TiPS - April 1991 [Vol. 221 the tissue damage seen in conditions such as Transplant rejection or vasculitis. SALVADOR MONCADA AND RICHARD M. J. PALMER The WeflcomeResearch Laboratories, Lungfey Court, BcckenhamBR3 3BS, UK.
131 References 1 Radomski, M. W., Palmer, R. M. j. and Moncada, 5. (1990) Proc. No!/ Amd. Sri. USA 87,100113-110047 2 Rees, D. D., Cellek. S.. Palmer.R. M. 1. and Moncada, S. (1990) Biochcm.Biuphys. Res. Cornmuu.173, 541-547 3 Knowles, R. G., Salter, M., Brooks, S. L. and Moncada, S. (1990) Biochem.Biophys. :?rs.Commun.172,1042-1048
Animal models as simulations of depression Paul Willner The most familiar usage of animal models of depression is as antidepressant screening tests Paul Willner rcuiews their usage in Qdifferent context - as simulatfons of depression. The behavioural features of aninud models of depressionare comparedwith clinical symptomatology, and the contribution of animal models to understanding the fofiowing aspects of dcprcssion arc reviewed: sources of population variability, natural history, psychological aspects, symptomatologyand mechanisms of antidepressant action. Finally, the role of animal models of depression is considered as a critical interface between basic khaviourul neuroscience and the clinic. Animal models of depression are most hrquently encountered within the pharmaceutical industry, where they are used as screening tests in the development of novel antidepressants. Increasingly, however, animal models are also used as simulations for investigating the psychobiology of depression, and a minority of models have been developed explicitly for this purpose. In this context, the validity of the model is an important consideration (though ltss valid models can also proviae cseful corroborative insights). The procedures tor validating animal models of psychiatric disorders have been discussed in detail elsewhere’-$ they include consideration of predictive validity (which concerns primarily the corresponP. Wifbter is Pro\mr itt the Department of Psychology, City of Lottdon Pdytechuic. Old Caslle Strrel. LuurlouEl 7NT, UK.
dence between drug actions in the model and in the clinic), face validity (phenomenological similarities between the model and the disorder), and construct validity (a sound theoretical rationale). Some desirable features in a simulation of depression are that the mode1 should respond to antidepressant drugs, should employ realistic inducing conditions and should model a core symptom of the disorder. In addition, for many purposes, such as investigating mechanisms of antidepressant action over a clinically relevant time scale, a prolonged timecourse is also desirable. This paper reviews the contribution of animal models as simulations of depression and assesses their potential to provide clinically relevant insights. BehrvlouraI features From its early beginnings in the reserpine reversal, amphetamine
4 Di Rosa, M., Radomski, M. W.. Camuccio, R. and Moncada. S. (199oj Biochem. Eiophys. Res. Comman. 172. 1246-1252 5 Hibbs, J. B., Jr et al. (19%) in Nitric Oxidr /mm L-Argiminr: A Bioregulfftory System (Moncada. S. and Higgs, E. A., eds), PP. lg9-22% Elsevier 6 Moncada, S., Palmer, R. M. J. and Higgs, E. A. (1989) Biochem. Pharmncol. 38, 17G9-1715
potentiation and muricide (mouse killing) tests, the list of animal models of depression has grown to include more than 20 experimental procedures in current use (see Table I; Refs 1 and 4). The common feature of these models is that behavioural abnormalities are reversed by antidepressant drugs. In other respects, animal models of depression vary widely - in the means of inducing abnormal behaviour, in the aspects of behaviour chosen for study and in the time-course of antidepressant action. Furthermore, antidepressant drugs are active in at least some animal models of anxiety, following chronic treatmc#. In the diagnostic system described in Table II (DSM-III-R), depression is defined by the presence of at least one core symptom combined with a number of additional subsidiary symptoms. It is clear that some of the symptoms of depression could be modelled in animals, though others could not. Table I provides an impressionistic summary of the major behavioural features of animal models of depression. (The list of symptoms surveyed is certainly not exhaustive: biological symptoms, such as neuroendocrine changes, are omitted, and in some of the models the behavioural changes are more complex than is implied in the Table.) It is apparent from Table 1 that the behaviour most frequently studied in animal models of depression is a decrease in locomotor activity. Unfortunately, while it is true that psychomotor changes are a central feature of severe depression’, it cannot be simply assumed that retardation and agitation are equivalent to decreases or increases in locomotor activity. Slowness of thinking is at least as important a feature of psychomotor retard-
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a5 a decrease in physical activity, and psychomotor agitation in humans involves such features as hand-wringing and outbursts of complaining, in addition to a restless increase in locomotion. Thus, the degree of resemblance between the changes in locomotor activity observed in animal models of depression and the psychomotor features of human depression is questionable. There is in fact only one model, sociai separation of infant o: juvenile primates, in which locomotor hypoactivity is accompanied by other psychomotor changes - a hunched posture and ‘sad’ facial expression - clearly reminiscent of clinical retardation’. In a further three instances (see Table I), the model could be described as demonstrating a decrease in motivation or persistence, rather than, or in addition to, a decrease in locomotion. This kind of behaviour may have some relevance in relation to the symptom of ‘loss of interest’. In one of these models, learned helplessness, behavioural studies have
ation
been carried out that support this interpretation9. Two further symptoms, characterized in Table I as impulaivity and decreased social contact, do not feature prominently among the diagnostic criteria for depression, perhaps because they have a low specificity for depre&on as compared to a range of other psychiatric disorders. A variety of social factors have been described that powerfully inauence vulnerabiiity to, and recovery from, depression. Two of these, the absence of social supporP and lack of social skills”, could be said to involve a decrease in social contact. However, decreased social contact appears among the DSMIII-R criteria for depression as an aspect of ‘loss of interest’, rather than as a symptom in its own right. Similarly, the concept of impulsivity is used increasingly by basic neuroscientiats to organize the behaviouml literature on the functions of the forebrain 5HT projections’? and may lead to a reassessment of the relationship between depression and other
disorders in which !i-HT is impiicated’); at present, however, as a symptom of deplpssian, impulsivity is at best a minor aspect of ychomotor agitatfon. #z e final symptom shown in Table I, anhedonial* (the decreased ability to experience pieaaur*) is somewhat diffemnt. Anhedonia is one of the core symptoms of depmwion, and defines the endogcaous subtype (mehnwholia). Ax&e&da has beenproposedb&kcta&ctease in the sensitivity of brain reward mechanismP, and as such may realirtically be mode&d in snimals as a decrease in aenaitivity to Rwards. In four of the models surveyed, animals display impairments of rewplykd behaviour, following fzxpoaure to stmaaors of various kinds; in three of the Courcaaes(kanredMti, chronic unpredictabk &Id atteas, and alnphetarnine withdmwal) there is evidence that a &creased sensitivity to reward is msponsible for these impairmenta*6. These mod& are clearly of particular interest.
