Chapter 6Behavioral Assessment of Antidepressant Activity in Rodents

Castagné V, Moser P, Porsolt RD.

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6.1. INTRODUCTION

Depression is one of several disorders affecting mood, along with mania, hypomania, and bipolar disorders. The present chapter focuses on behavioral assessment of antidepressant action in animals with a focus on simple tests performed in rodents. Many of the primary symptoms of depression (depressed mood, low self-esteem, guilt, difficulty in concentration, suicidal ideation, thoughts of death) are by their nature difficult to model in animals. This problem is further confounded by their unknown etiology. Several theories have been proposed [1] but most theories of depression concur in suggesting that stressful life events play an important role. There is also a small genetic component, as demonstrated by substantially increased risk in families with heritability being estimated at between 40% and 70%, leading to a much greater incidence than observed in the general population, which is nevertheless very high at around 10% [2].

If little is known about the etiology of depression, even less is known about mania and bipolar disorders. The genetic component appears to be greater than for unipolar depression [3]. Modeling the cycling, recurrent nature of bipolar disorder in animals has not even been attempted. There are, however, some models for mania that present an interesting pharmacology, in particular the combined amphetamine-chlordiazepoxide hyperactivity model, although the few publications on these models and their lack of reproducibility from one laboratory to another [4–7] make an overview of their utility difficult. They will not be further discussed in this chapter.

The clinical diagnosis of depression requires the presence of several “core” symptoms (depressed mood, decreased pleasure) often accompanied by more variable symptoms such as irritability, changes in weight, sleep disturbance, feelings of guilt, poor concentration, thoughts of death, suicidal ideation, etc. It is clearly not possible to reproduce in animals all symptoms observed clinically. Table 6.1 shows the principal symptoms observed in depressed patients and suggests analogous signs that can be observed in animals. These signs can be used as dependent variables (end point measures) allowing behavioral assessment in different animal models of depressive states.

TABLE 6.1

TABLE 6.1

Human Symptoms of Depressive States, Animal Behavioral Signs, Preclinical Tests

Several of the behavioral signs presented in Table 6.1 are, however, amenable to preclinical testing. Measures thought to be related to resignation (often termed “behavioral despair” or “learned helplessness”) are used as the main behavioral parameter in screening tests for antidepressant activity (forced swim and tail suspension tests), as well as in the learned helplessness model. In the first two tests, immobility induced by exposure to an inescapable aversive situation (forced swimming or suspension by the tail) serves as an indicator of resignation. In the learned helplessness model, animals (generally rats) are exposed to inescapable foot shocks and show “helplessness” by subsequently failing to learn to escape when the environment is modified to allow escape [8].

The forced swim and tail suspension procedures are best viewed as simple tests for antidepressants rather than as models of depression, because the dependent variable (immobility) is a direct reaction to the test itself and does not persist outside the test situation. There is no obvious induction of a “depressive state,” although there are elements of construct validity (stressful inducing conditions, decreased behavioral output). The learned helplessness procedure, where prior exposure to the aversive stress induces a more long lasting change in that animals are subsequently less able to learn appropriate escape responses, can be considered closer to a model of depression [8,9]. The above procedures have nonetheless been used not only to assess potential antidepressant activity of test substances, but also to study possible neurobiological substrates of depression [9–11]. The most obvious difference between these tests is the duration and frequency of the initiating factors. Prolonged and repeated stress is probably necessary for inducing a lasting change that could be construed as a “depressive state.”

