Dominant–submissive behavior as models of mania and depression

Neuroscience and Biobehavioral Reviews 29 (2005) 715–737 www.elsevier.com/locate/neubiorev

Review

Dominant–submissive behavior as models of mania and depression Ewa Malatynskaa,*, Richard J. Knappb a

Johnson and Johnson, Pharmaceutical Research and Development, Spring House, PA 19477, USA b Aventis Pharmaceuticals Inc., Bridgewater, NJ 08807, USA

Abstract This review examines the ways in which dominant–subordinate behavior in animals, as determined in laboratory studies, can be used to model depression and mania in humans. Affective disorders are mood illnesses with two opposite poles, melancholia (depression) and mania that are expressed to different degrees in affected individuals. Dominance and submissiveness are also two contrasting behavioral poles distributed as a continuum along an axis with less or more dominant or submissive animals. The premise of this article is that important elements of both mania and depression can be modeled in rats and mice based on observation of dominant and submissive behavior exhibited under well defined conditions. Studies from our own research, where dominance and submissiveness are defined in a competition test and measured as the relative success of two food-restricted rats to gain access to a feeder, have yielded a paradigm that we call the Dominant Submissive Relationship (DSR). This paradigm results in two models sensitive to drugs used to treat mood disorders. Specifically, drugs used to treat mania inhibit the dominant behavior of rats gaining access to food at the expense of an opponent (Reduction of Dominant Behavior Model or RDBM), whereas antidepressants counteract the behavior of rats losing such encounters; Reduction of Submissive Behavior Model (RSBM). The validation of these models, as well as their advantages and limitations, are discussed and compared with other animal paradigms that utilize animal social behavior to model human mood disturbances. q 2005 Published by Elsevier Ltd. Keywords: Dominance; Submissiveness; Mania; Depression; Antimanic drugs; Antidepressants; Food competition tests; Resident–intruder tests; Society

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Dominant–submissive behavior relative to human mania and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Definition and measurement of dominance and submissiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Formation of dominant–submissive relationship (DSR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clonidine reversal of dominance model (CRDM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reduction of submissive behavior model (RSBM) of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reduction of dominant behavior model (RDBM) of mania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Response of dominant and submissive behavior studied in different settings to psychotropic drugs. . . . . . . . . . . . . . . . . . . . . Biochemical differences found between dominant and submissive animals in relation to the changes observed in patients . . . . Neural systems contributing to dominant–submissive behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Dominant–submissive behavior relative to human mania and depression

* Corresponding author. Tel.: C215 628 5121; fax: C215 540 4666. E-mail address: [email protected] (E. Malatynska).

0149-7634/$ - see front matter q 2005 Published by Elsevier Ltd. doi:10.1016/j.neubiorev.2005.03.014

Mania and depression are polar opposites on a continuum between grandiose self-importance and self-perceived ability on one side and feelings of self-loathing, incompetence and apathy on the other. These two opposite states of mood can exist at different times in one individual forming

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E. Malatynska, R.J. Knapp / Neuroscience and Biobehavioral Reviews 29 (2005) 715–737 Bipolar I

Submissiveness

Dominance

Bipolar II Unipolar Melancholia Regulation of Mood

Regulation of social position

Mania Deviation From Mood Homeostasis

{ dysthymia hyperthymia cyclothymia normal range

Fig. 1. Graphical illustration of systematic of the affective disorders as defined in the Diagnostic and Statistical Manual of Mental Disorders produced by the American Psychiatric Association. Reproduced from Malatynska et al. (2002).

bipolar disorders (Fig. 1). While these descriptions involve internal self-perception there are overt behavioral consequences to these conditions. People with mania are hyperactive with a reduced desire for sleep and are socially assertive. Depressed individuals tend to be obsessed with personal failings, apathetic and socially withdrawn. The affective disorders are defined in the fourth Diagnostic and Statistical Manual of Mental Disorders (DSMIV) (American, Psychiatric, Association, 1994). Affective disorders include depressive disorders (major depressive disorder, dysthymic disorder and unspecified depressive disorders), bipolar disorders (bipolar I disorder, bipolar II disorder, cyclothymic disorder, unspecified bipolar disorder, and other mood disorders. The distribution of dominant–submissive behavior in a group of animals has similarities to affective disorders. Dominance has a tendency to be distributed as a gradual continuum along an axis with less and more dominant or less and more submissive animals. This continuum culminates in two opposite poles of extreme behavior (Fig. 2). Only a fraction of the human population develops depression and less than half of animals studied in our test form clear dominant–submissive relationships. The majority of animal subjects form flexible relationships without dominant or submissive behavior. The observation of this similarity led us to study submissiveness as a model of depression and dominance as a model of mania. Theories concerning the function of societies suggest that the role of dominance is to ensure homeostatic stability of relations within a group (Wynne-Edwards, 1963, 1965). In particular, three functions of the hierarchical structure of society are especially important as reviewed by van Kreveld (1970). They can be summarized as follows: (1) it is an integrative function-enabling group defense against unfavorable outside forces, (2) it provides a control over aggression within the group, (3) it serves to regulate the size of the population. This feedback mechanism (3) insures that the weakest individuals are destined to die or do not

Deviation from

{ more likely to form submissive relations

more likely to form dominant relations

environmentally flexible

Fig. 2. Graphical illustration of two polarized behavioral traits: dominance and submissiveness. These two behaviors are observed among animals that form social relations. Reproduced from Malatynska et al. (2002).

reproduce themselves when resources become scarce. The linkage between dominant–submissive behavior in animals and humans is provided by evolutionary theory. The concept of evolution suggests that Homo sapiens evolved from other species by developing new features on the base of existing ones. To the extent that social behavior promotes individual survival, physical traits that underlie social behavior may be selected. The value of social behavior to individual reproductive success and species survival is clear even if the genetic elements contributing to this are obscure. Social hierarchy is common in many animal phyla including fish, reptiles, birds, and mammals. This extends to different species of a phylum. For example, within mammals it is found among mice, rats, dogs, and most primates as well as humans. Investigators have studied the hierarchical structure of animal relationships as early as the beginning of the 20th century (for review see van Kreveld (1970)) and before. Based on these studies and his psychiatry practice, Price (1967) suggested that dominance and subordination were equivalent to mania and depression, respectively. Many studies have examined the similarity between submissive behavior in animals and depression in humans (for review see Gardner, 1982). Blanchard et al. (1987, 1988) describe the relationship between human depression and subordinate behavior of animals. They showed that dominant–submissive behavior in rats develops a few days after grouping and can stay unchanged during their lifetime. Subordinate animals, similarly to depressed humans, show increased defensive behavior, weight loss and major alterations in sleep, eating and active behaviors. In later studies, Price et al. (Price and Sloman, 1984; Price et al., 1994; Price, 1998) and Gardner (1982) analyzed different aspects of human elation and submissiveness that can be related to mania and depression. Specifically they postulated that in humans involuntary submission is causally related to depression. They also proposed a theory for modeling mania by dominant behavior in animals based on observations of human social interactions. Our research on submissive and dominant behavior of animals (Malatynska et al., 2002a,b)

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and its sensitivity to antidepressants and antimanic drugs used in clinic independently led us to the conclusion that depression can be modeled by animal submissiveness and mania by animal dominance. While there are several studies exploring the antidepressant drugs effect on different forms of submissive behavior (Zagrodzka et al., 1985; Koolhaas et al., 1990; Kudryavtseva et al., 1991; Mitchell and Redfern, 1992) there are no experimental studies to date fully validating a relationship between dominant behavior and mania. The sensitivity of dominant behavior to antimanic drugs in the RDBM was shown by Malatynska et al. (2002) and it is presented in this review.

2. Definition and measurement of dominance and submissiveness Dominance is a relative term that defines the social position or status of one individual in society toward others. van Kreveld (1970) defined dominance as ‘mutually respected rights one group member has over another’. It is defined by Webster’s dictionary (Merriam-Webster, 1983) as ‘ruling, prevailing, most influential or conspicuous’. Usually dominance is not absolute in that one animal can dominate another in some but not all situations. However, Gardner (1982) described extreme examples of alpha animals (absolute dominance) and omega animals (absolute subordination). An observation based on our experiments where dominance and submissiveness is defined in a competition test seems to support this concept. In our experimental paradigm some animals are always dominant or submissive when confronted with any other members of a given group (unpublished observations). Different investigators have used various endpoints to measure dominance: (1) observation of hierarchy in groups of animals (two or more) by denoting their communication through different body postures, (2) competition for priority of access to different resources with distinct types of scoring, and (3) social defeat, using mostly observation of body postures. Animals living in groups usually establish a hierarchy of individual relationships. To maintain their status animals in close proximity display certain behaviors that are perceived by investigators as characteristic postures (for definition of particular postures see Grant and Mackintosh (1963) and Panksepp (1998)). These postures can be interpreted as expressions of animal intention. Agonistic postures displayed by an animal define his/her behavior as dominant (Mitchell and Fletcher, 1993; Mitchell and Redfern, 1997; Willner et al., 1995). The display of defensive postures is a characteristic feature of submissive animals and is used to measure submissiveness (Kudryavtseva et al., 1991, 1989). In a laboratory environment groups of animals are observed in their home cage or the visible burrow system used by Blanchard et al. (Blanchard et al., 1988; Blanchard and Blanchard, 1989). The dominant–submissive relations

