European Journal of Pharmacology, 47 (1978) 379--391 379 © Elsevier/North-Holland Biomedical Press

BEHAVIOURAL DESPAIR IN RATS: A NEW MODEL SENSITIVE TO TREATMENTS

ROGER D. PORSOLT, GUY ANTON, NADINE BLAVET and MAURICE JALFRE Centre de Recherche Delalande, 10, rue des Carri~res, 92500 Rueil-Malmaison, France

Received 29 July 1977, revised MS received 10 October 1977, accepted 19 October 1977

R.D. PORSOLT, G. ANTON, N. BLAVET and M. JALFRE, Behavioural despair in rats: a new model sensitive to antidepressant treatments, European J. Pharmacol. 47 (1978) 379--391. Rats when forced to swim in a cylinder from which they cannot escape will, after an initial period of vigorous activity, adopt a characteristic immobile posture which can be readily identified. Immobility was reduced by vari- ous clinically effective antidepressant drugs at doses which otherwise decreased spontaneous motor activity in an open field. could thus be distinguished from psychostimulants which decreased immobility at doses which increased general activity. Anxiolytic compounds did not affect immobility whereas major tranquil- isers enhanced it. Immobility was also reduced by electroconvulsive shock, REM sleep deprivation and "enrich- ment" of the environment. It was concluded that immobility reflects a state of lowered mood in the rat which is selectively sensitive to antidepressant treatments. Positive findings with atypical antidepressant drugs such as and suggest that the method may be capable of discovering new antidepressants hitherto un- detectable with classical pharmacological tests.

Tricyclic antidepressants Mianserin Depression MAOI ECS Behavioural model

1. Introduction and mianserin, which although clinically effective, show little or no "antidepressant" A major problem in the search for new psy- activity in the usual animal tests. While there chotropic drugs is the absence of specific ani- do exist several convincing behavioural mod- mal models for the different mental disease els of depression in experimental animals states. This is particularly true in the case of (Scott et al., 1973; Harlow and Suomi, depression, where available screening methods 1974; Seligman, 1975) none has so far been are based mainly on empirical!y established used for the routine screening of drugs proba- relationships between the clinical efficacy bly for reasons of cost or practicability. There of known antidepressants and their effects is thus an urgent need for new and simple on various pharmacological test models. Be- tests which bear a closer relationship to the cause no direct relationship exists between clinical phenomena of depression and are most pharmacological tests for antidepres- selectively sensitive to treatments known to sants and depressive illness itself, it seems un- be effective in depressive illness. likely that such empirically based methods We have recently described a behavioural will lead to the discovery of antidepressant screening test which attempts to meet these agents with modes of action different from requirements (Porsolt et al., 1977). The test is those already in use. The inadequacy of pres- based on the observation that rats when ently available methods for finding novel anti- forced to swim in a restricted space from depressants is demonstrated by the recent dis- which they cannot escape will eventually covery of several drugs, for example iprindole cease apparent attempts to escape and 380 R.D. PORSOLT ET AL. become immobile apart from the small move- ments necessary to keep their heads above water. We suggested that this characteristic and readily identifiable behavioural immobil- ity reflects a state of despair in the rat and showed that immobility was reduced by a variety of agents which are therapeutically effective in depression. The experiments reported below expand these original findings and show that reduc- tion of immobility by antidepressant treat- ments can be clearly dissociated from mere stimulant effects on locomotor activity. Fur- ther findings indicate that the depressive behaviour measured in this test is also allevi- ated by non-pharmacological treatments such as electroconvulsive shock, deprivation of REM sleep and exposure to an "enriched" environment.

2. Materials and methods 2. I. Animals

Male Sprague--Dawley {Charles River) rats weighing 160--180 g were used. They were brought into the laboratory at least one day preceding an experiment and were housed singly in macrolon cages (24 X 11 × 8 cm) Fig. 1. Rat showing typical posture of immobility with free access to food and water. after 10 rain immersion in water. 2.2. Induction and measurement of immobil- ity 2.3. Measurement of locomotor activity