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133
The psychobiology of depression
TABLE II.DiagnoGotma@dqxe&on @Sk-III-Ft. 1987)
There are several aspects +o the problem of depression. Sources of popnlation uariabifify Recent research has identified a number of factors that cause individuals to vary in their susceptibility to depression. For example, there is strong evidence of a major genetic contribution to bipolar depressions”, and unipolar depressions are up to thret times more revaknt in women than in men3 Although animal models lend themselves readily to experimental investigation of genetic effects and sex differences, there has been surprisingly little attempt to exploit this potential. in one of the very few studies of sex differences, it was reported that female rats were less likely than males to adapt to repeated immobilization stress; some of their behavioural abnormalities were reversed by chronic desipramine, but not by acute desipramine or by anxiolyticst9. Subsequently, the same research group reported that the effect of stress was greater in singly housed than in group-housed animaksa, and suggested that this may model the protective effect of social support=. An&ma and colleagues have made the important observation that uncontrollable ekctrtc shock has variabk behavioural effects (most of which cannot be reversed by antidepressants) in different inbred mouse strains. An extreme example was seen in the CS7W6J mouse strain, in which uncontrollable shock severely impaired subsequent learning to escape shock, but had no effect on responding for brain stimulation reward, whereas the DBAIZJ mouse strain showed exactly the opposite pattern of deficits”? These studies may provide a starting point for investigation of the physiological mechanisms underlying individual differences in responses to stress. A number of other selective breeding programmes have produced strains of rodent that bear some behavioural and physiological reaembknces to depressed humans (for review see Ref. 24) (though as noted above, the behavioural simikritks tend to be superficial). Depressed patients are known to be hypersensitive to drugs that stimulate central acetyl-
Raquinr-everyNWevery)dw duelgthasametwowwkfmrtodof ofmoresymptomafKf four subsidiarysymploms(of thee with both me symptoms) -rylnptoms Depccwsed~
. . pqaomotorretardabjon’oragitaticn Fatigue, or loss of energy’ Far#ngsofworthlassnaaa, or excesstw orblappn@ateguitl Demasadsbilitytothkrka-’
Raanvntthoughtsofdaathorsuicida,ofaspedfn:sui~oianorattempt ‘CouldInprtnclplebemcbdekdlnsnimals
choline receptors, and some physiological abnormalities characteristic of depression are consistent with cholinergic hyperfunctior?. The Plinders Sensitive Line (PSL) of rats, which were bred for their sensitivity to a cholinergic agonist, show abnormalities, relative to outbred strains, in a number of behavioural tests. These include an animal model of depression, the Porsolt forced swim te&‘, which is of relatively low validity as a simulation of depresston’ but is used routinely in antidepressant screenir@. A preliminary communication reported that an avoidance learning deficit in these animals could be reversed by imipramine”. Studies using the FSL strain have not used the optimal behavioural models; nevertheless, they are of considerable interest, in that they represent an attempt to use an animal model of depression to test a clinical hypothesis. of depssion ‘IIrenafnrnl history Depression has a number of temporal features, including spontaneous recovery, the periodicity of recurrent unipokr depression, and the alternation of depressive and manic phases of bipolar disorder. This is another area which could usefully be investigated in animal models, but remains at present relatively under-researched. Spontaneous recovery has received some attention in animal models in studies of adaptation to repeated stress, but the clinical rekvance of this phenomenon is uncertainrr*m.28. So far, there have been no attempts to model bipolar disorder. The ad-
ministration of psychomotor stimuknt drugs (amphetamine and cocaine) is used extensive1 as an animal model of mania J , and them is an animal model of depression based on withdrawal from chronic amphetamines“. Clearly, there is a basis here for developing a model of bipolar disorder, but this will be a formidable undertaking. lJsych01ogicar aspects Perhaps surprisingly, research in animal models relating to the psychological features of depression has been relatively productive. Much of this work arises from models based on the application of stress, which form the largest group in the list of models summarized in Table I. The behavtoural sequelae of stress can usually be revemed by antidepressants. This is PIearly relevant to the ettologtrtr~ role of stress in and immediately depression focuses attentibn on the meaning of the term ‘stress’. Most research derives from the original stress model of depression, kamed helpksmess The learned helplessness hypothesis proposed that exposure to uncontrolkbk stress provides the basis, in animals as well as in people, for learning that stress is uncontrollable (helplessness); this learning has a number of debilitating consequences, induding depn&on9. The demonstration of performance impairmenta in animals subjjted to uncontrolkble stressors, and their absence in animals subjected to the same stressom but able to control them, led to extensive research on the import-
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131 ante of controllability over stress in human$‘. However, the hypothesized clinical role of a perception of helplessness in the etiology oi depression has passed through a number of incamations”*u, and now takes a form so complex that it is doubtful whether animal studies can make any direct contribution. Thus, while the learned helplessness paradigm has had an important influence on clinical thinking, this is now largely of historical importance. Within the animal literature, the status of the concept of helplessness has also changed. The hypothesis that animals can learn that their responses are without effect on their environment has been hotly debated, and a number of alternative, and simpler f’nonhave cognitive’) explanations been proposed for the disruptive effect of uncontrollable stress on later performance’. It is now clear that under some circumstances, stress can impair learning ability, but this appears to be secondary to an impairment of attention stressed animals are more easily distracted%. This effect is probably mediated by a functional incapacitation of noradrener ic transmission in the forebrai$‘. This evidence suggests that, influential as the learned helplessness hypothe,;s has been on clinical thinking, it is probably incorrect as an interpretation of the effects of uncontrollable stress in animals. Nevertheless, this research is important in suggesting some functional correlates of the disorders of noradrenergic transmission in depressed patients, which have frequently been observed but have proved extremely difficult to interprets7. The learned helplessness model has provided another, extremely important pmpective on depressive thinking. An attractive feature of this paradigm is the breadth of symptomatic paraliels to severe depression2”5. Among these behavioural abnormalities is a poor performance of rewarded behaviour. One manifestation of this effect is a long-lasting decrease in responding for brain stimulation reward, which is specific to certain electrode placements; this suggests a subsensitivity within part of the brain mechanism of reward rather than, for example, a motor impair-