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between animals in such settings depend mostly on the inter-individual dynamics. They are spontaneous and minimally manipulated by the investigator. However, dominant–submissive relations can be forced by scarce resources like food, water territory or sexual partners and measured by the priority of access. In such experiments submissiveness (‘loser’ like) and dominance (‘winner’ like) behavior is defined in competition tests (Uyeno, 1960, 1966; Masur et al., 1975; Rapaport and Maier, 1978). In laboratory settings difficulty of access and amount of resources can be manipulated by the investigator. Usually animals are given restricted access to a desired resource to increase their motivation (Malatynska et al., 1995, 2002; Rapaport and Maier, 1978; Malatynska and Kostowski, 1984; Schutz et al., 1978; Masur et al., 1971a; Plewako and Kostowski, 1984). In some experiments a palatable food like chocolate pieces or sucrose pellets has been used without food restriction (Gentsch et al., 1988a; File, 1986). Competition can be observed in groups, triads or pairs of animals. The definition of dominance as a winner behavior and submissiveness as a loser behavior in triads, or especially in pairs of animals, have better success than their definition within larger groups of subjects. Some authors questioned the use of priority of access as a measure of dominance (Syme and Syme, 1974; Benton et al., 1980). These authors characterized hierarchy in larger groups of animals where the priority of access is not always obvious (this is especially difficult to establish for rodents). The observation of postures requires extensive videotaping for analysis that is slow and requires subjective judgments by the scorer. In contrast, endpoints such as time spent on a feeder (Malatynska et al., 2002; Malatynska and Kostowski, 1984) or number of sucrose pellets consumed (Gentsch et al., 1988b) can be easily adapted for fast and objective automated behavioral analysis. Many investigators have used social defeat to produce or characterize dominant–submissive behavior (Kudryavtseva et al., 1991; Willner et al., 1995; Seward, 1946; Frischknecht et al., 1982; Ginsberg and Allee, 1942; Siegfried et al., 1982). In such tests animals are typically pre-selected for the presence or absence of aggressiveness by prior observation of their behavior. Aggressiveness of a selected ‘offender’ animal can be increased by social isolation or by utilization of animal territoriality. The latter is used in the resident–intruder test (Kudryavtseva et al., 1991; Mitchell and Fletcher, 1993). Most often a predetermined submissive animal is selected for the nonaggressive intruder role. Intruder animals are exposed to a single or series of attacks by placement in the resident animal’s cage. Submissive animals are especially sensitive to this procedure and develop pronounced features characteristic of depression (Kudryavtseva et al., 1991). The resident intruder test, which is often used to study dominant–submissive behavior in pharmacological settings, combines priority of access (to the territory) with observation of body postures. The group of tests based on

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social defeat emphasizes aggression and sensitivity to stress as the components of dominant–submissive behavior. However, the role of aggression in the establishment of dominance can be minor (Fonberg, 1988) and emotional disturbances in depression involve more than a simply reaction to stress since stress can also precipitate other psychiatric disorders (e.g. mania, schizophrenia, compulsive obsessive disorders).

3. Formation of dominant–submissive relationship (DSR) Dominant and submissive behavior can be objectively measured in the DSR test as time spent on the feeder by each of two food-restricted rats. Based on this test we are developing an animal behavioral model of mania, referred to as the Reduction of Dominant Behavior Model (RDBM) that is sensitive to antimanic drug activity (Malatynska et al., 2002). We are using submissive behavior observed in the DSR as a model of depression and the Reduction of Submissive Behavior Model (RSBM) as a test for antidepressant drug activity (Malatynska et al., 2002). Neither model, RDBM or RSBM, is a complete model of bipolar disorder but they can be used together to model individual poles of bipolar symptoms (for the discussion of these problem see Pillmann (2001). The apparatus presented in Fig. 3 was used to determine DSR in rats and mice. The methodology and equipment are described in several publications (Malatynska et al., 1995, 2002a,b; Malatynska and Kostowski, 1984; Knapp et al., 2002; Kostowski et al., 1986; Danysz et al., 1988) Testing pairs of rats having a dominant–submissive relationship begins with the random assignment into pairs. Animals from these pairs are housed separately between test sessions with other animals in groups of four. All rats are food-deprived overnight with free access to water. The test involves placing each member of a pair in opposite chambers of the testing apparatus. These chambers are connected through a narrow tunnel with a small container of sweetened milk at the center. Only one animal at the time can have comfortable access to the feeder. The test is conducted once a day over a 5 min period and the time spent on the feeder by each animal is recorded. At the end of the 5 min testing period the animals are separated, returned to their home cages and given free access to food for a limited period of time. The testing is suspended during weekends

Fig. 3. The RSBM apparatus consists of two plexiglass chambers connected by a passage having a small feeder dish with milk in the center from which only one rat can drink at a time. Reproduced from Malatynska and Kostowski (1984) and Malatynska (1985).

and the animals have free access to food during this time. During the first week (five days) of testing the drinking scores vary considerably and these data are used only to detect any apparent changes in dominance status (reversals) within the pairs of tested rats. Under such conditions animal behavior can be categorized into three types, dominant, submissive or neutral. This is determined by measuring differences in time spent at the feeder by each animal of a pair. Dominant animals out-compete submissive animals for food in the apparatus and spend more time on the feeder. Pairs meeting well-defined criteria (Table 1) are determined to have dominant–submissive relationship. They are clearly distinguished from pairs that do not develop a dominant– submissive relationship (neutral pairs). Dominant–submissive relationships in this model parallel human winner–loser relations. We propose that the relationship in a pair of neutral animals is mutually beneficial to the pair and serves as a definition for normal controls. We initially used only the two-tailed t-test criterion to determine the dominant and submissive status of an animal. About 44% of rat pairs formed a dominant–submissive relationship as judged by this single criterion (Table 1, #1). The number of Dominant–submissive pairs dropped to 33% when the second criterion was used in addition (Table 1, #2) and to 25% when the third criterion was included (Table 1, #3). It is important to use all three criteria to assure selection of animals with unambiguous dominant–submissive relationship or in the case of neutral pairs, animals that show little difference in behavior. If only one or two criteria are used, dominant animals paired with neutral animals, or subdominant animals with submissive animals are included in the selection. Such pairs have less stable relationships and a greater likelihood of relationship reversal in the following weeks of testing. It should be stressed that the selection process is critical for the experimental outcome since dominant and submissive behavior are graded along the axis of deviation from average (neutrality) (see Fig. 2). The data can be plotted separately for each rat to see the influence of the drug on individual rat (Fig. 4A and B and Fig. 5A). Alternatively, the behavioral difference between animals in a pair during the course of the study can be measured as the Dominance Level (Fig. 5B). This is defined as the difference in averaged daily drinking scores for a five-day week. Table 1 Criteria used to select dominant, submissive and neutral animals Difference in time spend on the feeder by each animal from the pair should be

Dominant–submissive pairs

Neutral pairs

1. At confidence level (two tail t-test) 2. % Difference of higher scoring animal 3. Reversal of dominance (occasions when submissive animal outscores its partner)a

P!0.05 At least 40%

PO0.6 Up to 8%

No

Yes

a Indicates reversals of daily success as expressed by longer and shorter time spend on the feeder by an animal from the pair.

A

300

Feeding Time (sec.)

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250

B

719

250 *** 200

200 *

*

150

150

100

100 1

2

3

4

5

6

7

8

1

2

3

4

5

6

7

8

Weeks in experiment Fig. 4. Stability of dominant- submissive relation in pairs of rats competing for food reward. (A) Plotted individually for dominant (&) and submissive rats (C), (B). Plotted as Dominance level (Data from Malatynska et al. (2002) nZ10).

Poland) as a part of Dr Malatynska’s graduate work. It is described in two early publications (Malatynska and Kostowski, 1984, 1988). The CRDM is a test of the noradrenergic theory of depression (Kostowski and Trzaskowska, 1980; Kostowski, 1982; Kostowski and Malatynska, 1983; Kostowski et al., 1984) The a2-adrenergic receptor agonist clonidine inhibits the release of noradrenaline and reduces the activity of noradrenergic neurons in the locus coeruleus. These actions suggested that a clonidinetreated animal could be used to test the hypothesis that depression is related to reduced brain noradrenergic activity. Male Wistar rats were subjected to the behavioral paradigm similar in principle as described in the previous section. However, instead of using a one-week habituation period there was two days of individual rat habituation to the apparatus and feeding regiments. Dominant–submissive pairs were selected after five experimental sessions (5 min each). For selection of the dominant and submissive animals only the first criterion (Table 1, #1) was used. The dominant animals selected by this procedure were divided into clonidine (0.1 mg/kg) and saline treatment control groups, respectively. Clonidine was injected intra peritoneal

Dominance level reflects behavior of both animals in pair. Sometimes the effect of the drug can be seen earlier with this measure. Typically, four to six pairs of animals are grouped together for each treatment condition under investigation. The average Dominance Level value for such groups is stable for up to six weeks (the longest time studied) in the absence of drug treatment. Table 2 shows the time and the number of animals required to for complete one experimental unit to study either one drug at one dose, or one animal strain, in order to have sufficient results for valid statistical analysis. Three experimental designs of this behavioral paradigm have been used: (1) the clonidine-reversal of dominance model (CRDM), (2) the reduction of submissive behavior model (RSBM), and (3) the reduction of dominance behavior model (RDBM).

4. Clonidine reversal of dominance model (CRDM) An apparatus similar to a described above was designed in the Institute of Psychiatry and Neurology (Warsaw, A

B 150 Dominance Level (sec.)

Time on Feeder (sec.)