Naive rats were individually forced to swim Naive rats were placed individually in one inside vertical plexiglass cylinders {height: 40 corner of an open field apparatus similar to cm; diameter: 18 cm) containing 15 cm of that described by Soubri~ {1971) and the water maintained at 25°C. After 15 min in number of quadrants entered in 5 min was the water they were removed and allowed to counted. dry for 15 min in a heated enclosure (32°C) before being returned to their home cages. 2.4. Drug treatment They were replaced in the cylinder 24 h later and the total duration of immobility was mea- The drugs and doses tested are shown in sured during a 5 min test. The rat was judged table 3. The drugs were either dissolved in dis- to be immobile whenever it remained floating tilled water or dispersed in a suspension of passively in the water in a slightly hunched Tween 80 {0.2% w/v 0.9% NaC1). Control ani- but upright position, its head just above the mals were given the vehicle only. On the basis surface (fig. 1). of preliminary experiments with {Results, section 3.2.) an injection schedule NEW ANIMAL MODEL OF DEPRESSION 381 was chosen in which drugs were administered proportion of REM, whereas those exposed to as a series of 3 i.p. injections 24, 5 and 1 h the smaller platform (4.5 cm) showed a simi- before the 5 min test on the second day. The lar reduction in SWS but a complete suppres- first injection was given at the end of the dry- sion of REM: the muscle atonia accompany- ing period (i.e. 15 min after removal from the ing REM causes the rat to fall in the water water). Drugs were injected in a constant vol- thereby waking it up. ume of 0.5 ml/kg and the dose, expressed in The effects of REM deprivation on open terms of the salt, was that given at each indi- field activity were also investigated following vidual injection. 5 rats were tested at each a similar procedure. In both the swimming dose. For the experiments using the open test and the open field test 6 rats were used field the same drug and dose injection sched- per group. ule was used, with 6 rats being tested at each dose. 2. 7. Enrichment of the environment

2.5. Electroconvulsive shock (ECS) After removal from the drying apparatus 6 "depressed" rats were exposed to an "en- Electroconvulsive shock (30 mA, 50 Hz, 1 riched" environment by placing them in a sec) was generated using a Grason Stadler 700 dry water maze (Apelab) containing a variety constant current shock generator and was of stimulus objects (paper rolls, a running delivered via ear-clip electrodes according to wheel, blocks of wood) as well as 6 naive rats the same time schedule as the drug injections. which had been placed in the enclosure just Control rats had the electrodes placed in a prior to the experiment. These rats were sub- similar manner but did not receive ECS. The sequently used as the experimental group in a effects of ECS on open field activity were parallel study of the effects of an "enriched" investigated in a similar manner. With both environment on open field activity. In addi- methods 10 rats were tested per group. tion to standard rat food pellets and water, rats in the enclosure had access to a varied 2. 6. Deprivation of REM sleep diet containing fresh vegetable and meat mat- ter. The rats were left in this environment Rats were selectively deprived of REM during the 24 h between trials. Control rats sleep according to the "island" method were housed in their individual home cages. described by Mouret et al. {1969). After A parallel experiment with the open field removal from the drying apparatus rats were was performed comparing rats from the "en- placed individually in macrolon cages (42 × riched" environment with rats which were 27 × 18 cm) each containing a small circular housed individually. platform (4.5 cm diameter) surrounded by water (10 cm deep). Food and water were available. They remained there under constant 3. Results illumination during the 24 h between trials. A "stress" control group was treated similarly 3. I. Behaviour without drugs except that a larger platform (11.5 cm diam- eter) was used. Normal control rats were Rats which were placed in the cylinders for housed in their individual home cages during the first time were initially highly active, vig- the 24 h inter-trial period. orously swimming around, scrabbling at the Mouret et al. (1969) have reported that rats walls or diving to the bottom apparently exposed to the larger platform (11.5 cm) searching for an exit. After 2--3 min their showed a 50% reduction in the amount of activity began to subside being interspersed slow wave sleep (SWS) without change in the with phases of immobility (fig. 1) of increas- 382 R.D. PORSOLT ET AL.