menf13*‘*.A similar subsensitivity to natural rewards (e.g. a weak sucrose solution) is seen following the chronic application of a variety of very mild stressors; normal responsiveness is restored in this paradigm by 2-5 weeks of hicychc antidepressant treatme@. These effects may model anhedonia, which is the defining symptom of melancholia, and is thought to be an inability to respond to pleasure”*r6. A long-lasting impairment of responding for brain stimulation reward is only found if the animals are tested in the immediate aftermath of stress; otherwise the effect dissipates rapidly”. Moreover, folfowing an initial exposure to severe stress, behavioural deficits may be reinstated by mild stressors that are without effect in normal animals27. These studies suggest that it may be possible to develop conditioning models to explain how the risk of depression is elevated for several months in the aftermath of a stressful life event. This predisposing influence of life events is at present poorly understood’s, The availability of a range of models of different kinds affords the opportunity to examine patterns of depressive symptoms across models and to ask whether different types of model relate to
different aspects of depression. The symptomatology of animals subjected to uncontrollable stress resembles that of a retarded endogenous depression: in both cases, the symptoms include hypoactivity, decreased food intake and weight loss, decreased aggression, and anhedonia. However, certain manipulations, such as destmction of the olfactory bulbs in the ventral forebrain, or social isolation, increase aggression and locomotor activity. Social isolation also causes cooperative social behaviour in rats to deteriorate; this deficit can be reversed by chronic treatment with imipramine or fluoxetinem. While anhedonia is a core symptom in depression, social dysfunction is found in a wide range of psychopathologies as incieed are the sequelae of social deprivation, which this paradigm may model. There is evidence that stressinduced anhedonia and the dis-
ruption of social cooperation by isolated housing involve different neurobiological substrates. Thus, the effect of stress on consumption of a sweet reward is mimicked by dopamine antagonists such as pimozide” but not by the 5-HT antagonist metergoline, whereas the opposite is true of cooperative social behaviour, which is disrupted by metergohne but not by pimozide“‘. This suggests that a dopaminergic dysfunction may mediate the anhedonia that defines melancholia, whereas serotonergic dysfunction may mediate the dele&ious e&&s of social deprivation. These simple deductions give rise to a number of testable clinical hypetheses - for example, social deprivation may be implicated in the range of disorders in which the clinical evidence suggests that serotonergic neumtrattsmfssion may be impaired”. (Such abnormalities have been described not only in depression but a&o inter alia in pathological aggression, alcoholism and bulimia nervosa.) Mechanisms of actjon Animal models of depression are currently making their greatest contribution in investigations of the mechanisms of action of antidepressant drugs. This information should be of considerable value for identifying novel treatment mod&ties that will feed back into the evaluation of antidepressant screening tests. Following chronic administration, antidepmasants cause multiple changes in the functioning of a variety of neuronal systems’2. AnimaI models of depression can be used to establish the functional significance of these effects. Indeed, a prior question is which, if any, of the changes described in normal animals also occur in the brains of depressed patients, bearing in mind the failure of antidepressants to elevate mood significantly in non-depress& individuals. This type of problem can only be addressed using models that maintain abnormal behaviour over the long periods necessary for chronic drug treatment. There are few such models, and those that exfst are not widely used. Consequently, there is very little information about the biochemical consequences of chronic antidepressant administration in
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[Vol. 221
The human condition of depression manifests itself in Particular behavtours. Above: Head of rueeping rwtltlm~, Pablo Picasso; dghtr Sorrov, Vincent van Gogh.
conditions that simulate the conditions under which the drugs are used clinically. The mechanisms by which antidepressants normalixe behaviour appear to de nd upon the behaviouml m otYet used. Metergoline reversed the improvement by imipramine of cooperative social behaviour in singly-housed animals’! However, with the same dose of imipramine (5 mg kg-‘) and a similar period of administration (4-5 weeks), metergoline did not antagonize the effect of imipramine on responsiveness to rewards in animals chronically subjected to mild stress. However, dopamine antagonists did reverse this e&t of imipramine, and also of other tricychcs’6~43. There are indications of this differentiation in earlier studies’s. For example, following one week of treatment, the effect of hicyclic antidepressants in the Porsolt forced swim test may be blocked by catecholamine antagonist@, while their effect in olfactory bulbectomixed animals was reversed by metergoiine”. A preferential role of 54iT in the olfactory bulbectomy model is also indicated
by the observation that inhibitors of IHT-uptake work acutely in this model, while chronic treatment is needed with tricyclics44; conversely, in the forced swim test, tricyclics work subacutdy but inhibitors of 5-HT-uptake are relatively ineffective%. Very little progress has been made in demonstrating clinically that antidepressants with a specific pharmacological profile act selectively in particular patient groups; it has been widely assumed that this lack of clinical selectivity arises from the fact that after chronic treatment, pharmacological specificity is also lost. It now appears that the different pharmacological actions of antidepressants that are present following chronic treatment have different functional consequences. This finding may have far-reaching implications. a psychobiology of depressive disorders Much recent work in biological psychiatry has been concerned with the identification of biological markers associated with depression. While varying consider-