The decreased sensitivity and lack of interest in pleasure observed in depressed patients has some analogy to anhedonia as measured in animals [12]. Anhedonia can be assessed by a variety of tests including the consumption of palatable food (such as sucrose), intracranial self-stimulation (ICSS), preference for novel objects or situations, or frequency of sexual interactions [13]. Several of these tests have been used to assess the effects of chronic mild stress and olfactory bulbectomy [13,14]. Preference for sucrose is the most widely used measure of anhedonia [15]. Other tests for anhedonia are technically challenging (ICSS) and are thus less widely used. Of all the available models, the chronic mild stress procedure possesses the greatest number of attributes of clinical depression, including putative inducing conditions and a wide variety of long-lasting behavioral changes. Rats (or mice) submitted to a series of mild stressors, such as food and water deprivation, soiled cages, and light cycle shifts, show clear and enduring signs of anhedonia (absence of preference for palatable foods or for novel objects, higher thresholds for ICSS, lowered sexual activity) and other signs (decreased food and water intake, weight loss, decreased locomotion, sleep disturbance). On the other hand, chronic mild stress procedures are very time consuming—a single study could last 2–3 months [16]—are frequently subject to methodological bias, and are reportedly difficult to reproduce from one laboratory to another [17–18].

The olfactory bulbectomy model in rats also induces several long-lasting behavioral changes (increased locomotor activity, passive avoidance deficit, mouse killing, and intra-specific aggressiveness as observed in dyadic social interaction tests), together with a variety of neurochemical changes [14–20]. Although most of these bear little direct relation to the clinical symptoms of depression, it is of more concern for this model that there is no clear analogy between the inducing conditions (olfactory bulbectomy) and the kind of life events thought to induce or favor depressive states in humans [21]. The usefulness of the olfactory bulbectomy model therefore resides largely on its predictive validity, in that most clinically effective antidepressants show activity in the test [14,22].

Another approach to assessing the potential antidepressant action of novel substances is to look at their effects on different behavioral signs that are observed in clinical depression, but are not necessarily linked to an induced “depressive” state in the animal. Although problems of body weight loss or gain feature prominently in depression, and tests for assessing changes in food/water intake or body weight gain present no major technical difficulty, no specific effects of antidepressants on these parameters have been described [13,23]. Sleep architecture, which is comparable between humans and animals [24], can be studied by electroencephalographic (EEG) analysis [25], or more simply by measurement of circadian changes in locomotor activity [26,27]. On the other hand, although it is known that antidepressants affect sleep architecture in rats [28], there are no data demonstrating the specificity of such changes to antidepressant action. Few data are available on sleep disturbance in animal models of depressive states [14,25,29].

Another behavior, the capacity of animals to repress a response over a predefined duration, which is assessed by the differential reinforcement of low rate (DRL) operant schedule, is thought to represent a measure of impulsivity [30]. An abundant amount of literature [31] has shown that numerous antidepressants show a characteristic profile in this test (moderate decreases in the number of responses accompanied by clear increases in the number of reinforcements), which can been interpreted as suggesting anti-impulsive activity. It is less clear whether anti-impulsivity characterizes clinical antidepressant activity.

The brief review presented above indicates the complexity of modeling depression in animals [18,32,33], in particular the low construct validity of available models [11,34]. The problem is less severe for antidepressant testing, where the lack of construct validity is tempered by an increase in predictive validity [35]. The procedures selected for the following sections (forced swim and tail suspension) represent a compromise in that they possess high predictive validity but also elements of construct validity. Furthermore, they do not present any major technical difficulty, are rapid to execute, and generate data that are highly reproducible.

6.2. METHODS

Rodents forced to swim in small enclosures (cylinders) from which there is no escape rapidly become immobile after an initial period of vigorous activity [36]. Initially, immobility was interpreted as evidence they had learned that escape was impossible and had given up hope. Immobility was therefore given the name “behavioral despair.” It has subsequently been shown in numerous laboratories that immobility is reduced by a wide range of clinically active antidepressant drugs [37]. As a consequence, this simple test is now widely used to screen novel substances for potential antidepressant activity. The following paragraphs describe the basic protocol (forced swimming test, protocol 1 [38]) for examining drug effects in the rat, an equivalent procedure in the mouse (protocol 2 [39]), and the conceptually related tail suspension test, where immobility is induced by suspending mice by the tail (protocol 3 [40]).