TABLE 1 10} and showed reduced spontaneous motor Effects of 5 sec and 15 min immersion in water activity (table 1). 25°C) on open field activity. The rats (n = 10 per We have found that a single exposure of 15 group) were tested immediately on being removed min was sufficient to produce a relatively con- from the water. The number of quadrants entered stant level of immobility in a subsequent test; during a 5 min period was counted. Differences from control were assessed statistically using the Dunnett on a second exposure to the cylinder, rats test (2-tailed). rapidly became immobile after a brief burst of activity and remained so for approximately Treatment Open field activity 75% of a 5 min test (fig. 2). As can be seen Mean (S.E.M.) from the control values in table 3, the immo- Control 18.5 (6.2) bility induced in this way was highly repro- Immersion (5 sec) 33.3 (5.8) 1 ducible between different groups of rats on Immersion (15 min) 4.1 (1.5) 1 different days. We therefore adopted this procedure for the studies described below be- 1 p < 0.05. cause it seemed to provide a suitable baseline for measuring the effects of treatments which ing length. After 5--6 min the duration of im- decrease or even increase immobility. mobility reached a plateau where the rats remained immobile for approximately 80% of 3.2. Effects of different injection schedules of the time (fig. 2). When left in the cylinders imipramine on immobility for 15 min the rats were hypothermic on Before beginning the drug studies described removal (mean: --3.15°C; S.E.: 0.16; n= below, a series of experiments were under-

TABLE 2 60 - Effects of different injection schedules of imipramine HC1 on the total duration of immobility during a 5 min test. Differences from control were assessed 3ta- tistically using the Dunnett test (2-tailed). 45 - Imipramine Dose Duration of injection (mg/kg immobility (sec) schedule i.p. ) Mean (S.E.M.) 30 (h before test) o E E 1 h Control 250.8 (11.6) 7.5 228.2 (26.9) 15 15 158.8 (41.2) o 30 152.6 (20.0) 5 h 7.5 212.0 (18.3) 15 168.8 (25.8) 30 165.2 (29.9) 24 h 7.5 251.4 (16.4) I,,,ll,,,I .... I l,,,I 15 226.8 (5.6) 5 10 15 5 30 192.4 (27.8) 24h + 1 h 7.5 180.4 (18.9) rain rain 15 180.4 (25.6) 30 88.6 (11.0) Trial 1 Trial 2 24 h + 5 h + 1 h 7.5 233.4 (17.8) Fig. 2. Mean duration of immobility in sec per min 15 124.0 (24.8) +-S.E.M. (ordinate) as a function of time in the water 30 78.6 (16.9) (abscissa). On trial 1 rats (n = 10) were placed in the water for the first time. There was a 24 h interval be- 1 p < 0.05. tween trials 1 and 2. 2 p < 0.01. NEW ANIMAL MODEL OF DEPRESSION 383 taken with imipramine to discover the opti- ical antidepressants. With fenfluramine, tol- mal schedule of injections for producing a oxatone and , a clear and dose-de- maximal pharmacological effect. Previous pendent reduction in immobility was observed experience (Jalfre and Haefely, 1971) had at doses which generally decreased open field indicated that multiple doses were superior to activity. Biphasic effects occurred with iprin- a single dose, as is also the case with the clini- dole and mianserin, a reduction in immobility cal use of antidepressant drugs. with lower doses followed by a return to con- Different groups of rats (n = 5) were given trol levels and a loss of muscle tonus with either 1, 2 or 3 injections of imipramine HC1 higher doses. There was no correlation (7.5, 15 or 30 mg/kg i.p.) as indicated in table between the effects of these drugs on immo- 2. All animals received a total of three injec- bility and locomotor activity which was gen- tions, 0.9% NaC1 being given when a drug erally reduced. Qualitatively different effects injection was not due. were observed with where the The results (table 2) indicate that single i.p. decrease in immobility observed at 10 mg/kg injections of imipramine 1, 5 or 24 h before seemed to be due more to hyperactivity than the test reduced immobility in a dose-depen- to the persisting attempts to escape seen with dent manner but that more pronounced and the other antidepressants; open field activity stable effects were observed when either 2 or was very variable with some animals showing 3 injections were given. The 3 injection sched- amphetamine-like stereotyped head move- ule was chosen for subsequent experiments. ments and little locomotion whereas in others locomotion was noticeably increased. 3.3. Effects of different drugs on immobility The two psychostimulants, d-amphetamine and on open field activity and caffeine, also reduced immobility but as with nomifensine, this effect appeared to be The results obtained with different psycho- due to motor stimulation rather than to per- tropic drugs and are shown in table 3. sistent attempts to escape; with d-ampheta- The antidepressants tested (imipra- mine stereotyped head movements during mine, , , nortripty- swimming were observed at 1.5 and 3 mg/kg. line} all caused a dose-dependent decrease in Both drugs caused a marked increase in open immobility; in the treated animals, in contrast field activity; stereotyped behaviour with to the controls, apparent attempts to escape d-amphetamine was, however, less apparent persisted for a greater proportion of the 5 min than in the swimming test. test. These effects were observed despite a Neither chlordiazepoxide nor diazepam marked loss of muscle tonus at the highest affected the duration of immobility even in doses and the fact that the same drugs under doses which produced noticeable ataxia. With identical conditions of administration gener- chlordiazepoxide there was a tendency ally decreased open field activity. towards an increase in open field activity, an The two monoamine oxidase inhibitors, effect usually taken to refect its anxiolytic and , also reduced immo- properties. In contrast chlorpromazine and bility in doses which otherwise diminished the reserpine-like compound Ro 4-1284 general motor activity. The disappearance of increased immobility and at the same doses the antidepressant effect of iproniazid at 120 decreased activity in the open field. mg/kg seemed to be due to the pronounced hypotonia observed at this dose; the animals 3.4. Effects of non-pharmacological treat- appeared quite limp and open field activity ments on immobility and on open field activ- was greatly reduced. ity Several different profiles of activity were The three non-pharmacological treatments observed with the compounds classed as atyp- investigated, electroconvulsive shock (ECS}, 384 R.D. PORSOLT ET AL.