Towards
ably in their selectivity and specificity for depression, the list of such markers is now extensive and includes several abnormalities of neurotransmitter metabolism, several nemoendocrine tests indicative of abnormal receptor function, sleep and other electroabnormalities, encephalogram and a number of peripheral markers, mainly associated with blood plateletss7. Studies of the effects of chronic antidepressant administration have been similarly prolific in identifying numerous changes in pre- and postsynaptic indices of nemotransmitter and receptor function37~42. Far less prominent, however, are attempts to specify either the origin of the biological markers associated with depression, the psychological pmcesses that represent the functional correlates turfthese markers or the biochemical actions of antidepressants3’. Animal models of depression provide an arena within which these questions may be addressed. An illustration is provided by recent work concerning the involvement of dopaminergic systems in the behavioural abnor-
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136 malities seen in certain animal models of depression, and in the action of antidepressants”. This work presents a relatively novel perspective on depressive disorders and highlights the potential of animal models to broaden the scope of clinical debate. In animals subjected to chronic mild stress, abnormalities of dopaminhave ergic neurotransmission been identified in the nucleus accumbens of the mesolimbic system that are very probably responsible for the subsensitivity to reward observed in this model specifically, chronic mild stress causes a decrease in the sensitivity of postsynaptic Dz receptors, secondary to a chronic increase in dopamine release’b*Js-‘7.Chronic administration of antidepressant drugs increases the responsiveness of D2 receptors in the nucleus accumbensr2 and this change mediates the therapeutic effect of tricyclic antidepressants in the chronic mild stress mode116*43. The mesolimbic dopamine system is similarly implicated in scbsensitivity to brain stimulation reward following acute exposure to uncontrollable footshock’s. Dopamine has traditionally received little attention in theoretical or empirical accounts of depression, which have largely focused on noradrenergic and semtonergic systems (for review see Ref. 24). However, recent evidence clearly implicates dopamine in the depressions that “ccur with high prevalence in Parkinson’s disease49and there is some evidence that depression may be successfully treated by drug regimes that enhance the functioning of the mesolimbic dopamine system45fl. This is a particularly promising area for future research. 0
0
cl
Animal models form an interface between psychiatry and basic research in behavioural neuroscience. On the one hand, they are the major channel through which developments at the basic level are brought into clinical perspective; on the other, they provide a particularly informative means of investigating the psychobiological foundations of psychopathology. ft cannot be overemphasized that models must always be judged by the predictions they make; only time will tell whether simulations
24 Overstreet, D. H., Russ& R. W., Cracker, A. D., Giftin, J. C. and Janowsky, D. 5. (19%) Expcricntia 44, 465-472 25 Janowsky, D. S. and Riscb, S. C. (1984) Drug Dm. Res. 4.129-142 26 Bonini, F. and MeE, A. (19BB)Psychopharmrcdogy 94,147-X0 27 A&man, H. A. and Eadmrko, R. M. (1982) Bchoo. Brnin Sci. 5,69-137 26 Kant, G. J. et al. (19B3) Pharmacof. Bfochcm.Behuu. 22,631-634 29 Post, R. M., Wetss, S. 8. and Pert, A. References (1991) in The McaeffmhicDapaminc Sys1 Willner, P. (1984) Psychopharmacology tem: From Moffvatfon to Actfan (Willner, 83.1-16 P. and Scbeel-KruBer, J., eds), pp. z Willncr, P. (1986) bog. Nem-psycho445-474, Wiley phnrmacol.Biol. Psychiatry10,677-690 30 Kokkinidis, L., Eacbarko, R. M. and 3 Willner, P. (1991) in BrhaaiouralModels Predy, P. A. (19BO)Phanaacof.Biochem. in ?sychopharnm-ology: Thconticuf, Behao. 13,379-383 Industrial and Clinical Pcrspcctioes 31 Garber, J. and SeRBman, M. E. P., eds (Wil!ner, P., ed.), pp. 3-18, Cambridge (1980) Hamm HetpfessnesxTheory and University Press Applications,Academic Press 4 Willner, P. (1990) Plrarmricol. Ther. 45, 32 Abramson, L. Y., Se&man, M. E P. and 425-455 Teasdate, J. D. (197B)J. Abnorm.Psycho/. 5 Bodnoff, S. R.. Suranyi-Codotte, B., 67,49-74 Aitken, D. H., Q&ton, R. and Meaney, 33 Abramson, L. Y., Metal&y, G. I. and M. Y. (1988) Psychopharatacofogy 95, Alloy, L B. (19%) Psychol. Rm. %, 2cmn2 -._ __35B-372 6 Fcmtana, D. J., Carbary, T. J. and .34 Minor, T. R., Jackson, R. L. and Mater, Commissarfs, R. L. (1989) PsychoS. F. (19B4)J. Eqt. Psychof.:Anfm. Behao. pharmacology 98.157-162 Pmt. 10, !H3-556 7 Nelson, 1. C. and Cbamev. D. S. (1981) 35 Wefsa, J. M. et al., eds (1982) Behruioral Am 1. tiychiab 138, l-15 Mod& and the Analysis of Drug Action, pp. 195-223, Elaevfn 8 Suomi. S. J. (1976) in Animal Models in Human Psyrhehfology(Serban, C. and 36 Minor, T. R., Pellqmounter, M. A. and Ming, A.. eds), pp. 9-26, Plenum Main, S. F. (l%B) Psycbobi&qy 16, 9 Maier, S. F. and Se&man, M. E. P. 135-145 (1976) /. Exp. Psychol.: General 1,3-46 37 WEMar, P. (198s) Dcpmrior: A Psycho10 Brown, Cf. W. in Connmmitypsychiatry biological Syntws, Wiley (Bennett, D. H. and Freeman, H., eds), R. M., Bowers, W. J., 38 Zachwko, Churchifl-Livingtone (in press) Kokkinidis. L and Antsman, H. (1983) 11 Lewinsohn, P. M. (1974) in The PrvBehar. B&I Rex. 9,129-141 chology of Dcpnssiofl: Coiitcnpora~ 59 Wfllner, P., ToweE, A., Sampson, D., Theory and Rwwch (Friedman, R. J. Muscat, R. and E@tokMoua, S. (1987) and Katz, M. M., eds), pp. 157-185, Psychophannwkgy 93,3!&364 Winston/Wiley 40 WiEner, P. et al. (1%9) Bchau. Phana12 Soubrfe, P. (19%) Bchau. Brain Sci. 9, col. 1, 8590 319-364 41 ToweU, A., Muscat, R. and Witfner, P. 13 Willner, P. (1989) in Bchauioural (1987) Rychophannacafgy 92,262-264 Phar~nacology of 5HT (Bevan, P., Cools, 42 Wiifner, P. (19B9)in Rychaactfuc Drugs: A. R. and Archer, T., eds), pp. 157-175, Tolcrancc and SndlftrNsrr (EmmettEdbaum 14 Fawcett, J., Clark, D. C., Scbeftner, W. A. and Gibbons, R. D. (19B3) Arch. 43 Muscat, R., Sampam, 0. and WElner, P. Gn. Prychiuty 40,79-&l (19%) Bid. psychfafry28,223-229 15 Klein, D. F. (1974) Arch. Gcn. Psuchiatry 44 Broekkamp. C. L, Garr@u, D. and I _ 31,447-454 Uoyd, K. G. (1990) PharmacoL Biochcm. Bchm. 13.643&46 16 Wil!ner, P., Sampson, D., Papp, M., Phillips, C. and Muscat, R. (1991) in 45 Wiflner, P., &meat, R., plpp, M. and Anitnul Models of PsychiatrfcDisorders Sampson, D. (1991) in The Mesofhnbic (Vol. 3) (Soubrie, P., ed.), pp. 71-99, Dopuminc System: Frvn Motfuaffon lo Kargcr Action (Willner, P. and S~hd-KNEW, 17 Allen, M. C. (1976) Arch. Gen. Psychiatry J., eds). pp. J87-410, Wii 33,1476-147E 46 WiUner, P., Gokmbfowaka, K., Kfimek, 18 Weissman, M. S. and Paykef, E. S. (1974) V. and Muscat, R. PsychohfoloBy(in The Depressed Woman: A Study of Social Pm@ Relutioaships,University of Chicago 47 Papp, M., WiUner, P. and Muscat, R. PnXS Psychopbumnwdogy (in press) 19 Kennett, G. A., Chaouloff, F., Marcou, 48 Zachatiro, R. M. and A&man, H. (1991) M. and Curzon, G. (19%) Brain Rn. 382, in The MesoffmhfcDopaminc System: 416-421 From Motfoaffoa to AC&I (Wflbter, P. 20 Dourish. C. T.. Corka. 2.. Williams. and Scbeef-Kruger, J., eds), pp. 411-442, A. R. and lversen, S. D. (lk) J. Psyche: WilPV . .--, rrhrrmacof.3.3BP 49 Mouret. J., LeMoine, P. and Minuit, M. 21 AnesbenseL~C.S. and Stone, J. D. (1982) (19B7) C. R. Acad. Scf. S&c ffl 305, Arch. Ccn. Psyrhiafry39,1X?-13% Ml-3% 22 Shanks, N. and Anisman, H. (19B6) M Def Zompo, M., Bo&atta, A., Bernardi, BehaD. Ncurosci. 102,8%-%5 F.. Burrat, C. and Corsfnl, C. U. (1990) 23 Zacharko, R. M., Lalonde, G. T., Kasian, in Dopaatiuc and Met&l Deprksion M. and Anisman. H. (19B7) Bmitt Res ((+a, C. L. and Serra, C., eds), pp. 426. W-168 177-154, Pergamon