300

200

100

100

50

0

0 0

1

2

3

4

5

6

Weeks in Experiment

7

8

2

3

4

5

6

7

Weeks in experiment

Fig. 5. Individual plots. Mean time spent on feeder measure in seconds for dominant (&) and submissive (C) rats. (A) Submissive rat was treated with 10 mg/kg/day of fluoxetine starting third week. The paired dominant rat was treated with vehicle. (B). Dominant rat was treated with lithium chloride 100 mg/kg/day starting third week. The paired submissive rat was treated with vehicle. Data from Malatynska et al. (2002a,b)

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Table 2 Timetable for basic experimental unit Time

No. of animals

Habituation Selection Drug dosing

5 days 5 days 3–6 weeks

32 32 10–14

No. of animals selected 10–14

No. pairs with D/S relation 5–7 5–7

(i.p.) 30 m before the experimental session. Pretreatment drugs were usually injected i.p. 15 m before clonidine. Both drugs were injected for five consecutive days. Over the subsequent week clonidine treatment reversed the dominant–submissive relationship between paired animals. Pretreatment of the clonidine-treated animals with antidepressants (2 mg/kg imipramine, amitriptyline, desipramine, clomipramine and mianserine) or the a2-adrenergic receptor antagonist yohimbine blocked the inhibitory effect of clonidine on dominant behavior. Other non-antidepressant drugs (amphetamine, diazepam, pimozide and flupentixol) had no significant effect on clonidine-induced reversal of dominance (Mann-Whitney two tailed test, 6–8 animal pairs/group). These results are shown in Fig. 6. Treatment of dominant animals with these drugs alone (no clonidine treatment) produced either no significant effect on dominance behavior (amitriptyline, desipramine, clomipramine, diazepam and flupentixol) or increased it (yohimbine, imipramine, mianserine, amphetamine and pimozide) as shown in Fig. 7. The effect of clonidine on feeding behavior 15

daily 0.1 mg/kgclonidine treatment ***

*** ***

Dominance Level

10 5

**

**

0 Untreated dominant Clonidine-treated dominant i α2 adrenergic antagonist Antidepressants i Non-antidepressant drugs

–5 –10 –15 Cont.CL

Y IMI AMI DMI M CMI A

F

P

D

Treatment Fig. 6. Drug Actions in the CRDM. The figure shows the effect of selected drugs on dominance behavior in CRDM test. The ordinate scale represents the daily difference in milk drinking scores between dominant and submissive rats averaged over 5 days. The positive value for saline treated dominant rats reflects their higher scores while clonidine (Cl) treatment reverses this difference to give a negative value. Abbreviations: Yohimbine (Y), imipramine (IMI), amitriptyline (AMI), desipramine (DMI), mianserine (M) clomipramine (CMI), amphetamine (A), flupentixol (F), pimozide (P) and diazepam (D). **P!0.01; **P!0.001 from clonidine treated rats. Data from Malatynska (1985).

***

25 Dominance Leveli

Procedure

30

20

**

Untreated dominant α2 adrenergic antagonist Antidepressants Non-antidepressant drugs

*

*

15 10 5 0 Cont. Y

IMI AMI DMI M CMI A

F

P

D

Treatment Fig. 7. Drug actions on dominance behavior. The figure shows the effect of selected drugs on dominance behavior in the absence of clonidine treatment. The ordinate scale represents the dominance level calculated from averaged drinking scores. Only yohimbine (Y), imipramine (IMI), miaserine (M), amphetamine (A) and pimozide (P) significantly (p!0.05) increased the dominance level relative to control. Other drugs tested include the antidepressants amitriptyline (AIM), desipramine (DIM) and clomipramine (CMI) and the other drugs flupentixol (F) and diazepam (D).* P!0.05; **P!0.01; *** P!0.001 from clonidine treated rats. Data from Malatynska (1985).

is a concern in this test as clonidine alone significantly reduced feeding by about half. Interestingly, only desipramine and pimozide antagonized the effect of clonidine on feeding suggesting that the ability of the antidepressants to block clonidine reversal of dominant behavior was not a result of an effect on feeding. In this regard it is important to consider that dominant behavior is not simply a measure of the attraction to food in this test but also includes the prevention of food intake by the submissive animal relative to the dominant one. Our previous work addressed this issue (Malatynska et al., 2002). In the lower doses clonidine has sedative activity measured as decreased locomotor activity. Some of the drugs studied (antidepressant and nonantidepressants inhibited this clonidine sedative effect and some potentiated it) however, there was no correlation with the reversal of the clonidine effect on dominance, suggesting that sedation and dominance suppression use different biochemical pathways (Malatynska and Kostowski, 1984). The specificity of the CRDM response to antidepressants is shown by a study of the antidepressant, alprazolam (Kostowski et al., 1986). Alprazolam is a benzodiazepine derivative with negligible activity at adrenergic receptors and is an effective antidepressant in clinical trials. Like diazepam, alprazolam shows anxiolytic action in conflict tests but is a weaker muscle relaxant. Unlike the antidepressant desipramine, alprazolam is inactive in the Porsolt forced swim test and has no effect on clonidineinduced hypothermia (Kostowski et al., 1986). The inability

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of alprazolam to affect clonidine-induced synchronization of EEG further shows its lack of noradrenergic activity. However, alprazolam fully blocked the reversal of dominant behavior produced by clonidine in the CRDM test (Kostowski et al., 1986). This result further demonstrates that the antidepressant effects seen in the CRDM are not simply a result of a2-adrenergic receptor antagonism. Results from the CRDM studies suggest that while dominant behavior is reduced by a2-adrenergic receptor stimulation, antidepressants exert their effect in the CRDM through another mechanism since they have no effect on clonidine-induced reduction of food consumption outside the behavioral paradigm. Furthermore, antidepressants clearly lacking a direct effect on the noradrenergic system like alprazolam effectively reverse the suppression of dominant behavior by clonidine. The clonidine reversal of dominance model of depression has important strengths. These include good predictive validity since a wide range of antidepressants having several presumed modes of action give a clear positive response. Its face validity rests on observations that a2-adrenergic receptor sensitivity is changed in depression leading to a hypo-noradrenergic state. Clonidine acts to inhibit noradrenergic activity and this is sufficient to reverse dominant behavior since it is blocked by yohimbine. The principle weakness of the CRDM can be summarized as a lack of construct validity. The behavioral state associated with depression in this model is a clonidineinduced reduction of the dominant rat drinking score. Thus, the CRDM is only as good a model of depression as clonidine treatment is as a cause. The behavioral paradigm appears to measure clonidine effects that are more related to depression than other simple measures of clonidine activity. Studies of the selective serotonergic reuptake inhibitor zimeldine show that this drug produces little effect in the CRDM test suggesting that the CRDM may not model elements of depression acted upon by SSRI drugs. The subacute nature of the effect of clonidine and antidepressants in the CRDM makes it difficult to establish the construct validity of this model to human depression. For these reasons the CRDM test has been abandoned for the RSBM that appears to be a more valid model of depression.

5. Reduction of submissive behavior model (RSBM) of depression The RSBM differs from the CRDM model just described in that the ‘depressed’ state is represented by the behavior of the submissive animal and not induced by clonidine treatment of its dominant partner. The period for the development of the dominant–submissive relationship is extended to two weeks (a habituation week followed by the selection week) instead of two days of habituation by individual rats followed by one week in which they are paired for treatment studies. The dominant and submissive

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animals are identified during the second week of testing in the RSBM. The strength of the dominant–submissive relationship is measured as the average daily difference in drinking scores (dominance level) between the paired animals. Drug treatments are extended over 3–6 weeks instead of the 5-day period used in the CRDM. The dominant–submissive relationship formed during the twoweek selection period is stable enough to allow studies of treatment effects for at least five weeks after selection (Malatynska et al., 2002). During the initial two-week testing period before treatment rats have daily sessions in which they face the social stress of competition for the feeder. During this period the submissive rat suffers from a form of defeat every day. In this sense the submissive animal resembles the defeated intruder animal from the resident–intruder model. Studies with the Resident–intruder model (Kudryavtseva et al., 1991; Willner et al., 1995). Kudryavtseva et al. (1991) have shown that ‘depressivelike’ symptoms, as assessed by behavioral tests, developed in submissive intruder mice within three weeks. The clinically-effective antidepressants, imipramine, desipramine, and fluoxetine, reduce submissive behavior in the RSBM (Malatynska et al., 2002). Daily dosing at 10 mg/kg i.p. with these drugs produces a significant reduction of dominance level scores, relative to second week control values, in two to four weeks. This time delay distinguishes the RSBM from most other models of depression (e.g. forced swim, learned helplessness, tail suspension and others) in which behavioral changes are measured after only a few treatments. The RSBM is more like the chronic mild stress model of depression in this regard. The treatment time requirement for antidepressant effects in the RSBM is an important characteristic of this model since it is consistent with the well-known time delay of therapeutic efficacy of these drugs in depressed patients. Dose-dependent effects of fluoxetine were measured in the RSBM by administering 2.5, 5.0 and 10 mg/kg daily to submissive rats. Dominant rats were dosed with an equal volume of vehicle. Treatment was continued over three weeks with testing every weekday. After two weeks of treatment both the 5.0 and 10 mg/kg treatment produced a significant reduction of the mean dominance level relative to the second week control value. There was no significant effect for the 2.5 mg/kg dose after three weeks of treatment. The dominance level values (see Section 3 for definition) at three weeks showed a graded reduction (due to the increased competitiveness of the submissive rat) that was linear relative to the log dose. The ED50 was about 5.0 mg/kg in this study. It is noteworthy that fluoxetine also increased social status in vervet monkeys (Raleigh et al., 1991). Tse and Bond (2002) reported that human subjects on another selective serotonin reuptake inhibitor, citalopram (20 mg/ day), in a double blind control study were rated as significantly less submissive by people living with them and they showed a dominant pattern of eye contact in the stranger-dyadic social interaction paradigm.

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Male and female submissive rats respond to treatment with imipramine and desipramine similarly in the RSBM (Malatynska et al., 2002). A significant reduction of the dominance level value was seen for male rats treated with imipramine in three weeks and female rats treated for four weeks. Both male and female rats showed a significant response to 10 mg/kg daily injections of desipramine after two weeks of treatment. These studies suggest that male and female animals are likely to have similar sensitivity to tricyclic antidepressants, which is consistent with clinical studies of male and female patients. The selectivity of the RSBM for antidepressants was tested with the anxiolytic diazepam and the psychostimulant amphetamine. Submissive male rats meeting the selection criteria were treated for five weeks with daily injections of diazepam (1.0 mg/kg i.p.) or amphetamine (1.0 mg/kg i.p.). No significant change in the mean dominance level-value relative to the second week control value was observed during any of the treatment weeks for either diazepam (Malatynska et al., 2002) or amphetamine.(Fig. 8) Amphetamine had a tendency to increase submissiveness. Studies showing that depressed patients exhibit impaired cognition that can be relieved by antidepressant treatment (for review see Amado-Boccara et al. (1995)) suggests that drugs developed to improve learning and memory might have antidepressant activity. This hypothesis was tested using the nootropic drugs piracetam, aniracetam and members of a class of AMPA receptor positive modulators called Ampakines (Knapp et al., 2002). These compounds improve rat performance in several different learning and memory tests (Larson et al., 1995; Johnson et al., 1999). Piracetam and aniracetam showed weak effects on dominance level values over time consistent with their low potency in learning and memory tests. The Ampakines tested in the RSBM showed much more dramatic activity than piracetam and aniracetam consistent with their greater

Feeding Time (sec.)