6.2.1. Animal Subjects

A large number of rodent strains have been used in the following procedures. Different strains of rats display different durations of immobility and variable sensitivity to antidepressants in the forced swimming test [41,42]. Likewise, marked strain differences have been described in the forced swimming and the tail suspension tests in the mouse [43–45]. To control the variability between different experiments, we recommend using the same rodent strains within a specific laboratory.

House animals in standard plastic cages (usually 41 × 25 × 15 cm, four to six rats per cage, or 25 × 19 × 13 cm, 10 mice per cage) containing wood shavings, and provide free access to a standard rodent diet and tap water, except during the test. Maintain the animals under strictly controlled environmental conditions (usually 21°C ± 3°C on a standard light-dark cycle with illumination from 0700 to 1900 hr).

Note 1: We recommend that the animals are delivered to the laboratory at least 5 days before the experiment, and are placed in the experimental room at least 60 min before the test. Experiments should be performed during the light phase of the cycle, although it is also possible to perform the test under dim red light during the dark phase of the cycle. In this latter case the light-dark cycle should also be reversed.

Note 2: All protocols using live animals must first be reviewed and approved by an Institutional Animal Care and Use Committee (IACUC) or must conform to governmental regulations regarding the care and use of laboratory animals.

6.2.2. Equipment

  1. Forced Swimming Test in the Rat (Protocol 1). Transparent Plexiglas cylinders (20 cm in diameter × 40 cm high) containing water (25°C) to a depth of 13 cm (made in house or obtained from local commercial suppliers). Opaque screens for visually separating cylinders.
  2. Forced Swimming Test in the Mouse (Protocol 2). Transparent Plexiglas cylinders (13 cm in diameter × 24 cm high) containing water (22°C) to a depth of 10 cm. Opaque screens for visually separating cylinders.
  3. Tail Suspension Test in the Mouse (Protocol 3). Automated tail suspension apparatus (e.g., Tail Suspension Test System, Bioseb, France) consisting of plastic enclosures (20 × 25 × 30 cm) fitted with a ceiling hook connected to a strain gauge and computer assembly [46,47]. Without an automated apparatus it is possible to perform the test using standard laboratory chronometers.

Note: All tests should be performed blind with coded solutions to avoid bias in evaluating the animal’s behavior. Decoding of treatment group codes should be performed after all evaluations have been completed.

6.2.3. Procedure: Forced Swimming Test in the Rat (Protocol 1)

In two sessions separated by 24 hr, rats are forced to swim in a cylinder from which they cannot escape. The first 15-min session is conducted prior to drug administration and without behavioral recording. This prior habituation session ensures a stable and high duration of immobility during the 5-min test session, usually performed 24 hr later. In the standard procedure, rats are administered the test substance three times: 24 hr (i.e., immediately after the first session), 4 hr, and 60 or 30 min before the test (the last pretreatment time depending on the route of administration). Two or three test substance administrations before the test provide more stable pharmacological results than a single administration. Control animals receive the same number of administrations of vehicle.

A variation of the protocol is to insert repeated treatments between the two sessions. In these cases, the interval between the two sessions usually has to be increased. We have used intersession intervals of up to 15 days without observing any change in the behavior during the second session. Repeated administration in animals is more comparable to the clinical situation where the therapeutic effect of the majority of antidepressants appears only after several weeks of treatment [48].

Equip the experimental room with white neon ceiling lights (standard lighting). Set up two transparent cylinders separated visually from each other by opaque screens. On day 1, at least 60 min before the beginning of the habituation session, mark the animals and randomly assign them to a drug treatment. All animals within a cage receive the same treatment. Weigh two animals individually, then place one rat in each of the two cylinders for 15 min (habituation session). No scoring of immobility is performed during the habituation session. Remove the rats from the cylinders, dry them with a cloth towel, and place them into a cage adjacent to their home cage. Immediately after the habituation session, treat the first group of two rats with the appropriate treatment (the first pretest administration), and place them back in their home cages. Change the water in the cylinders after every three rats. When the day 1 session is completed, return the animals to the colony room and provide food and water ad libitum.