of depression provide clinically relevant information. However, it is important to recognize that research using animal models of psychopathology also makes a direct contribution to the development of behavioural neuroscience, and is therefore of value in its own right, outside the clinical context.
131 References 1 Radomski, M. W., Palmer, R. M. j. and Moncada, 5. (1990) Proc. No!/ Amd. Sri. USA 87,100113-110047 2 Rees, D. D., Cellek. S.. Palmer.R. M. 1. and Moncada, S. (1990) Biochcm.Biuphys. Res. Cornmuu.173, 541-547 3 Knowles, R. G., Salter, M., Brooks, S. L. and Moncada, S. (1990) Biochem.Biophys. :?rs.Commun.172,1042-1048
Animal models as simulations of depression Paul Willner The most familiar usage of animal models of depression is as antidepressant screening tests Paul Willner rcuiews their usage in Qdifferent context - as simulatfons of depression. The behavioural features of aninud models of depressionare comparedwith clinical symptomatology, and the contribution of animal models to understanding the fofiowing aspects of dcprcssion arc reviewed: sources of population variability, natural history, psychological aspects, symptomatologyand mechanisms of antidepressant action. Finally, the role of animal models of depression is considered as a critical interface between basic khaviourul neuroscience and the clinic. Animal models of depression are most hrquently encountered within the pharmaceutical industry, where they are used as screening tests in the development of novel antidepressants. Increasingly, however, animal models are also used as simulations for investigating the psychobiology of depression, and a minority of models have been developed explicitly for this purpose. In this context, the validity of the model is an important consideration (though ltss valid models can also proviae cseful corroborative insights). The procedures tor validating animal models of psychiatric disorders have been discussed in detail elsewhere’-$ they include consideration of predictive validity (which concerns primarily the corresponP. Wifbter is Pro\mr itt the Department of Psychology, City of Lottdon Pdytechuic. Old Caslle Strrel. LuurlouEl 7NT, UK.
dence between drug actions in the model and in the clinic), face validity (phenomenological similarities between the model and the disorder), and construct validity (a sound theoretical rationale). Some desirable features in a simulation of depression are that the mode1 should respond to antidepressant drugs, should employ realistic inducing conditions and should model a core symptom of the disorder. In addition, for many purposes, such as investigating mechanisms of antidepressant action over a clinically relevant time scale, a prolonged timecourse is also desirable. This paper reviews the contribution of animal models as simulations of depression and assesses their potential to provide clinically relevant insights. BehrvlouraI features From its early beginnings in the reserpine reversal, amphetamine
4 Di Rosa, M., Radomski, M. W.. Camuccio, R. and Moncada. S. (199oj Biochem. Eiophys. Res. Comman. 172. 1246-1252 5 Hibbs, J. B., Jr et al. (19%) in Nitric Oxidr /mm L-Argiminr: A Bioregulfftory System (Moncada. S. and Higgs, E. A., eds), PP. lg9-22% Elsevier 6 Moncada, S., Palmer, R. M. J. and Higgs, E. A. (1989) Biochem. Pharmncol. 38, 17G9-1715
potentiation and muricide (mouse killing) tests, the list of animal models of depression has grown to include more than 20 experimental procedures in current use (see Table I; Refs 1 and 4). The common feature of these models is that behavioural abnormalities are reversed by antidepressant drugs. In other respects, animal models of depression vary widely - in the means of inducing abnormal behaviour, in the aspects of behaviour chosen for study and in the time-course of antidepressant action. Furthermore, antidepressant drugs are active in at least some animal models of anxiety, following chronic treatmc#. In the diagnostic system described in Table II (DSM-III-R), depression is defined by the presence of at least one core symptom combined with a number of additional subsidiary symptoms. It is clear that some of the symptoms of depression could be modelled in animals, though others could not. Table I provides an impressionistic summary of the major behavioural features of animal models of depression. (The list of symptoms surveyed is certainly not exhaustive: biological symptoms, such as neuroendocrine changes, are omitted, and in some of the models the behavioural changes are more complex than is implied in the Table.) It is apparent from Table 1 that the behaviour most frequently studied in animal models of depression is a decrease in locomotor activity. Unfortunately, while it is true that psychomotor changes are a central feature of severe depression’, it cannot be simply assumed that retardation and agitation are equivalent to decreases or increases in locomotor activity. Slowness of thinking is at least as important a feature of psychomotor retard-
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a5 a decrease in physical activity, and psychomotor agitation in humans involves such features as hand-wringing and outbursts of complaining, in addition to a restless increase in locomotion. Thus, the degree of resemblance between the changes in locomotor activity observed in animal models of depression and the psychomotor features of human depression is questionable. There is in fact only one model, sociai separation of infant o: juvenile primates, in which locomotor hypoactivity is accompanied by other psychomotor changes - a hunched posture and ‘sad’ facial expression - clearly reminiscent of clinical retardation’. In a further three instances (see Table I), the model could be described as demonstrating a decrease in motivation or persistence, rather than, or in addition to, a decrease in locomotion. This kind of behaviour may have some relevance in relation to the symptom of ‘loss of interest’. In one of these models, learned helplessness, behavioural studies have