400

300

200

100

0 0

2

3

4

5

6

7

Weeks in Experiment

Fig. 8. Amphetamine effect on rat submissive behavior. Submissive (C) rats (nZ6) were injected with amphetamine (1 mg/kg). Dominant (&) rats from the pair were injected with vehicle.

potency in spatial memory tests. For example CX691, at 2 mg/kg i.p. or CX731, at 1mg/kg produced a significant effect after one week and reversed the dominancesubmissive relationship between some pairs of rats after two weeks of treatment resulting in a negative dominance level value that was highly significant relative to the second week control value (Knapp et al., 2002). Further evidence for the stability of dominance levels in the RSBM and the reversibility of treatment effects was obtained in a study where submissive members of a pair were given injections with CX691 (2 mg/kg) or desipramine (10 mg/kg) each day starting at the beginning of the third week. The mean dominance level value decreased relative to the second week control value and was significantly different after three weeks of treatment at which point treatment was stopped. Testing was continued following cessation of treatment for another three weeks during which the dominance level approached the initial second week value again. This study showed that the reduction of submissive behavior was dependent on C!691 or desipramine treatment and that this effect was lost following the end of treatment (Malatynska et al., 2002; Knapp et al., 2002). The studies with Ampakines and other antidepressants raise several interesting but unanswered questions. One question concerns the nature of the tendency toward dominant and submissive behavior. It would not seem that the experience of a submissive animal at being dominant under drug treatment creates a permanent change in that animal’s behavior since it is lost with discontinuation of treatment. Perhaps a longer treatment period might effect a more stable change. It is interesting to note that patients successfully treated for depression are considered in danger of relapse with discontinuation of treatment and are encouraged to continue treatment even after their symptoms are gone. The RSBM might provide some insight into this condition. Another question would be what effect in the RSBM corresponds to a successful clinical outcome? Is a drug that only eliminates the dominant–submissive relationship better than one that reverses it? Given evidence suggesting that dominance in a Dominant–submissive relationship can model mania to some degree it might seem that a potent ability to reverse this relationship might be an adverse effect. Antidepressants have been show to precipitate mania in some bipolar patients suggesting a possible clinical correlate. Finally, there is little evidence for differences in efficacy between existing antidepressant drugs whether efficacy is defined as the percent of patients treated that respond or the extent that they become completely symptom free. Our observations suggest that the maximum effect of a drug on dominance level values might provide a means of measuring antidepressant efficacy if it can be related to differences in clinical efficacy in the future. The extent to which submissive behavior of an animal resembles the behavior of a depressed individual supports the face validity of the Reduction of Submissive Behavior

E. Malatynska, R.J. Knapp / Neuroscience and Biobehavioral Reviews 29 (2005) 715–737

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Table 3 Comparison of characteristic features for the human MDD and for the submissive behavior in the RSBM (based Malatynska et al., 2002) Unit Studied a

MDD

Submissive behavior in the RSBM

Characteristic feature

MDD patients

In the RSBM

Duration of weeks or months rather than days Indifference to reward Hopelessness or helplessness Weight change (gain or loss) Locomotor activity change (agitation or impairment) Presence of psychosocial stressor Learned low energy response to social stressor developing over time Involves only a fraction of population Susceptibility of both genders Sensitivity to antidepressants Requirement for chronic treatment to have an effect

C C C C C C C C C C C

C (K?)b (C)c – – C C C C C C

a Major depressive disorder (MDD); Contains features listed in DSM-IV (American, Psychiatric, Association, 1994) that are relevant to study in animals. Cognitive features (e.g. recurrent thoughts of death, feelings of worthlessness) are omitted. b Not adequately studied. c Helplessness in food acquisition in the presence of dominant animal.

Model. The most salient features of submissive behavior in the RSBM are: (1) it is a learned response, developing over time to the stress of competition, (2) both male and female animals may become submissive, (3) only a small fraction of animals become submissive, (4) submissive animals show a reduced rate of weight gain suggesting a loss of the rewarding properties of food, (5) the sensitivity of submissive behavior to antidepressant treatment and (6) the requirement for prolonged antidepressant treatment before there is a change in submissive status. Relevant features of depressive disorders as described in the DSM IV (American, Psychiatric, Association, 1994) for major depressive episode and dysthymic disorder to submissive behavior in the RSBM include: (1) duration of weeks to months rather than days, (2) indifference to reward (anhedonia), (3) hopelessness or helplessness, (4) weight change, (5) a change in the pattern of social interactions, (6) over sensitivity to psychosocial stressors, energy preservation response, and (7) susceptibility of both women and men to the development of depression Table 3. 6. Reduction of dominant behavior model (RDBM) of mania In contrast to mood depression, abnormal mood elevation does not render itself to easy modeling in animals. How then to model mania in animals? The majority of tests used to date are based on different types of increased activity. Most tests use increases in locomotor activity as a measure of manic-like activity. Different drugs such as cocaine, quabain, amphetamine, dexamphetamine, chlordiazepoxide, and 6-hydroxydopamine produce increased activity in animals. This includes cocaine-induced cyclicity; (Antelman et al., 1998; Post, 1975) quabain or amphetamine-induced hyperlocomotion; (Li et al., 1997) amphetamine-conditioned behavioral excitation; (Poncelet et al., 1987) dexamphetamine and chlordiazepoxide-induced hyperactivity; (Cao and Peng, 1993) 6-hydroxydopamine -

induced hyper-reactivity to environmental stimuli, e.g. mild food shock (Petty and Sherman, 1981). Models that do not use drug-precipitated symptoms assuming a specific mechanism of disease can better serve to define new mechanisms of the disease and identify medications with new modes of activity. One example of a mania model that does not use drugs to precipitate maniclike symptoms in animals is sleep deprivation in rats (Gessa et al., 1995). In this model rats are deprived of sleep for 72 h by placing them on a small platform surrounded by water. After returning to their home cage rats are extremely agitated and aggressive during the first half hour. Antimanic drugs (e.g. lithium) reduce this reaction. Dominant behavior as a model of mania would fall in the same category. However, in contrast to sleep deprivation, dominance behavior develops over a longer period of time and also enables observation of the effects of chronic treatment including onset time for drug activity. A theoretical background for using dominant behavior as a model of mania was suggested by Price (1967) and Gardner (1982). In the CRDM test we have shown that clonidine reversed dominance behavior (Malatynska and Kostowski, 1984; Malatynska, 2002a). This effect of clonidine was dose dependent.(Fig. 9) Reversals of several other clonidine effects by antidepressant drugs were used in preclinical tests to measure antidepressant activity. For example, in small doses clonidine (0.1, 1.0 mg/kg) decreases rat locomotor activity and rearing (Kostowski et al., 1980; Delini-Stula et al., 1979) inhibits the acquisition of conditioned behavior (Kostowski et al., 1980; Robson et al., 1978) and produces hypothermia (Kostowski et al., 1986; Danysz et al., 1988; Harkin et al., 1999; Zarrindast et al., 2003). All of these effects of clonidine were reversed by different antidepressant drugs. The effect of clonidine in the CRDM was evident after acute treatment (within the first few days). Clonidine is used in the clinic to alleviate acute symptoms of mania while awaiting onset of the therapeutic effect of lithium (Chou,

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E. Malatynska, R.J. Knapp / Neuroscience and Biobehavioral Reviews 29 (2005) 715–737

100

10

CRB 20

5 Dominance Level %

Dominance Level

50

0 –5 –10 –15

LI 100 SV30

0

–50

–100

–20 –25 0

0.05

0.1

0.15

0.2

0.25

Clonidine (mg / kg) Fig. 9. The effect of increasing concentrations of clonidine on the dominance levels in pairs of rats. Dominant rats were injected with increasing doses of clonidine (0.05, or 0.1 or 0.2 mg/kg) and submissive rats with water (nZ8). Data from Malatynska (1985).

1991; Maguire and Singh, 1987; Jouvent et al., 1988; Zubenko et al., 1984; Hardy et al., 1986; Tudorache and Diacicov, 1991). Three cases of mania precipitation by yohimbine (a2-receptor antagonist) in bipolar patients during a depressive state have also been described (Price et al., 1984). These data prompted us to study the effects of other antimanic drugs used as a first line therapy for mania (Stahl, 2000) on dominant behavior. We have shown that dominant behavior as defined under the condition of our experiment is sensitive to lithium, sodium valproate and carbamazepine (Fig. 10). The onset of this effect for the three drugs is similar to the onset of their therapeutic effect in the clinic (Malatynska et al., 2002). Lithium is used for long-term mood stabilization and the prevention of manic episodes. The effect of lithium in the clinic is delayed by three weeks and we have observed the same time of onset in the reduction of dominant behavior in our test in rats. Sodium valproate is an anticonvulsant drug that is also used to bring about a rapid antimanic effect. Similarly, the onset of significant reduction of the dominance behavior induced by sodium valproate occurs in the first week of treatment. Carbamazepine activity in the clinic and in the RDBM occurs after about two weeks of treatment. Carbamazepine and particularly sodium valproate are increasingly employed to prevent bipolar disorder episodes. The efficacy of antimanic drugs in our test was sodium valproateO lithiumOcarbamazepine. Clinical studies suggest that carbamazepine is weaker than lithium and that sodium valproate is superior to lithium in reducing symptoms of mania (Post et al., 2000; Davis et al., 2000; Dardennes et al., 1995). Sodium valproate is used very often in patients resistant to lithium treatment. Criteria for major manic episodes listed in DSM IV include (1) inflated self-esteem and grandiosity, (2) decreased need for sleep (3) pressure to keep talking (4)