On the test day, administer the test substance 4 hr prior to the session and 30 min (for intraperitoneal or subcutaneous injection) or 60 min (for oral administration) prior to the session. Test two animals simultaneously in adjacent cylinders separated by an opaque screen. Observe their behavior for 5 min. Score the duration of immobility by summing the total time spent immobile (i.e., the time not spent actively exploring the cylinder or trying to escape from it). Included within the time spent immobile are the short periods of slight activity where the animals just make those movements necessary to maintain their heads above water.

Note: A standard forced swimming test using 30 rats (five treatment groups of N = 6) requires two consecutive afternoons to perform the two sessions, with the morning of day 2 reserved for the 4-hr pretest drug administration. If necessary, one extra group can be tested within the same time frame (i.e., the maximum number of rats tested per experiment is 36). Experiments requiring more animals should be performed in separate sub-experiments, with the same number of animals from each treatment group being tested in each sub-experiment.

6.2.4. Procedure: Forced Swimming Test in the Mouse (Protocol 2)

In a single session, mice are forced to swim in a narrow cylinder from which they cannot escape. Equip the experimental room with white neon ceiling lights (standard lighting). Set up two transparent cylinders separated visually from each other by opaque screens. At least 60 min before testing, mark the animals and randomly assign them to a drug treatment. All animals within a cage receive the same treatment. Weigh two mice individually, administer the test substance 30 min (for intraperitoneal or subcutaneous injection) or 60 min (for oral administration) prior to the test and place them back in their home cages. Test two animals simultaneously in adjacent cylinders separated by an opaque screen. Score immobility during the last 4 min of the 6-min test session by summing the total time spent immobile (i.e., the time not spent actively exploring the cylinder or trying to escape from it). Included within the time spent immobile are the short periods of slight activity where the animals just make those movements necessary to maintain their heads above water.

Whereas mice show a high frequency of exploratory and escape-directed behaviors during the first 2 min of the test session, the last 4 min is the time during which the animals show the most immobility. The first 2 min of the session can be used for preparing other animals.

Note: A standard forced swimming test using 50 mice (five treatment groups of N = 10) requires a morning or an afternoon. If necessary, two extra groups can be tested within the same time frame (i.e., the maximum number of mice tested per experiment is 70). Experiments requiring more animals should be performed in separate sub-experiments, with the same number of animals from each treatment group being tested in each sub-experiment.

6.2.5. Procedure: Tail Suspension Test in the Mouse (Protocol 3)

This protocol describes a procedure in mice that is conceptually related to the forced swimming test, except that immobility is induced by suspending the mice by the tail. After initially trying to escape by engaging in vigorous movements, mice rapidly become immobile. The duration of immobility is reduced by a wide variety of antidepressants. This procedure has several advantages over the forced swim procedure (protocol 2). No hypothermia is induced and the animals resume normal spontaneous activity immediately after the test. No special post-experimental treatment (rubbing down, maintenance in a warmed environment) is required. The procedure readily lends itself to automation, permitting testing of a greater number of mice simultaneously.

Equip the experimental room with white neon ceiling lights (standard lighting). With the automated tail suspension apparatus (we use the TST System, Bioseb, France), six mice are tested simultaneously. Weigh the mice and administer the test substance 30 min (for intraperitoneal or subcutaneous injection) or 60 min (for oral administration) prior to the test and place the mice back in their home cages. The different treatments should be administered to individual animals in a fixed rotation to ensure a regular distribution of the different treatments over time. Our automated apparatus provides randomization sequences, permitting balanced distribution over time and over the different positions in the apparatus. Wrap adhesive tape around the animal’s tail in a constant position three quarters of the distance from the base of the tail. Suspend the animals by passing the suspension hook through the adhesive tape so that the animal hangs with its tail in a straight line. Measure the duration of immobility continuously for 6 min. If an automated testing apparatus is not available, the duration of immobility can be measured using separate chronometers for each animal.