ation
been carried out that support this interpretation9. Two further symptoms, characterized in Table I as impulaivity and decreased social contact, do not feature prominently among the diagnostic criteria for depression, perhaps because they have a low specificity for depre&on as compared to a range of other psychiatric disorders. A variety of social factors have been described that powerfully inauence vulnerabiiity to, and recovery from, depression. Two of these, the absence of social supporP and lack of social skills”, could be said to involve a decrease in social contact. However, decreased social contact appears among the DSMIII-R criteria for depression as an aspect of ‘loss of interest’, rather than as a symptom in its own right. Similarly, the concept of impulsivity is used increasingly by basic neuroscientiats to organize the behaviouml literature on the functions of the forebrain 5HT projections’? and may lead to a reassessment of the relationship between depression and other
disorders in which !i-HT is impiicated’); at present, however, as a symptom of deplpssian, impulsivity is at best a minor aspect of ychomotor agitatfon. #z e final symptom shown in Table I, anhedonial* (the decreased ability to experience pieaaur*) is somewhat diffemnt. Anhedonia is one of the core symptoms of depmwion, and defines the endogcaous subtype (mehnwholia). Ax&e&da has beenproposedb&kcta&ctease in the sensitivity of brain reward mechanismP, and as such may realirtically be mode&d in snimals as a decrease in aenaitivity to Rwards. In four of the models surveyed, animals display impairments of rewplykd behaviour, following fzxpoaure to stmaaors of various kinds; in three of the Courcaaes(kanredMti, chronic unpredictabk &Id atteas, and alnphetarnine withdmwal) there is evidence that a &creased sensitivity to reward is msponsible for these impairmenta*6. These mod& are clearly of particular interest.
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133
The psychobiology of depression
TABLE II.DiagnoGotma@dqxe&on @Sk-III-Ft. 1987)
There are several aspects +o the problem of depression. Sources of popnlation uariabifify Recent research has identified a number of factors that cause individuals to vary in their susceptibility to depression. For example, there is strong evidence of a major genetic contribution to bipolar depressions”, and unipolar depressions are up to thret times more revaknt in women than in men3 Although animal models lend themselves readily to experimental investigation of genetic effects and sex differences, there has been surprisingly little attempt to exploit this potential. in one of the very few studies of sex differences, it was reported that female rats were less likely than males to adapt to repeated immobilization stress; some of their behavioural abnormalities were reversed by chronic desipramine, but not by acute desipramine or by anxiolyticst9. Subsequently, the same research group reported that the effect of stress was greater in singly housed than in group-housed animaksa, and suggested that this may model the protective effect of social support=. An&ma and colleagues have made the important observation that uncontrollable ekctrtc shock has variabk behavioural effects (most of which cannot be reversed by antidepressants) in different inbred mouse strains. An extreme example was seen in the CS7W6J mouse strain, in which uncontrollable shock severely impaired subsequent learning to escape shock, but had no effect on responding for brain stimulation reward, whereas the DBAIZJ mouse strain showed exactly the opposite pattern of deficits”? These studies may provide a starting point for investigation of the physiological mechanisms underlying individual differences in responses to stress. A number of other selective breeding programmes have produced strains of rodent that bear some behavioural and physiological reaembknces to depressed humans (for review see Ref. 24) (though as noted above, the behavioural simikritks tend to be superficial). Depressed patients are known to be hypersensitive to drugs that stimulate central acetyl-
Raquinr-everyNWevery)dw duelgthasametwowwkfmrtodof ofmoresymptomafKf four subsidiarysymploms(of thee with both me symptoms) -rylnptoms Depccwsed~
. . pqaomotorretardabjon’oragitaticn Fatigue, or loss of energy’ Far#ngsofworthlassnaaa, or excesstw orblappn@ateguitl Demasadsbilitytothkrka-’
Raanvntthoughtsofdaathorsuicida,ofaspedfn:sui~oianorattempt ‘CouldInprtnclplebemcbdekdlnsnimals
choline receptors, and some physiological abnormalities characteristic of depression are consistent with cholinergic hyperfunctior?. The Plinders Sensitive Line (PSL) of rats, which were bred for their sensitivity to a cholinergic agonist, show abnormalities, relative to outbred strains, in a number of behavioural tests. These include an animal model of depression, the Porsolt forced swim te&‘, which is of relatively low validity as a simulation of depresston’ but is used routinely in antidepressant screenir@. A preliminary communication reported that an avoidance learning deficit in these animals could be reversed by imipramine”. Studies using the FSL strain have not used the optimal behavioural models; nevertheless, they are of considerable interest, in that they represent an attempt to use an animal model of depression to test a clinical hypothesis. of depssion ‘IIrenafnrnl history Depression has a number of temporal features, including spontaneous recovery, the periodicity of recurrent unipokr depression, and the alternation of depressive and manic phases of bipolar disorder. This is another area which could usefully be investigated in animal models, but remains at present relatively under-researched. Spontaneous recovery has received some attention in animal models in studies of adaptation to repeated stress, but the clinical rekvance of this phenomenon is uncertainrr*m.28. So far, there have been no attempts to model bipolar disorder. The ad-
ministration of psychomotor stimuknt drugs (amphetamine and cocaine) is used extensive1 as an animal model of mania J , and them is an animal model of depression based on withdrawal from chronic amphetamines“. Clearly, there is a basis here for developing a model of bipolar disorder, but this will be a formidable undertaking. lJsych01ogicar aspects Perhaps surprisingly, research in animal models relating to the psychological features of depression has been relatively productive. Much of this work arises from models based on the application of stress, which form the largest group in the list of models summarized in Table I. The behavtoural sequelae of stress can usually be revemed by antidepressants. This is PIearly relevant to the ettologtrtr~ role of stress in and immediately depression focuses attentibn on the meaning of the term ‘stress’. Most research derives from the original stress model of depression, kamed helpksmess The learned helplessness hypothesis proposed that exposure to uncontrolkbk stress provides the basis, in animals as well as in people, for learning that stress is uncontrollable (helplessness); this learning has a number of debilitating consequences, induding depn&on9. The demonstration of performance impairmenta in animals subjjted to uncontrolkble stressors, and their absence in animals subjected to the same stressom but able to control them, led to extensive research on the import-