–150 0

2

4

6

Weeks of Treatment Fig. 10. The effect of different antimanic drugs on dominance levels in pairs of rats. Dominant rats were injected with lithium (100 mg/kg), carbamazepine (20 mg/kg) or sodium valproate (30 mg/kg) and submissive rats with water (nZ6). Data from Malatynska et al. (2002).

subjective experience of flights of ideas, racing thoughts (5) distractibility (6) increase in goal directed activity (7) excessive involvement in pleasurable activities that have high potential for painful consequences. To simplify these criteria, we can summarize that mania is characterized by a highly increased drive and a strong belief in one’s possibility to achieve a chosen goal regardless of circumstances. To such an individual the value of a reward is tremendous and existing obstacles are almost not noticeable. Manic people seem to have large energy reserves looking for an application. The energy is there regardless of what can or needs to be done. This definition may be also applied to the behavior of dominant animals. The presence of another competing animal is not an important obstacle on the way to the feeder for dominant animal. Thus it seems that, the necessary energy must be there to call upon resources to achieve the goal. Similar features of mania formulated on the basis of the DSM IV criteria and dominant behavior are depicted in the Table 4. We concluded from our preliminary studies that the three drugs used as a first line therapy for bipolar disorder reduced dominance behavior in the DSR. The efficacy and onset of these drugs in RDBM closely resembles the efficacy and onset of these drugs in the clinic. We propose that RDBM has the potential to be a suitable model of mania. Further studies to validate this model are necessary. The major advantage of this model over other existing models of mania is the possibility of monitoring the time of onset.

7. Response of dominant and submissive behavior studied in different settings to psychotropic drugs. Several groups have described the ability of psychotropic drugs to change the social status of dominant or submissive

E. Malatynska, R.J. Knapp / Neuroscience and Biobehavioral Reviews 29 (2005) 715–737

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Table 4 Comparison of characteristic features for the human mania and for the dominant behavior in the RDBM Unit studied

Characteristic feature

Mania patients

In the RSBM

Mania

Duration of weeks or months rather than days Supersensitivity to (overimportance of) chosen rewards High motivation, resourcefulness High energy focused on desired goal to the exclusion of general picture Locomotor activity change (agitation) Cognitive impairment (impaired perception of consequences) Compulsion (with aggressive component) to fulfill immediate need Energizing response to social stressor developing over time Involves only a fraction of population Susceptibility of both genders Sensitivity to antimanic drugs Requirement for chronic treatment to have an effect Genetic component

C C C C C/K C C C C C C C C

C C C C – K? C C C C C C C

Dominant behavior in the RDBM

animals including mice, rats and monkeys. In early work animals were observed in groups or pairs for agonistic or defensive postures as defined by Grant and Mackintosh (1963). The number of such postures was used to determine what behavioral status to assign to the animal. The studies usually measured several other postures and behaviors allowing detailed behavioral analysis (Blanchard et al., 1987, 1988, 1977; File, 1982; Miczek and Gold, 1983). Examples of drugs studied by this method are given in Table 5. Early work, assessing drug effects in studies measuring priority of access to resources, used methodology developed by Uyeno (1960, 1966, 1967) that was modified by Masur et al. (1971b) All these groups studied competition over food resources by using food-restricted animals. The competition took place in an apparatus consisting two wooden open boxes connected with a narrow runway with the central feeder (Uyeno, 1960, 1966, 1967) or feeders placed in the wooden boxes (Masur et al., 1971b). The rats were injected with drugs or water and than paired with those injected with water. The effect of drug was measured by calculating time spent on the feeder (Uyeno, 1960, 1966, 1967) or the number of wins for each group (Masur et al., 1971a; Masur and Benedito, 1974). Drugs studied were LSD, mescaline, psylocibin and apomorphine. It is difficult to compare results obtained in these experiments and our experiments (earlier and recent) because dominance was not established before drug treatment so the effect of the treatment on dominance was not actually determined.

Antidepressants of different classes reversed or reduced clonidine precipitated submissive state in an originally dominant animal.(Table 6) Details of these studies are described in Section 4, ‘Clonidine Reversal of Dominant Behavior Model’. In the control experiment dominant rats not treated with clonidine received the same antidepressant drugs. Imipramine and mianserin increased dominance while other antidepressants including amitriptyline had no effect on dominant rats not treated with clonidine. (Table 6) However, the amitriptyline dose used, 2 mg/kg, was very low and the duration of treatment was only five days. In later experiments, where the dominant rat was treated with amitriptyline (10 mg/kg) for three weeks, decreased dominant behavior was seen (Malatynska et al., 1995) Table 7). Mianserin and clomipramine were studied in triads of animals competing for placement in the newly formed group (Mitchell and Redfern, 1992). Sub-dominant rats were injected with antidepressants resulting in an increase of their competitive status (Table 6). Imipramine, desipramine, and fluoxetine were studied directly on submissive rats resulting in the reduction of their submissive status (Malatynska et al., 2002). Amitriptyline did not have an effect on submissive behavior of rats (Malatynska et al., 1995). However, it is possible that the dose was too high (a sedative dose was used), or the time of treatment was to short. For example, the effect of imipramine in female rats was evident only after four weeks of treatment Table 7 (Malatynska et al., 2002).

Table 5 Effect of drug on dominant and submissive behavior. Studies using posture observation in groups of animals Drug

Dose (mg/kg)

Route

Duration (days)

Species

Animal status before treatment

Effect

References

Chlordiazepoxide Amphetamine

5 0.1,0.3

i.p. p.o.

5 1

Rat Monkey

Submissive Dominant

Decrease S Decrease D

Amphetamine

0.1,0.3

p.o.

1

Monkey

Submissive

No effect

File (1982) Miczek and Gold (1983) Miczek and Gold (1983)

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Table 6 Effect of clinically effective antidepressants on submissive (in pairs) or subdominant (in triad) animals selected in competition tests Antidepressant

Dose (mg/kg)

Route

Treat. time (days)

Species

Effect

References

Imipramine

2

i.p

5a

Rat

Return to dominance

Cat Rat

Reduced submissiveness Reduced submissiveness Return to dominance

Malatynska et al. (2002) and Malatynska and Kostowski (1984) Zagrodzka et al. (1985)

Rat

Reduced submissiveness Return to dominance

10 Desipramine

2

i.p.

21 ? 5a

Amitriptyline

10 2

i.p.

21 5a

10 2 0.33mmole/kg/day 2 10mmole/kg/day

i.p. s.c. i.p. s.c.

21 5a 14 5a 14

10

i.p.

21

Mianserin Clomipramine

Fluoxetine a

Malatynska et al. (2002) and Malatynska and Kostowski (1984) Malatynska and Kostowski (1984) and Malatynska et al. (1995)

Rat

No effect Reduced submissiveness Reduced submissiveness Reduced submissiveness

Malatynska and Kostowski (1984) Mitchell and Redfern (1992) Malatynska and Kostowski (1984)

Rat

Reduced submissiveness Reduced submissiveness

Mitchell and Redfern (1992) Malatynska et al. (2002)

Rat

Dominant rat becomes submissive after clonidine treatment. The antidepressant effect was to prevent the clonidine effect.

Many non-antidepressant drugs were studied on submissive behavior in different settings. Amphetamine, flupentixol, pimozide, and diazepam had no effect on submissive behavior consistent with a selective effect of antidepressants on submissive behavior (Table 6A). Results with chlordiazepoxide, a drug similar to diazepam, are more ambiguous. Subchronic but not acute treatment with chlordiazepoxide was shown to increase the competitiveness of submissive rats in the competition for sucrose pellets test (Gentsch et al., 1988b), Table 6A) and to decrease the number of defensive postures by submissive animals in group hierarchy observations (File, 1982) Table 5). However, in an experiment in which the animals competed for chocolate pieces, subchronic

chlordiazepoxide failed to have an effect on the performance of submissive rats (File, 1986) Table 6A). It is difficult to explain the discrepancy in these findings other than to note the profound differences in experimental methods. The positive effects of other drugs listed in Table 7A on submissive animal status are easier to explain. DOPA may produce an antidepressant effect by increasing the level of motivation of the depressed subject. Yohimbine is an a2 adrenergic receptor antagonist and its inhibition of clonidine activity is expected. Yohimbine treatment of submissive C57Bl/J6 mice reduced submissiveness (unpublished observations). Generally antagonism of a2 adrenergic autoreceptors would be expected to have antidepressant activity.

Table 6A Effect of non-antidepressant drugs on submissive (in pairs) or subdominant (in triad) animals selected in competition tests Drug

Dose (mg/kg)

Route

Treat. time (days)

Species

Effect

References

DOPA Amphetamine Flupentixol Pimozide Diazepam

100–200 1 2 0.2 1

i.p. i.p i.p. i.p. i.p.

1 5a 5a 5a 5a

Rat Rat Rat Rat Rat

Reduced submissiveness No effect No effect No effect No effect

Masur et al. (1975) Malatynska and Kostowski (1984) Malatynska and Kostowski (1984) Malatynska and Kostowski (1984) Malatynska et al. (2002) and Malatynska and Kostowski (1984)

yohimbine PCPA 6F-Trp chlordiazepoxide

2 100 122 5 5 1–20 10 mg 50 15 5 2 1

i.p. i.p i.p. i.p. i.p. i.p. Iamyg i.p. i.p. i.p. i.p. i.p.

21 5a 3 3 5 5 1 1 21 21 21 21 21

Rat Rat Rat Rat

Reduced submissiveness Reduced submissiveness Reduced submissiveness No effect Reduced submissiveness No effect Reduced submissiveness Reduced submissiveness Reduced submissiveness Reversed submissiveness Reversed submissiveness Reversed submissiveness

Malatynska and Kostowski (1984) Gentsch et al. (1988a) Gentsch et al. (1988a) File (1986) Gentsch et al. (1990) Gentsch et al. (1990) Pucilowski et al. (1990) Knapp et al. (2002) Knapp et al. (2002) Knapp et al. (2002) Knapp et al. (2002) Knapp et al. (2002)

TRH Piracetam Aniracetam CX516 CX691 CX731 a

Rat Rat Rat Rat Rat Rat

Dominant rat become submissive after clonidine treatment. The drug effect was to prevent clonidine effect.