Note: Our automated procedure (TST System, Bioseb, France) permits testing of six animals simultaneously, with all animals being placed in the apparatus before starting the measurement. For nonautomatic observation, the same observer can comfortably observe two animals simultaneously. Whatever the configuration, the animals should be visually shielded from one another during the test.

Note: A standard tail suspension test in the mouse using our automated device (five treatment groups of N = 12) requires an afternoon. If necessary, three extra groups can be tested within the same time frame (i.e., the maximum number of mice tested per experiment is 96). If an automated device cannot be used, the throughput becomes similar to the forced swimming test in the mouse (i.e., 70 animals can be tested during the same session).

6.3. TYPICAL APPLICATIONS

The forced swimming test in the rat and the mouse, and the tail suspension test in the mouse are widely used for early behavioral screening of antidepressants [49,50]. Some false positives (mainly excitatory substances) and some false negatives (mainly serotonin reuptake inhibitors) have been described (see Section 6.5). As a consequence, we recommend using all three procedures to evaluate new test substances, instead of relying on a single procedure [34]. This reduces the number of false positives and false negatives and thereby enhances the efficiency of drug discovery programs. The forced swimming and the tail suspension tests can also be used to characterize the phenotype of different strains of animals, including transgenic mice [51]. In this respect, the forced swimming and the tail suspension tests can also be used as research tools for investigating the neurobiological bases of depressive states.

6.4. ANALYSIS AND INTERPRETATION

Compare data from treated groups with data from the control group using unpaired Student’s t-tests (two tailed), although other statistical evaluations (e.g., analysis of variance followed by post-hoc tests) can also be used. For initial screening, we strongly recommend two-by-two t-test comparisons of treated groups with control. Although increasing the risk of a type I error (false positive), there is a decreased risk of a type II error, i.e., missing a potential drug effect at a particular dose (false negative), as can happen with more global analyses including all treatments.

Antidepressants decrease the duration of immobility in the forced swimming test in the rat and the mouse (protocols 1 and 2), and in the tail suspension test in the mouse (protocol 3). Sedative/myorelaxant substances are generally inactive or even increase the duration of immobility in the different tests.

6.5. REPRESENTATIVE DATA

Pharmacotherapy of depressed patients uses various classes of antidepressants that generally target central monoaminergic systems [52,53]. Besides monoamine oxidase inhibitors (MAOIs), the majority of antidepressants belong to different classes of monoamine reuptake inhibitors, including selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (NRIs), and mixed reuptake inhibitors (SNRIs) [54].

The etiology of depression is, however, insufficiently understood to limit discovery efforts to substances with clearly identified targets [1]. Although the involvement of central monoaminergic systems in antidepressant action is widely accepted, the long delay between the initiation of monoamine-based treatments and the first clinical effects suggests that more complex mechanisms are involved [53]. In addition, studies showing that multiple central neurotransmitter systems are implicated in depression suggest that non-monoamine-based treatments may represent potentially interesting new therapeutic approaches [55]. The major problem with current pharmacological treatments is that they either fail to produce complete recovery or induce unwanted side effects. Thus there is urgency for the development of new pharmacological treatments.

The data presented in Table 6.2 show the effects of diverse substances after i.p. administration in the forced swimming test in the rat. All substances were administered 24 hr, 4 hr, and 30 min before the test. Dose-dependent decreases in the duration of immobility are observed with imipramine (8–64 mg/kg), fluoxetine (32 and 64 mg/kg), desipramine (8–32 mg/kg, but not 64 mg/kg), and venlafaxine (16–64 mg/kg). Some serotonergic substances targeting the 5-HT1A receptor also decrease immobility. This was observed for 8-OH-DPAT (0.5–4 mg/kg), flesinoxan (4 and 16 mg/kg), and idazoxan (4 mg/kg).