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131 ante of controllability over stress in human$‘. However, the hypothesized clinical role of a perception of helplessness in the etiology oi depression has passed through a number of incamations”*u, and now takes a form so complex that it is doubtful whether animal studies can make any direct contribution. Thus, while the learned helplessness paradigm has had an important influence on clinical thinking, this is now largely of historical importance. Within the animal literature, the status of the concept of helplessness has also changed. The hypothesis that animals can learn that their responses are without effect on their environment has been hotly debated, and a number of alternative, and simpler f’nonhave cognitive’) explanations been proposed for the disruptive effect of uncontrollable stress on later performance’. It is now clear that under some circumstances, stress can impair learning ability, but this appears to be secondary to an impairment of attention stressed animals are more easily distracted%. This effect is probably mediated by a functional incapacitation of noradrener ic transmission in the forebrai$‘. This evidence suggests that, influential as the learned helplessness hypothe,;s has been on clinical thinking, it is probably incorrect as an interpretation of the effects of uncontrollable stress in animals. Nevertheless, this research is important in suggesting some functional correlates of the disorders of noradrenergic transmission in depressed patients, which have frequently been observed but have proved extremely difficult to interprets7. The learned helplessness model has provided another, extremely important pmpective on depressive thinking. An attractive feature of this paradigm is the breadth of symptomatic paraliels to severe depression2”5. Among these behavioural abnormalities is a poor performance of rewarded behaviour. One manifestation of this effect is a long-lasting decrease in responding for brain stimulation reward, which is specific to certain electrode placements; this suggests a subsensitivity within part of the brain mechanism of reward rather than, for example, a motor impair-
menf13*‘*.A similar subsensitivity to natural rewards (e.g. a weak sucrose solution) is seen following the chronic application of a variety of very mild stressors; normal responsiveness is restored in this paradigm by 2-5 weeks of hicychc antidepressant treatme@. These effects may model anhedonia, which is the defining symptom of melancholia, and is thought to be an inability to respond to pleasure”*r6. A long-lasting impairment of responding for brain stimulation reward is only found if the animals are tested in the immediate aftermath of stress; otherwise the effect dissipates rapidly”. Moreover, folfowing an initial exposure to severe stress, behavioural deficits may be reinstated by mild stressors that are without effect in normal animals27. These studies suggest that it may be possible to develop conditioning models to explain how the risk of depression is elevated for several months in the aftermath of a stressful life event. This predisposing influence of life events is at present poorly understood’s, The availability of a range of models of different kinds affords the opportunity to examine patterns of depressive symptoms across models and to ask whether different types of model relate to
different aspects of depression. The symptomatology of animals subjected to uncontrollable stress resembles that of a retarded endogenous depression: in both cases, the symptoms include hypoactivity, decreased food intake and weight loss, decreased aggression, and anhedonia. However, certain manipulations, such as destmction of the olfactory bulbs in the ventral forebrain, or social isolation, increase aggression and locomotor activity. Social isolation also causes cooperative social behaviour in rats to deteriorate; this deficit can be reversed by chronic treatment with imipramine or fluoxetinem. While anhedonia is a core symptom in depression, social dysfunction is found in a wide range of psychopathologies as incieed are the sequelae of social deprivation, which this paradigm may model. There is evidence that stressinduced anhedonia and the dis-
ruption of social cooperation by isolated housing involve different neurobiological substrates. Thus, the effect of stress on consumption of a sweet reward is mimicked by dopamine antagonists such as pimozide” but not by the 5-HT antagonist metergoline, whereas the opposite is true of cooperative social behaviour, which is disrupted by metergohne but not by pimozide“‘. This suggests that a dopaminergic dysfunction may mediate the anhedonia that defines melancholia, whereas serotonergic dysfunction may mediate the dele&ious e&&s of social deprivation. These simple deductions give rise to a number of testable clinical hypetheses - for example, social deprivation may be implicated in the range of disorders in which the clinical evidence suggests that serotonergic neumtrattsmfssion may be impaired”. (Such abnormalities have been described not only in depression but a&o inter alia in pathological aggression, alcoholism and bulimia nervosa.) Mechanisms of actjon Animal models of depression are currently making their greatest contribution in investigations of the mechanisms of action of antidepressant drugs. This information should be of considerable value for identifying novel treatment mod&ties that will feed back into the evaluation of antidepressant screening tests. Following chronic administration, antidepmasants cause multiple changes in the functioning of a variety of neuronal systems’2. AnimaI models of depression can be used to establish the functional significance of these effects. Indeed, a prior question is which, if any, of the changes described in normal animals also occur in the brains of depressed patients, bearing in mind the failure of antidepressants to elevate mood significantly in non-depress& individuals. This type of problem can only be addressed using models that maintain abnormal behaviour over the long periods necessary for chronic drug treatment. There are few such models, and those that exfst are not widely used. Consequently, there is very little information about the biochemical consequences of chronic antidepressant administration in
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The human condition of depression manifests itself in Particular behavtours. Above: Head of rueeping rwtltlm~, Pablo Picasso; dghtr Sorrov, Vincent van Gogh.