E. Malatynska, R.J. Knapp / Neuroscience and Biobehavioral Reviews 29 (2005) 715–737

727

Table 7 Effect of clinically effective antidepressants on dominant rats selected in competition tests Antidepressant

Dose (mg/kg)

Route

Treat. time (days)

Species

Effect

References

Imipramine Desipramine Amitriptyline

2 2 2 10 2 2

i.p i.p. i.p.

5 5 5 21 5 5

Rat Rat Rat

Increased dominance No effect No effect Reduced dominance Increased dominance No effect

Malatynska and Kostowski (1984) Malatynska and Kostowski (1984) Malatynska and Kostowski (1984) Malatynska et al. (1995) Malatynska and Kostowski (1984) Malatynska and Kostowski (1984)

Mianserin Clomipramine

i.p. i.p.

Rat Rat

Mitrazapine is a new antidepressant on the market that inhibits a2 adrenergic receptors. The same is true about the tryptophan hydroxylase (TrpH) inhibitors PCPA and 6F-Trp that transiently increase competitiveness of poorly performing (submissive) rats (Gentsch et al., 1988a), Table 6A). TrpH is a rate-limiting enzyme in serotonin synthesis. A transient increase in the competitiveness of poorly performing rats corresponded to the serotonin depletion time (Gentsch et al., 1988a). We have observed an opposite effect in submissive rats injected with fluoxetine, a serotonin-reuptake inhibitor. The performance of these rats may be worse during the first days of injections. Continuation of the treatment with fluoxetine for two or more weeks resulted in reduced submissiveness of these animals (Malatynska et al., 2002). All remaining drugs listed in Table 6A, TRH, piracetam, aniracetam, and ampakines were reported to have antidepressant effects in other tests used to detect antidepressant drug activity (Knapp et al., 2002; Sattin, 1998; Mazurov et al., 1997; Takahashi et al., 1973; Lloyd et al., 2001). Some models of aggression can be used to detect antidepressant activity of drugs (Nakamura et al., 1989; Sofia, 1969; Sanchez and Meier, 1997). The Resident intruder paradigm was originally used to study aggression in rodents (Thor and Flannelly, 1976a,b; Miczek, 1974; Miczek and Barry, 1974) and it is not surprising that aggressive behavior in this model is also sensitive to antidepressant drugs. Initially Willner et al., reported that after 7 days of desipramine administration resident rats increased their aggression toward intruder rats (Table 8). Mitchell et al. (1991) and Millan et al. (2001) has shown that a range of antidepressant drugs and electroconvulsant shock (ECS) were active in this test (Table 8) in contrast to

haloperidol and diazepam that were not (Table 8A). They also differentiated acute and chronic effect of antidepressants in this test (Table 8). In contrast to dominant–submissive relationships formed on the basis of competition for priority of resources, the Resident–intruder test uses the territorial instinct of animals as the basis for the formation of a social hierarchy. Under such conditions the intruder animal is in a disadvantageous position relative to the resident. When the resident is aggressive and the intruder is submissive this results in the predictable defeat of the intruder. This situation is similar to a submissive animal losing a competition for resources. Koolhaas et al. (1990, 1980), Kudryavtseva et al. (1991) and Willner et al. (1995) proposed using the defeated animal as a model of depression. They (Kudryavtseva et al., 1991) showed that defeated animals have behaviors resembling symptoms of depression. The antidepressant drugs clomipramine, imipramine and citalopram reduced signs of defeat (see Table 9) similarly as they reduced submissiveness in competition tests (Table 6). Some CRF receptor antagonists (proposed as a novel treatment for depression) also decreased signs of defeat in contrast to THC that was ineffective (Table 9A).

8. Biochemical differences found between dominant and submissive animals in relation to the changes observed in patients There are biochemical differences, found between dominant and submissive animals, in several neuronal

Table 7A Effect of non-antidepressant drugs on dominant animals selected in competition tests Drug

Dose (mg/kg)

Route

Treat. time (days)

Species

Effect

References

Clonidine Amphetamine Flupentixol Pimozide Diazepam

0.1 1 2 0.2 1

i.p i.p. i.p. i.p.

5 5 5 5 5

Rat Rat Rat Rat

Reduced dominance Increase dominance No effect Increase dominance No effect

Yohimbine Quipazine Chlordiazepoxide TRH

2 0.2–6.7 5 10 mg

i.p. i.p i.p. iamyg

5 3 5 1

Rat Rat Rat Rat

Increase dominance Reduced dominance No effect Reduced dominance

Malatynska and Kostowski (1984) Malatynska and Kostowski (1984) Malatynska and Kostowski (1984) Malatynska and Kostowski (1984) Malatynska et al. (2002) and Malatynska and Kostowski (1984) Malatynska and Kostowski (1984) Gentsch et al. (1988a) File (1986) Pucilowski et al. (1990)

728

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Table 8 8 Effect of clinically effective antidepressants on resident animals in Resident–intruder tests Antidepressant

Dose (mg/kg)

Route

Treat. time (days)

Species

Effect

References

Desipramine Clomipramine

20 10–40

i.p. s.c.

7 7 and 14

Rat Rat

Increased aggression Increased aggression Reduced aggression

Willner et al. (1981) Mitchell et al. (1991)

5.54

i.p. s.c. s.c. s.c. s.c

1 7 and 14 7 and 14 7 and 14 1

Rat Rat Rat Rat

Increased aggression Increased aggression Increased aggression Reduced aggression

7 and 14

Rat

Increased aggression

Mitchell et al. (1991) Mitchell et al. (1991) Mitchell et al. (1991) Mitchell and Redfern (1997) and Mitchell et al. (1991) Mitchell and Redfern (1997) and Mitchell et al. (1991) Millan et al. (2001)

Iprindole Mianserin Phenelzine Venlafaxine

5.54 10–40

Reduced aggression Mice

Fluoxetine

0.34

s.c.

1 1

Rat

Reduced aggression

Paroxetine

0.33

s.c.

7 and 14 1

Rat

Increased aggression Reduced aggression

Citalopram

0.5 10–40 10–40 0.8ms pulse 100Hz

i.p. i.p. i.p. Ear clips

7 and 14 1 1 1 1

Reboxetine ECS

Mice Mice Rat

14

systems that were previously linked with human depression or mania. Depression is associated with emotional stress and increased adrenal cortisol levels are measured in most, but not all, depressed patients (Holsboer, 1989). Elevation of plasma cortisol due to endocrine dysfunction (e.g. Cushing’s disease) or drug administration is frequently associated with depressed mood that is resolved with restoration of normal endocrine function (Haskett, 1985). Cognitive theories of depression hypothesize that persistent stress can initiate abnormal cognitive processes leading to maladaptive neurochemical changes in CNS function (Beck, 1979). Animal studies show that subjection of animals to extended stressful conditions leads to behavioral patterns having elements of those seen in depressed people (Lechin et al., 1996). These studies are consistent with the hypothesis that depression is linked to hyperactivity of the hypothalmicpituitary-adrenal (HPA) axis. Higher corticosterone levels

Increased aggression No effect Reduced aggression Reduced aggression Reduced aggression

Mitchell and Redfern (1997) and Mitchell et al. (1991) Mitchell and Redfern (1997) and Mitchell et al. (1991) Rilke et al. (2001) Millan et al. (2001) Millan et al. (2001) Mitchell and Redfern (1997) and Mitchell et al. (1991, 2003)

Increased aggression

are observed in subordinate rats following handling or footshock (Schutz et al., 1978) or after presentation of a novel restraint stressor (Albeck et al., 1997). Socially defeated male rats display a blunted adrenocortical response to 8-OH-DPAT (Korte et al., 1995). Socially subordinate female cynomolgus monkeys are hypercortisolemic (Shively et al., 1997). The same is true for submissive baboons (Sapolsky, 1982, 1989). Sapolsky (1989) showed that hypercortisolemia in submissive animals is most likely of CNS and not peripheral origin. Jasnow et al. (1999) found that CRF1 receptor antagonists can decrease signs of intruder defeat in the resident–intruder test. Many early studies attempting to identify neurochemical correlates of depression studied disturbances of catecholamine systems. Changes in platelet monoamine-oxidase (MAO) activity or the ratio of MAO to cortisol levels were seen in some depressed patients (Agren and Oreland, 1982). These changes depend on the symptoms (depressed or

Table 8A Effect of non-antidepressants on resident animals in resident–intruder tests Drug

Dose (mg/kg)

Route

Treat. time (days)

Species

Effect

References

THC

0.2–2

i.p.

Miczek (1978)

2.5–7.5

Mice Rat Monkey Rat Rat Mice

Decreased aggression

s.c. s.c. i.p.

1 1 1 7 and 14 7 and 14 1

No effect No effect Decreased aggression

Mitchell et al. (1991) Mitchell et al. (1991) Mendoza et al. (1999)

Haloperidol Diazepam Gepirone

E. Malatynska, R.J. Knapp / Neuroscience and Biobehavioral Reviews 29 (2005) 715–737

729

Table 9 Effect of clinically effective antidepressants on intruder animals in Resident–intruder tests Antidepressant clomipramine Imipramine Citalopram

Dose (mg/kg)

Route

Treat. time (days)

Species

Effect

References

10 5, 10 20

Rat i.p. i.p. i.p.