TABLE 3 Effects of different drugs on the total duration of immobility and on open field activity (number of quadrants entered) during 5 min tests. Differences from control were assessed statistically using the Dunnett test (2-tailed). 1 p < 0.05, 2 p < 0.0l.

Drug Dose Duration of Open field (mg/kg i.p.) immobility (sec) activity Mean (S.E.M.) Mean (S.E.M.)

Tricyclic antidepressants Imipramine control 250.8 (11.6) 73.3 (13.2) HCI 7.5 233.4 (17.8) 33.8 (11.4) 15 124.0 (24.8) 2 31.5 (10.7) 1 30 78.6 (16.9) 2 27.5 (9.0) 1

Desipramine control 214.2 (8.2) 67.2 (12.4) HC1 5 202.2 (14.3) 31.5 (14.3) 10 174.8 (16.8) 23.0 (6.1) 1 20 98.8 (17.6) 2 27.7 (12.9)

Amitriptyline control 245.4 (8.0) 63.2 (14.3) HC1 3.75 184.4 (5.5) 1 48.0 (15.4) 7.5 189.7 (18.9) 1 27.3 (11.4) 15.0 150.7 (22.2) 2 38.8 (13.5)

Nortriptyline control 233.0 (19.4) 50.7 (13.0) HC1 5 202.2 (23.6) 15.8 (7.9) 1 10 185,6(18.5) 23.3 (9.0) 20 90.4 (18.4) 2 9.0 (1.8) 2

Monoamine oxidase inhibitors (MAOI) Iproniazid phosphate control 249.2 (18.1) 56.2 (12.4) 15 218.6 (7.0) 16.7 (4.4) 30 196.8 (12.5) 27.7 (13.9) 6O 145.2 (15.8) 2 28.3 (17.3) 120 238.6 (22.7) 9.7 (4.7) 1

Nialamide control 224.1 (9.6) 54.5 (17.0) HC1 40 231.2 (20.3) 19.3 (8.3) 80 127.4 (29.6) 35.0 (19.8) 100 83.4 (43.0) 2 8.0 (5.1) 1

Atypical antidepressants Fenfluramine control 248.2 (14.7) 57.2 (12.5) HC1 1.5 168.2 (18.6) 1 73.5 (12.4) 3 142.2 (12.5) 2 32.2 (10.2) 6 152.4 (32.8) 1 20.7 (11.5) 12 127.8 (17.0) 2 11.0 (5.4)1

Iprindole control 243.1 (14.1) 53.8 (15.6) HC1 15 237.8 (15.9) 1.3 (0.8) 2 30 229.4 (21.3) 20.0 (6.1) 40 155.6 (24.8) 2 13.3 (3.3) 1 60 260.6 (15.8) 6.5 (2.6) 1

Mianserin control 210.6 {21.1) 43.8 {11.7) HC1 7.5 187.6 (11.2) 41.3 (17.6) 15 140.0 (14.7) 2 ]5.8 (5.7) 30 147.2 (11.5) 1 5.0 (2.1) 1 60 256.4 (16.6) 6.3 (3.8) 1 NEW ANIMAL MODEL OF DEPRESSION 385

TABLE 3 (continued)

Drug Dose Duration of Open field (mg/kg i.p.) immobility (sec) activity Mean (S.E.M.) Mean (S.E.M.)