TABLE 6.2

TABLE 6.2

Effects of Diverse Substances in the Forced Swimming Test in the Rat

The data presented in Table 6.3 show the effects of diverse substances after i.p. administration in the forced swimming test in the mouse. All substances were administered 30 min before the test. Dose-dependent activity is observed for imipramine (8–64 mg/kg). Monoamine reuptake inhibitors show clear activity, generally more marked than in the rat, as observed with fluoxetine (16–64 mg/kg), and desipramine and venlafaxine (8–64 mg/kg). Clobazam (32 and 64 mg/kg) increases immobility consistently with its sedative/myorelaxant effects. Clozapine (1–8 mg/kg) is devoid of activity. Nicotine decreases immobility at 1 mg/kg. Serotonergic substances targeting the 5-HT1A receptor have variable effects in the mouse. 8-OH-DPAT (2 and 8 mg/kg), idazoxan (4 and 8 mg/kg), and alnespirone (4 and 16 mg/kg) decrease immobility, whereas buspirone (1–16 mg/kg) is devoid of activity, and flesinoxan increases immobility at 16 mg/kg.

TABLE 6.3

TABLE 6.3

Effects of Diverse Substances in the Forced Swimming Test in the Mouse

The data presented in Table 6.4 show the effects of diverse substances after i.p. administration in the tail suspension test in the mouse. All substances were administered 30 min before the test. Decreases in immobility are observed for imipramine (8–32 mg/kg), and fluoxetine, desipramine, and venlafaxine (all over the dose range 8–64 mg/kg). Clobazam (8–32 mg/kg) and clozapine (4 and 8 mg/kg) increase immobility. Nicotine (0.5–2 mg/kg) does not affect immobility. 5-HT1A agonists increase immobility in the tail suspension test. This is observed for 8-OH-DPAT (8 mg/kg), and buspirone, flesinoxan, and alnespirone (all at 4 and 16 mg/kg).

TABLE 6.4

TABLE 6.4

Effects of Diverse Substances in the Tail Suspension Test in the Mouse

Taken together, these results confirm the specificity of the forced swimming test toward antidepressant substances [36]. In our hands, the mouse version appears somewhat more sensitive to serotonin reuptake inhibitors. The weak but significant activity of nicotine at 1 mg/kg is consistent with the fact that excitatory substances may constitute false positives in the forced swimming test [41,56]. Nevertheless, antidepressant-like activity for nicotine has also been described in the mouse [57] and in the rat [58]. The tail suspension test is sensitive toward a wide variety of antidepressant substances that are clearly distinguished from other psychotropic substances such as anxiolytics, neuroleptics, and other diverse agents [47,59]. It is interesting to note that the tail suspension test in the mouse appears to be more sensitive to the sedative activity (increase in immobility) of 5-HT1A agonists, in contrast to the forced swimming test in the rat, which detects mainly their antidepressant-like activity (decrease in immobility).

6.6. COMPARISON WITH RELATED PROCEDURES

The methods of testing clearly influence the results of the tests. Some studies suggest absence of activity of serotonin reuptake inhibitors using the standard forced swimming test [60,61]. Modifications of the original procedure, including measurement of active behaviors such as swimming and climbing and increasing the water depth, have been claimed to facilitate detection of SSRIs [62]. Although this scoring method is now used by several laboratories [63], other data cast doubt on a clear behavioral distinction of the effects of SSRIs and NRIs [64]. Since the standard forced swimming test allows detection of multiple classes of antidepressants, we prefer to limit the behavioral analysis to the measure of immobility, which is simpler to estimate than the measure of active behaviors. Extensive training of the observers to score immobility is needed even in the standard version of the forced swimming test [10].

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