8 14 21 21

Rat Mice Rat Mice

Reduced signs of defeat Reduced signs of defeat

Koolhaas et al. (1990) Kudryavtseva et al. (1991) Willner et al. (1995) Keeney and Hogg (1999)

manic) that bipolar patients display (Schatzberg et al., 1985). An alternate decrease and increase in noradrenergic transmission is considered to be one cause for affective disorders. It was shown that the urinary secretion of 3methoxy-4-hydroxyphenylglycol (MHPG), a noradrenaline metabolite, is decreased in some patients with depression (Maas et al., 1972) and is increased in patients with depression or mania (Esler et al., 1982; Potter et al., 1993; Rothschild et al., 1987). Key noradrenergic receptor systems involved include a2 presynaptic receptors and a1 and b postsynaptic receptors. When catecholaminergic systems are studied in brain tissue of submissive and dominant animals they exhibit subtle differences that vary between brain structures. A submissive position in the predatory hierarchy of cats produces an increase in the concentration of NA in the hypothalamus and decreases of DA, MHPG and the MHPG/NA ratio in the hippocampus relative to dominant cats (Krotewicz and Romaniuk, 1995). Socially subordinate female cynomolgus monkeys also have altered dopaminergic activity (Shively et al., 1997). The serotoninergic theory of depression is based on changes in serotonin metabolism and the observed effectiveness of SSRI drugs. Originally it was shown that levels of hydroxyindoloacetic acid are decreased in the cerebrospinal fluid of patients with depression. However, others found that it is difficult to demonstrate this finding (for review see Meltzer and Lowy (1987). There is some evidence of decreased serotonin levels in the platelets and plasma of patients with depression (Sarrias et al., 1987). Many studies (Blier et al., 1990; de Montigny, 1984; Fuxe et al., 1984) show that 5-HT neurotransmission is enhanced in animals after extended, but not acute, electroconvulsive shock and antidepressant drug treatment. These results are consistent with the delayed effect of these treatments in clinical studies. Thus, there is no simple answer for the role of the serotonergic system in depression. Similarly, there is also no simple answer for the role of the serotonergic system in dominant–submissive behavior. When the serotonergic

Reduced signs of defeat

system was studied in dominant and submissive animals, decreased or increased serotonin levels were found in different brain structures. A submissive position in the predatory hierarchy of cats produces a decrease of 5-HT in the hippocampus and in the prefrontal cortex relative to dominant cats (Krotewicz and Romaniuk, 1995). Elevation of 5-HIAA (5-hydroxyindoloacetic acid, a metabolite of 5HT) was found in limbic brain regions, amygdala, hypothalamus, preoptic area, hippocampus and spinal cord of submissive rats (Blanchard et al., 1991). Studies on animals usually concentrate on brain tissue and fine brain regions while the studies with patients are, understandably, conducted using body fluids; this makes them difficult to compare. However, SSRIs that generally facilitate serotonin transmission are effective antidepressants and they also reduce submissiveness of animals. It seems unlikely that the entire CNS serotonergic system has to be activated to reduce submissiveness or to alleviate depression. For example, it was found that 5-HT1A receptors were decreased in the hippocampus of submissive rats but not 5-HT1B receptors (McKittrick et al., 1995). It seems increasingly likely that neural plasticity is a critical feature of antidepressant drug action and that antidepressants work through changes in cogitative systems to exert their therapeutic effect. The high level of placebo effect observed in clinical trials of antidepressants could result from the ability of the trial environment to affect patient cognition. This idea suggests that the principle excitatory and inhibitory amino acid ion channel receptor systems are involved since their activity is critical for learning and memory. Several studies (Lloyd et al., 1983, 1987) support the idea that some GABAergic drugs have antidepressant properties. Increased GABA metabolism is reported to be responsible for decreased fear drive in the predatory hierarchy test for cats (Krotewicz and Romaniuk, 1998). We have also demonstrated differences between behaviorally dominant and submissive rats in the GABAA receptor chloride ionophore complex response to

Table 9A Effect of non-antidepressants on intruder animals in Resident–intruder tests Drug

Dose (mg/kg)

Route

Treat. time (days)

Species

Effect

References

THC

0.2–2

i.p.

Miczek (1978)

15, 30 5, 25 mg 5, 25 mg

i.p. icv icv

Mice Rat Monkey Rat Mice Mice

No effect

CP-154,526 D-phe CRF(12–41) D-phe CRF(12–41)

1 1 1 8 21 21

No effect Reduced signs of defeat Reduced signs of defeat

Jasnow et al. (1999) Jasnow et al. (1999) Jasnow et al. (1999)

730

E. Malatynska, R.J. Knapp / Neuroscience and Biobehavioral Reviews 29 (2005) 715–737

amitriptyline and fluoxetine (Malatynska et al., 1995; Tunnicliff et al., 1999). Amitriptyline augmented GABAstimulated 36ClK uptake in membrane vesicles prepared from cerebral cortical tissue taken from untreated dominant animals (Malatynska et al., 1995). Tissue taken from their untreated submissive partners showed an inhibitory response to these antidepressants in the 36 K Cl uptake assay. When submissive rats were treated chronically with amitriptyline the effect shifted toward augmentation of GABA-stimulated 36ClK influx (Malatynska et al., 1995). However, this shift did not reach the level of stimulation observed in dominant rats. These observations suggest that the negative efficacy of amitriptyline and fluoxetine toward GABA-stimulated 36 K Cl influx can be related to the depressed state as modeled by submissive animals and that the greater positive efficacy of amitriptyline can be related to the antidepressant effect of these drugs and the recovery from depression as modeled in the behavioral paradigm. The significance of these observations lies in the establishment of a linkage between basic neuronal activity at the molecular level and animal behavior having an apparent relationship to human depression.

9. Neural systems contributing to dominant–submissive behavior Panksepp (1998) discussed evidence for the existence of specific neural systems responsible for different emotional states. There are four basic emotional states of animals: stress response, cognition, motivation and aggression. Distinct neuronal systems are believed to regulate each emotional state. Malfunction of one neuronal system can cause disturbances in others complicating the results of these studies. Animal models based on dominant–submissive behavior may encompass more neural-emotional systems that are disturbed in depression and mania than models based on other principles e.g. changes in locomotor activity. Depression is commonly linked to stress. This linkage is supported by clinical research showing that depressed people perceive their lives as being stressful and often exhibit signs of excessive adrenal activity, including elevated cortisol levels. Most animal models of depression (e.g. forced swim, learned helplessness, chronic mild stress) employ physical stress as a means of inducing a ‘depressed’ state in animal subjects. However, people who experience even extreme physical stress rarely become depressed. It is usually some form of emotional stress like family conflict, workplace problems and social harassment that promotes depression in people. The behavior measured in the RSBM is a good model of depression because it is based on social conflict rather than physical stress. The RSBM measures the innate reaction of the submissive animal to a natural social stress that has obvious correlates to competitive human

social behavior. A characteristic feature of both mania and depression is a high sensitivity to stress. Mania could be defined as super-energizing responses to stress in contrast to depression, an energy preserving responses to stress. While low levels of mania symptoms can be adaptive and viewed as normal in a competitive environment, low levels of depression symptoms are more likely to be viewed as abnormal. Sub-manic states characterize energetic, motivated, high achievers and leaders that are valuable for society as a whole. Only when the state of elevated mood is combined with cognitive impairment, compulsion or frequent swings down to depression is mania viewed as pathological. Depression can also be viewed as a disease of cognition. Depressed people see the world and themselves in negative terms. They see themselves as being beset by insurmountable problems that they think themselves too incompetent to overcome. There is no pleasure in the present and no hope in the future. Delusional states are seen among depressed individuals further supporting a cognitive dysfunction. The idea that depression results from impaired cognition is consistent with psychotherapeutic treatments directed at changing cognitive processes (Crews and Harrison, 1995) and by studies showing that long term antidepressant therapy improves cognitive function in depressed patients (Amado-Boccara et al., 1995). In addition, there are clinical findings showing that neuronal degeneration resulting in impaired cognition may be present in bipolar disorder or unipolar depression (Cotter et al., 2001; Lee et al., 2002). This includes dysfunction of prefrontal cortex in depression (Dougherty et al., 2003; Goldapple et al., 2004; Jankowski and Sesack, 2004; Pizzagalli et al., 2003; Rocher et al., 2004). A reduced volume of prefrontal and orbitofrontal cortex was shown in depressed patients using positron emission tomography and magnetic resonance imaging (Bremner et al., 2002; Lai et al., 2000). Postmortem studies have revealed a reduced density of neurons and glia in the same region (Rajkowska et al., 1999; Rajkowska, 2000). Others have shown a reduced volume of hippocampus (Bremner et al., 1997; Sheline, 1996) in major depression. Treatment with antidepressants was shown to reduce cognitive deficits (Goldapple et al., 2004; Rocher et al., 2004; Brody et al., 1999; Martinot et al., 1990). We have demonstrated that memory enhancing drugs reverse submissiveness of rats in the RSBM (Knapp et al., 2002). The cognitive impairment of depressed patients and memory enhancing features of antidepressant drugs is a common observation related to this disease (Kumar and Kulkarni, 1996; Nowakowska et al., 2000). A relationship between depression, aggression and motivation is suggested by some clinical studies (Berkowitz, 1990). There are also models of depression utilizing different types of aggression (Pucilowski and Kostowski, 1983; Pucilowski and Valzelli, 1986; Pucilowski et al., 1988). It was shown, however, that submissive behavior is

E. Malatynska, R.J. Knapp / Neuroscience and Biobehavioral Reviews 29 (2005) 715–737

140

Time on Feeder (sec.)