Nomifensine maleate control 224.4 (15.6) 39.5 (12.0) 2.5 162.4 (38.8) 52.0 (14.4) 5 200.0 (38.6) 19.0 (4.9) 10 38.6 (13.3) 2 39.2 (17.9)

Toloxatone control 227.0 (8.1) 75.8 (13.8) 25 203.8 (6.7) 65.2 (6.6) 50 168.0 (18.9) 2 37.5 (16.0) 100 128.4 (18.7) 2 22.8 (8.1) 200 120.5 (12.3) 2 21.3 (5.6)

Viloxazine control 214.8 (12.1) 63.3 (14.2) HC1 12.5 205.6 (12.9) 30.8 (11.5) 25 176.0 (23.2) 15.5 (6.9) 50 144.8 (15.3) 2 34.7 (11.5)

Psychostimulants d-Amphetamine sulfate control 202.8 (17.9) 49.8 (11.9) 0.75 175.0 (9.2) 43.0 (5.5) 1.5 85.4 (19.4) 2 92.7 (10.7) 3 25.4 (23.2) 2 166.3 (16.7)

Caffeine control 219.6 (20.7) 50.5 (15.3) 3.75 257.4 (8.7) 57.5 (15.2) 7.5 177.2 (21.7) 65.2 (22.0) 15 99.8 (21.0) 1 97.8 (10.3) Minor tranquilisers Chlordiazepoxide control 237.6 (8.9) 65.8 (10.9) HCI 2 237.2 (16.0) 90.3 (9.5) 4 225.6 (9.6) 85.2 (25.8) 8 234.6 (9.4) 93.3 (18.1)

Diazepam control 218.0 (10.7) 74.8 (15.9) 0.5 224.6 (10.7) 56.3 (10.1) 1 242.6 (12.7) 57.8(15.0) 2 216.6 (19.8) 46.3(15.2) 4 222.2 (21.1) 49.0 (15.5) Major tranquilisers Chlorpromazine control 218.2 (2.2) 50.8 (8.4) HC1 0.75 220.6 (11.8) 11.3 (5.8) 1 1.5 224.0 (18.1) 10.2 (7.0) I 3 263.0 (8.2) 10.0 (9.2) 1

Ro 4-1284 control 202.6 (7.3) 74.7 (20.2) 1 271.2 (12.6) 0.3 (0.1) 2 2 271.0 (12.0) 0 (0) 2 4 257.8 (15.9) 0 (0) 2 1 p < 0.05. 2p< 0.01. 386 R.D. PORSOLT ET AL.

TABLE 4 Effects of different non-pharmacological treatments on the total duration of immobility and an open field activ- ity (number of quadrants entered) during 5 min tests. Differences from control were assessed statistically using the Dunnett test (2-tailed). 1 p < 0.05, 2 p < 0.01.

Treatment Duration of Open field immobility activity Mean (S.E.M.) Mean (S.E.M.)

Electroconvulsive shock (ECS) control 238.7 (13.2) 26.8 (9.3) ECS 166.0 (24.7) 1 21.8 (11.3)

Deprivation of REM sleep control 229.9 (10.2) 75.2 (9.6) 'stress' 231.1 (14.2) 112.3 (6.2) 1 REM depriv. 162.4 (11.6) 2 133.8 (17.5) 1

Enriched environement (EE) control 232.0 (9.2) 99.1 (16.1) EE 182.7 (4.5) 2 113.2(11.0)

