not be effective in coping with stress. LH produces changes in affective, cognitive, and motor functions, although controversy has centered on whether the effects of LH represent cognitive impairment or motoric inactivity. In LH, animals that are exposed to inescapable stress will subsequently fail to escape from a situation where escape is possible. Usually, rodents are tested for escape from electric shock in a shuttle box. Animals are compared to several control groups, including yoked control animals that receive the same amount of shock but are allowed to terminate the shock through a response. Differences are then attributable to control over shock termination.

LH animals show several neurovegetative changes that are similar to depression, such as rapid eye movement sleep alterations, reduced body weight, diminished sexual behavior, and elevated levels of corticotropin releasing factor and corticosterone. Repeated treatment with anti-depressants reduces the latency to escape and decreases the number of animals that develop LH.

It remains unclear whether LH is a better model ofpost-traumatic stress disorder and other conditions where acute stress is a clear etiological factor than of depression. Since there is variability in the susceptibility of different animals to LH, some studies have used the variability to segment vulnerable populations from resilient populations. The effects of LH training depend on genetic background, and lines of rodents have been bred with increased vulnerability that may amplify its effects (Table 4). Nevertheless, the effects of LH training are usually not long-lasting.

Depression: Animal Models. Table 3. Models of depression as a response to environmental adversity (i.e., stress).

Models of depression as a response to environmental adversity (i.e., stress)

Chronic stress

Learned helplessness

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