120 100 80 60 40 20 0

0

2

4

8

12

16

Food Restriction Time (hrs) Fig. 11. Effect of food restriction time on the formation of dominant– submissive relationships. The figure shows number of D–S pairs formed. (D–SZDominant–submissive; nZ16).

restriction time decreased. Thus the maximum number of DSR pairs formed after 8 h of food restriction time. The data are shown on Fig. 12. This non-linear function of the number of DSR pairs formed with food restriction time may indicate the involvement of a motivational component in the formation of DSR relationships. At a low level of stimulus intensity (short food restriction time) only animals that are easily motivated will show dominance. On the other hand, at a high level of stimulus intensity (long food restriction time), only animals with impaired motivation will show submissiveness. Other processes such as high or low sensitivity to food deprivation may overlap with the motivational pathways in this paradigm. However, depression is a disease that may have impairments in both pathways responsible for motivational and energy metabolism processes. Second of the nine criteria that define a major depressive episode in the 8

6 No. D-S Pairs

not dependent on defeat nor it is a simple response to aggression. Fonberg (1988) has shown that aggression can be a tool to gain predatory dominance between cats in the presence of prey (a live mouse). While some cats achieved dominance with respect to monopolizing the opportunity to catch and eat mice by aggressive behavior, others achieved dominance without any display of aggression (Fonberg, 1988). Perhaps only a certain type of aggression, corresponding more to human assertiveness, is involved in the formation of dominant behavior. Submissive behavior in the RSBM is related to the unwillingness of an animal to compete with its partner for the food source. None of the behaviors seen in the resident–intruder paradigm (aggressive display, fighting, infliction of injury) occur during the two-week period that the dominant–submissive relationship is established. The limited correlation observed between aggression and dominant -submissive behavior is also seen between motivation and dominant–submissive behavior. A marked change in food intake (increased or decreased) is listed in the DSM IV as a feature of human depression. Motivational or seeking neural systems are engaged in the RSBM by the use of food restriction. Our studies with C57/Bl/J6 mice show that increased access to food results in a decreased number of pairs forming dominant–submissive relationships (unpublished observation). The measure of the degree of dominance in our test (dominance level) has at least two components. First, the motivation to get a food reward by a food restricted animal and second, a social obstacle to get an immediate need fulfilled, resulting from the presence of a partner motivated in the same way. We have previously shown that social pressure imposed by the latter component can be demonstrated by separating animals with developed dominant and submissive relations. The time spent on the feeder was not different for dominant and submissive animals when tested alone (Malatynska et al., 2002). Thus, the time spent in the feeder area corresponds in our experimental settings to the degree of dominance and it is not a simple function of the animal’s attraction to the food reward. We have shown a lack of correlation between the influence on food intake by different psychotropic drugs and their effect in the dominance–submissive relationship test (Malatynska and Kostowski, 1984). Our recent experiments aimed to establish the RSBM in C57/Bl/J6 mice confirm the importance of the motivational component in the formation of dominance submissive relationships. The time spent on the feeder by both dominant and submissive mice was proportional to the length of food restriction time. The data are shown in Fig. 11. The number of mouse pairs that formed a Dominant– submissive relationship (DSR) was also affected by the food restriction time. However, this effect was not monotonic. Increased food restriction time from 0 to 8 h resulted in larger number of mouse pairs forming D/S relationships. The number of DSR pairs formed after 12 and 16 h of food

731

4

2

0 0

2

4

6

8

10

12

14

16

Food Restriction Time (hrs) Fig. 12. Effect of food restriction time on the formation of dominant– submissive relationships. The figure shows number of D–S pairs formed. (D–SZDominant–submissive; nZ16).

732

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DSM IV is ‘markedly decreased interest or pleasure in all or almost all activities.’ This statement relates to a general level of motivation. Sixth of the nine criteria is ‘fatigue or loss of energy nearly every day’. This criterion may relate to energy metabolism. It was shown by Haller and Wittenberger (1988) that among Betta splendens winners and dominant individuals were able to produce more energy per unit time than losers and submissives. Taking data from Figs.11 and 12 together we can speculate that to model depression, we need to choose animals that are still submissive under a strong stimulus. Under such experimental circumstances animals that have motivational and/or energy metabolism problems will be identified as being submissive. The opposite is true for selecting dominant animals for RDBM. It seems that the animals still dominant under the condition of a weak stimulus should model mania better.

10. Summary and conclusions We have discussed several animal models of disturbed human affect based on social interactions between animals that can be shown to have elements of mania and depression. Three types of interactions are emerging from this research. First, the dominant–submissive interactions seen in groups of animals and measured mainly by observation of agonistic and defensive postures (Blanchard et al., 1987; , 1988; Grant and Mackintosh, 1963; File, 1982; Miczek, 1977). Second, winner–looser relations that are measured in competition tests (Malatynska et al., 2002; Uyeno, 1960, 1967; Malatynska and Kostowski, 1984; Masur et al., 1971b; Masur and Benedito, 1974). Third, resident–intruder interactions that result in a defeated state resembling aspects of depression (Kudryavtseva et al., 1991; Mitchell and Fletcher, 1993; Willner et al., 1995). These three types of animal behavioral models measure the same principal process, the ability of some animals to be superior (dominance) to others and the acceptance of others to be inferior (submissiveness), in different ways. Being dominant (superior) or being submissive (inferior) is a dynamic process rather than a fixed state and has several dimensions including the presence of genetic and environmental factors. Inherent differences between subjects are visible in the resident–intruder test where animals are preselected for a specific role on the basis of prior behavior (Kudryavtseva et al., 1991). It is also visible in the winner– looser relations where the animal selection process is important and where genetic selection of dominant and submissive animal lines is possible (Schutz et al., 1978; Masur and Benedito, 1974). The contribution of environmental factors is exemplified in the version of the resident intruder test by Willner et al. (1995). They showed that initially dominant animals can be defeated when faced with a more dominant partner. Winner–looser relations develop over time under the pressure of specific conditions within

the behavioral paradigm (Malatynska et al., 2002; Malatynska and Kostowski, 1984). Another of these dynamic processes is that individuals within a society can be dominant or submissive to different degrees. The axis of the deviation from the average culminates in two opposite poles of dominant-alpha and submissive-omega animals with neutral animals in the middle. Finally, different, but probably overlapping, neuronal systems control dominance, submissiveness, and neutrality. The three dominant–submissive paradigms discussed, although measuring the same behavioral process in principal, differ in details. Observation of dominant– submissive behavior in large groups of animals happens in more natural settings with minimal experimenter intervention. In the resident–intruder and priority of access tests experimental conditions must be carefully defined and maintained. An investigator performing the resident– intruder test needs to pre-select animals for aggressiveness by the display of agonistic or defensive postures. In the priority of access tests animals are resource deprived to increase their motivation threshold and placed under conditions that force them to compete. In the resident– intruder and winner–looser relations animals are preselected for two types, dominant, (winner or resident) and submissive (looser or intruder) behavior. Animals selected for winner-type (dominant) behavior can model aspects of mania and those with loser-type (submissive) behavior can model aspects of depression. We have shown that winner-type animals in the RDBM can model mania (Malatynska et al., 2002) and this could be true for resident animals in the resident–intruder paradigm, though this needs to be tested. Mitchell and Fletcher (1993), Mitchell and Redfern (1997) and Mitchell et al. (2003) show that acute treatment with antidepressant drugs can decrease aggressive behavior of resident animals but aggressive behavior increases after chronic treatment. Only a limited number of antidepressants have been tested on dominant animals in the food competition test. It was shown that intruder animals (Kudryavtseva et al., 1991; Willner et al., 1995) and looser animals (Malatynska et al., 2002; Malatynska and Kostowski, 1984) model depression. The interesting feature of both depression models is that the underlying dominant–submissive behavior must be developed over time. In the experiments of Kudriavtsheva and co-workers (1991) animals were subjected to repeated defeat for three weeks to develop ‘depressive’ features as assessed by other tests. In the RSBM (Malatynska et al., 2002) dominant–submissive relations develop after daily encounters during a two-week period. One of the most significant clinical findings of depression concerns its time course, both in its development and response to treatment. Depression tends to wax and wane over time without treatment though the period of these cycles varies widely. Submissive behavior develops gradually over time similar to how depression develops in humans. This is in

E. Malatynska, R.J. Knapp / Neuroscience and Biobehavioral Reviews 29 (2005) 715–737

sharp contrast to animal models like forced swim or learned helplessness where the behavioral change occurs in a one or two day period. We have shown in the RSBM and RDBM that antidepressant or antimanic drugs need to be administered chronically to submissive or dominant rats to contradict submissive behavior or dominant behavior. Thus, the response of submissive animals to antidepressant treatment and dominant animals to antimanic drug treatment requires chronic administration as seen for human patients. The RSBM and RDBM can model both the time-dependent neuronal activity changes associated with the development of depression and mania and those associated with the response to treatment. The major difficulty for explanations of how antidepressant drugs work is accounting for their therapeutic delay. If depression and antidepressant treatments involve post-receptor signal transduction systems and neuroplastic mechanisms as suggested by Duman et al. (1997) and others then they can best be studied by models like the RSBM and RDBM that recapitulate this time course. An important characteristic of the RSBM and RDBM paradigms is that using the full set of selection criteria only about 25% of all rat pairs tested develop well established dominant–submissive relationships. The ability to select subpopulations of animals may provide an important tool for identifying underlying biochemical differences that could be reflected in the disease modeled. This opens the way to genomic and proteomic studies of how these animals differ from each other and the general population and may ultimately lead to new hypotheses of therapeutic interventions. It is important to recognize that the RSBM and RDBM are only models of depression and mania. By definition they lack some elements of depressive illness and manic state in patients (Tables 1 and 2). There is no evidence that rats or mice have any of the same cognitive symptoms of depression or feelings of helplessness or despair that are diagnostic of human depression. Obviously they do not have pressure to keep talking that is diagnostic of human mania. It is also not clear what form of depression, such as major depression or dysthymic or unspecified depressive disorders, is being modeled. As previously discussed we think that the RSBM probably better resembles a chronic depressive state and RDBM models a manic episode or unipolar mania (Solomon et al., 2003) better than a cyclic one but the kind of long term study necessary to determine this has not been done. Models of disease provide a means of conducting studies that would otherwise be difficult if not impossible to do in humans. This has special importance for psychiatric illnesses where most of our knowledge of neural systems comes from animal studies. Behavioral models of mental disorders are essential for linking disease to what we know of brain function. This approach requires us to accept the inherent limitations of our models and, to whatever degree is possible, understand them. To understand the limitations of a disease model it is necessary to understand the disease,

733

which results in a circular process between studies of a disease and its models.

Acknowledgements The authors are grateful to Dr Moore Arnold for reading the manuscript and helpful comments and suggestions.

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