1 p < 0.05. 2p< 0.01. deprivation of REM sleep and "enrichment" method for inducing in rats a behavioural of the environment all caused a significant state resembling depression by exposing them reduction in immobility without greatly to a mildly aversive situation from which affecting open field activity (table 4). there is no possibility of escape. Preliminary With ECS, open field activity in the control experiments showed that prolonged exposure group was lower than that usually observed to such a situation produced increasing peri- (table 3) which may have been due to the ods of virtually complete immobility which multiple placement of the ear-clip electrodes contrasted markedly with the vigorous (Materials and methods, section 2.5.). There attempts to escape observed when the animals was, however, no difference between the open were first introduced to the situation. These field activity of the ECS and of the control behavioural observations suggested that the group suggesting that the decrease in immobil- animals, on finding that escape was impossi- ity observed with ECS was relatively selective. ble, gave up trying and resigned themselves to The results in the sleep deprivation studies the experimental conditions. We hypothesised also suggested fairly specific effects of REM that the immobility observed reflected a state deprivation on immobility. A decrease in im- of lowered mood or hopelessness in the rat mobility was observed in the REM depriva- and predicted that immobility would be tion group but not in the "stress" control reduced by treatments which are known to be group whereas both the "stress" control effective in alleviating depression in humans. group and the REM deprivation group showed Our hypothesis received support from the a significant increase in open field activity. results obtained in the experiments reported Finally, "enrichment" of the environment here not only with pharmacological agents caused a significant decrease in immobility but also with a variety of other treatments with only a slight and non-significant increase which are generally thought to be effective in in open field activity. depression. Furthermore several aspects of our findings suggest that the immobility ob- served in the water is a relatively specific 4. Discussion depressive phenomenon. Firstly, it is apparent The present paper has described a new that the effects observed with the different NEW ANIMAL MODEL OF DEPRESSION 387 antidepressant treatments were not merely antidepressants would not be readily predict- due to a stimulation of motor activity. able on the basis of their pharmacological pro- Indeed, antidepressant effects as measured by file alone. For example iprindole, a tricyclic reductions in immobility in the water gener- indole, although potentiating the stimulant ally occurred at doses which otherwise effects of amphetamine, only weakly antago- decreased activity as measured in the open nises the hypothermia and ptosis induced by field. Antidepressant effects could thus be reserpine (Gluckman and Baum, 1969) and clearly distinguished from the effects of psy- does not block the uptake of noradrenaline chostimulants which markedly increased open or {Ross et al., 1971; Fan et al., field activity. Even in the water the decrease 1972; Koe, 1976). Nonetheless its clinical in immobility observed with d-amphetamine efficacy appears comparable with that of imi- and caffeine was accompanied by signs of a pramine {Ayd, 1969; Rickels et al., 1973). A non escape-directed hyperactivity which, with further example is the tetracyclic compound the exception of nomifensine, was not seen mianserin which possesses a profile of phar- with the antidepressants. Secondly it seems macological and biochemical activity radically unlikely that the reductions in immobility ob- different from that expected of a classical served were due to either diminished fear or tricyclic antidepressant. In animal tests the drug-induced impairment of memory; chlor- compound is strongly sedative having only diazepoxide and diazepam which, in addition slight and transient antireserpine activity iVan to their well known anxiolytic effects, are Riezen, 1972; Gouret et al., 1977} while also thought to impair memory (Soubri~ et antagonising the stimulant effects of ampheta- al., 1976) were without effect whereas those mine (Van Riezen, 1972). Although it inhibits agents which were effective in reducing immo- the brain uptake of noradrenaline in vitro bility are not known for either their anxiolytic (Koe, 1976; Raiteri et al., 1976)mianserin effects or their ability to impair memory in increases the turnover of noradrenaline in vivo animal tests. Finally immobility was even {Kafoe and Leonard, 1973) and is moreover a enhanced by the two major tranquilisers potent central serotonin receptor blocking chlorpromazine and the reserpine-like com- agent {Jalfre et al., 1974; Van Riezen, 1972; pound Ro 4-1284. While the increase in im- Maj et al., 1976). Indeed the antidepressant mobility may have been due to their pro- potential of mianserin was not predicted from nounced sedative effects, it is possible that animal tests but was discovered virtually by these drugs actually potentiated the depres- chance during EEG studies in normal volun- sive state induced in the experimental situa- teers {Itil et al., 1972). Several double blind tion; it is widely accepted that reserpine-like studies {Murphy, 1975; Wheatley, 1975; Cop- compounds can cause clinical depressions in pen and Ghose, 1976; Vogel, 1976; Jaskari et man (Schildkraut, 1972) and it has been sug- al., 1977) have subsequently confirmed its gested that depressive states can also result antidepressant activity. A similarly incomplete from treatment with neuroleptics (Helmchen antidepressant profile in pharmacological and and Hippius, 1967; De Alarcon and Carney, biochemical tests is seen with the clinically 1969}. active/~-blocker derivative viloxazine (Vivalan The results obtained with the "atypical" Symposium, 1975; Floru et al., 1976; Moizes- antidepressants deserve special comment zowicz and Subira, 1977). Although it antag- because these compounds, although clinically onises reserpine-induced hypothermia and effective, differ in terms of both chemical sedation {Greenwood, 1975) viloxazine nei- structure and pharmacological activity from ther inhibits monoamine oxidase nor blocks classical tricyclic antidepressants or mono- the uptake of monoamines in brain (Mallion amine oxidase inhibitors. Indeed the antide- et al., 1972; Lippman and Pugsley, 1976; pressant activity of some of these "atypical" Koe, 1976). Another compound, nomifen- 388 R.D. PORSOLT ET AL. sine, has also been reported to be an effective is the first animal test model which clearly antidepressant (Angst et al., 1974; Acebal et predicts an antidepressant action for mian- al., 1976; Moizeszowicz and Subira, 1977) serin. which strongly antagonises the effects of Further evidence for the validity of our reserpine but, in contrast to tricyclic antide- model is provided by the positive findings ob- pressants, markedly stimulates motor activity tained with non-pharmacological antidepres- (Hoffmann, 1973; Maj et al., 1976) and in sant treatments. Electroconvulsive treatment, addition to blocking noradrenaline uptake is a despite increasing caution in its use, is still potent blocker of dopamine uptake in brain widely accepted as being the most effective (Hunt et al., 1974; Samanin et al., 1975; Koe, and rapid of existing treatments for endoge- 1976; Tuomisto, 1977). The relatively new nous depression (Ilaria and Prange, 1975). compound , an oxazolidinone Similarly, sleep deprivation, although less derivative, also causes moderate antagonism effective in the long term, is widely used for of several effects of reserpine and potentiates the treatment of various kinds of depression amphetamine-induced stereotypies at doses (Post et al., 1976; Rudolf et al., 1977) espe- which are otherwise markedly sedative (Gou- cially as an adjunct to more classical phar- ret et al., 1973; Coston et al., 1975; Gouret macotherapy (Loosen et al., 1976). Further- and Raynaud, 1975). In contrast to the more there is increasing evidence that the above-mentioned compounds toloxatone therapeutic effects of sleep deprivation are appears to act through a relatively specific specifically related to deprivation of REM inhibition of type A monoamine oxidase but sleep (Vogel, 1975; Schilgen et al., 1976). unlike other MAOIs in clinical use this inhibi- The present results provide added evidence tory effect is reversible and of short duration for this in that they show a highly selective (Kan et al., 1977). Preliminary studies indi- effect of REM sleep deprivation in reducing cate that toloxatone is clinically effective immobility in the rat. The fact that exposure (Martin, 1973; Suttel and Duplan, 1973). The to an "enriched environment" also selectively remaining compound in the series of "atypi- reduced immobility in the rat, although intu- cal" antidepressants, fenfluramine, a non- itively predictable, is more difficult to inter- stimulant derivative of amphetamine (LeDou- pret in view of the absence of systematic arec and Neveu, 1970), is best known for its research in this area. Nonetheless the positive anorexic properties (Pinder et al., 1975). Fen- findings obtained heuristically suggest that fluramine nonetheless possesses other pharma- further research into the role of environmen- cological properties, e.g. the release of sero- tal and social factors in antidepressant ther- tonin from central storage sites (Trulson and apy would be worthwhile (Benson, 1975). Jacobs, 1976} and the inhibition of its uptake We conclude from the findings described into blood platelets (Wielosz et al., 1976). and discussed above that our test procedure These properties are not inconsistent with reproduces some aspects of human depression antidepressant activity and indeed such activ- in the rat. It is therefore of interest to seek ity has recently been reported in man (Murphy parallels between our model and other behav- et al., 1976). The fact that all these clinically ioural models described in the experimental effective compounds showed antidepressant literature. The most striking of these is the effects in our test procedure despite their depressive syndrome occurring in young rhe- widely differing modes of action provides sus monkeys after separation from their additional support for our hypothesis that mothers, their age mates or after confinement the immobility observed reflects a state of in "vertical chambers" (Harlow and Suomi, depression in the rat. It is noteworthy that 1974). The syndrome consists typically of the present procedure, which is based on two phases, first a high level of agitation and behavioural rather than biochemical concepts, vocalisation (protest) followed by a marked NEW ANIMAL MODEL OF DEPRESSION 389 reduction in general activity, together with simplicity it should lend itself readily to experi- increases in huddling and self-clasping (de- mental manipulation; studies of the biochem- spair). A similar behavioural pattern has been ical and electrophysiological correlates of im- observed in young dogs (Scott et al., 1973} mobility are already in progress in our labora- and resembles the anaclitic depression tory. Furthermore the fact that several atypi- described in young children who are separated cal antidepressant compounds, for example from their parents (Bowlby, 1977). Although mianserin and iprindole, show a clear antide- the time scale is greatly reduced, it is tempt- pressant activity in the test procedure, raises ing to see a resemblance between these pro- the intriguing possibility that the present test and despair reactions and the behaviour method may be capable of discovering new observed in our test procedure where a short types of antidepressant agents hitherto unde- period of frantic activity is followed by peri- tectable using classical screening tests. ods of immobility of increasing duration. An- other model which is currently gaining wide interest is Seligrnan's "learned helplessness" References (Seligman, 1975). According to this model animals and even humans, when exposed to Acebal, E., S. Subira, J. Spatz, R. Faleni, B. Merz- aversive situations over which they have no bacher, A. Gales and J. Moizeszowicz, 1976, A control, are subsequently less able to respond double blind comparative trial of nomifensin and desimipramine in depression, European J. Clin. adaptively to traumatic events. For example, Pharmacol. 10, 109. dogs when given inescapable electric shocks Angst, J., M. Koukkou, M. Bleuler Herzog and H. were unable on a later occasion to learn the Martens, 1974, Ergebnisse eines offenen und eines responses necessary to escape from shocks Doppelblindversuches yon Nomifensin im Ver- of similar intensity (Seligman and Maier, gleich zu Imipramin, Arch. Psychiat. Nervenkr. 1967). Similar deficits have been observed in 219, 265. Ayd, F.J., 1969, Clinical evaluation of a new tricyclic experiments with man and have been accom- antidepressant iprindole, Dis. Nerv. Syst. 30, 818. panied by mood changes similar to those Benson, R., 1975, The forgotten treatment modality occurring in clinical depression (Miller and in bipolar illness: psychotherapy, Dis. Nerv. Syst. Seligman, 1975). Seligman calls the behav- 36, 634. ioural disturbance "helplessness" and suggests Bowlby, J., 1977, The making and breaking of affec- tional bonds. I. Aetiology and psychopathology in that "helplessness" occurs because the orga- the light of attachment theory, Brit. J. Psychiat. nism has learned that attempting to escape is 130, 201. futile. Although the present experiments do Coppen, A.J. and K. Ghose, 1976, Clinical and phar- not test whether rats inescapable exposed to macological effects of treatment with a new anti- depressant, Arzneim. Forsch. 26, 1166. water are subsequently less able to learn to Coston, A., C. Gouret and G. Raynaud, 1975, Etude escape, there is an obvious parallel between neuro41ectrophysiologique chez le chat d'un nou- the kind of situation investigated in our pro- veau psychotrope: la toloxatone, Th~rapie 30, cedure and that described by Seligman. If so, 725. Seligman's findings suggest that our experi- De Alarcon, R. and M.W. Carney, 1969, Severe depressive mood changes following slow-release mental situation may well induce feelings of intramuscular fluphenazine injection, Brit. Med. J. helplessness in the rat whereas our findings 3,564. provide pharmacological evidence that Farm, W.E., J.M. Davis, D.S. Janowski, J.S. Kauf- "learned helplessness" is indeed related to mann, J.D. Griffith and J.A. Oates, 1972, Effect depression. of iprindole on amine uptake in man, Arch. Gen. In conclusion, we think that our test proce- Psychiat. 26, 158. Floru, L., G. Czarny and Tegeler, 1976, Doppelblind- dure represents a new approach to the study of studie mit dem neuen Antidepressivum Viloxazin depression in animals and is both pharmacolo- im Vergleich zu Imipramin bei 50 station~ren gically and behaviourally valid. Because of its Patientinnen, Arzneim. Forsch. 26, 1170. 390 R.D. PORSOLT ET AL.

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