conditions that simulate the conditions under which the drugs are used clinically. The mechanisms by which antidepressants normalixe behaviour appear to de nd upon the behaviouml m otYet used. Metergoline reversed the improvement by imipramine of cooperative social behaviour in singly-housed animals’! However, with the same dose of imipramine (5 mg kg-‘) and a similar period of administration (4-5 weeks), metergoline did not antagonize the effect of imipramine on responsiveness to rewards in animals chronically subjected to mild stress. However, dopamine antagonists did reverse this e&t of imipramine, and also of other tricychcs’6~43. There are indications of this differentiation in earlier studies’s. For example, following one week of treatment, the effect of hicyclic antidepressants in the Porsolt forced swim test may be blocked by catecholamine antagonist@, while their effect in olfactory bulbectomixed animals was reversed by metergoiine”. A preferential role of 54iT in the olfactory bulbectomy model is also indicated
by the observation that inhibitors of IHT-uptake work acutely in this model, while chronic treatment is needed with tricyclics44; conversely, in the forced swim test, tricyclics work subacutdy but inhibitors of 5-HT-uptake are relatively ineffective%. Very little progress has been made in demonstrating clinically that antidepressants with a specific pharmacological profile act selectively in particular patient groups; it has been widely assumed that this lack of clinical selectivity arises from the fact that after chronic treatment, pharmacological specificity is also lost. It now appears that the different pharmacological actions of antidepressants that are present following chronic treatment have different functional consequences. This finding may have far-reaching implications. a psychobiology of depressive disorders Much recent work in biological psychiatry has been concerned with the identification of biological markers associated with depression. While varying consider-
Towards
ably in their selectivity and specificity for depression, the list of such markers is now extensive and includes several abnormalities of neurotransmitter metabolism, several nemoendocrine tests indicative of abnormal receptor function, sleep and other electroabnormalities, encephalogram and a number of peripheral markers, mainly associated with blood plateletss7. Studies of the effects of chronic antidepressant administration have been similarly prolific in identifying numerous changes in pre- and postsynaptic indices of nemotransmitter and receptor function37~42. Far less prominent, however, are attempts to specify either the origin of the biological markers associated with depression, the psychological pmcesses that represent the functional correlates turfthese markers or the biochemical actions of antidepressants3’. Animal models of depression provide an arena within which these questions may be addressed. An illustration is provided by recent work concerning the involvement of dopaminergic systems in the behavioural abnor-
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136 malities seen in certain animal models of depression, and in the action of antidepressants”. This work presents a relatively novel perspective on depressive disorders and highlights the potential of animal models to broaden the scope of clinical debate. In animals subjected to chronic mild stress, abnormalities of dopaminhave ergic neurotransmission been identified in the nucleus accumbens of the mesolimbic system that are very probably responsible for the subsensitivity to reward observed in this model specifically, chronic mild stress causes a decrease in the sensitivity of postsynaptic Dz receptors, secondary to a chronic increase in dopamine release’b*Js-‘7.Chronic administration of antidepressant drugs increases the responsiveness of D2 receptors in the nucleus accumbensr2 and this change mediates the therapeutic effect of tricyclic antidepressants in the chronic mild stress mode116*43. The mesolimbic dopamine system is similarly implicated in scbsensitivity to brain stimulation reward following acute exposure to uncontrollable footshock’s. Dopamine has traditionally received little attention in theoretical or empirical accounts of depression, which have largely focused on noradrenergic and semtonergic systems (for review see Ref. 24). However, recent evidence clearly implicates dopamine in the depressions that “ccur with high prevalence in Parkinson’s disease49and there is some evidence that depression may be successfully treated by drug regimes that enhance the functioning of the mesolimbic dopamine system45fl. This is a particularly promising area for future research. 0
0
cl
Animal models form an interface between psychiatry and basic research in behavioural neuroscience. On the one hand, they are the major channel through which developments at the basic level are brought into clinical perspective; on the other, they provide a particularly informative means of investigating the psychobiological foundations of psychopathology. ft cannot be overemphasized that models must always be judged by the predictions they make; only time will tell whether simulations
24 Overstreet, D. H., Russ& R. W., Cracker, A. D., Giftin, J. C. and Janowsky, D. 5. (19%) Expcricntia 44, 465-472 25 Janowsky, D. S. and Riscb, S. C. (1984) Drug Dm. Res. 4.129-142 26 Bonini, F. and MeE, A. (19BB)Psychopharmrcdogy 94,147-X0 27 A&man, H. A. and Eadmrko, R. M. (1982) Bchoo. Brnin Sci. 5,69-137 26 Kant, G. J. et al. (19B3) Pharmacof. Bfochcm.Behuu. 22,631-634 29 Post, R. M., Wetss, S. 8. and Pert, A. References (1991) in The McaeffmhicDapaminc Sys1 Willner, P. (1984) Psychopharmacology tem: From Moffvatfon to Actfan (Willner, 83.1-16 P. and Scbeel-KruBer, J., eds), pp. z Willncr, P. (1986) bog. Nem-psycho445-474, Wiley phnrmacol.Biol. Psychiatry10,677-690 30 Kokkinidis, L., Eacbarko, R. M. and 3 Willner, P. (1991) in BrhaaiouralModels Predy, P. A. (19BO)Phanaacof.Biochem. in ?sychopharnm-ology: Thconticuf, Behao. 13,379-383 Industrial and Clinical Pcrspcctioes 31 Garber, J. and SeRBman, M. E. P., eds (Wil!ner, P., ed.), pp. 3-18, Cambridge (1980) Hamm HetpfessnesxTheory and University Press Applications,Academic Press 4 Willner, P. (1990) Plrarmricol. Ther. 45, 32 Abramson, L. Y., Se&man, M. E P. and 425-455 Teasdate, J. D. (197B)J. Abnorm.Psycho/. 5 Bodnoff, S. R.. Suranyi-Codotte, B., 67,49-74 Aitken, D. H., Q&ton, R. and Meaney, 33 Abramson, L. Y., Metal&y, G. I. and M. Y. (1988) Psychopharatacofogy 95, Alloy, L B. (19%) Psychol. Rm. %, 2cmn2 -._ __35B-372 6 Fcmtana, D. J., Carbary, T. J. and .34 Minor, T. R., Jackson, R. L. and Mater, Commissarfs, R. L. (1989) PsychoS. F. (19B4)J. Eqt. Psychof.:Anfm. Behao. pharmacology 98.157-162 Pmt. 10, !H3-556 7 Nelson, 1. C. and Cbamev. D. S. (1981) 35 Wefsa, J. M. et al., eds (1982) Behruioral Am 1. tiychiab 138, l-15 Mod& and the Analysis of Drug Action, pp. 195-223, Elaevfn 8 Suomi. S. J. (1976) in Animal Models in Human Psyrhehfology(Serban, C. and 36 Minor, T. R., Pellqmounter, M. A. and Ming, A.. eds), pp. 9-26, Plenum Main, S. F. (l%B) Psycbobi&qy 16, 9 Maier, S. F. and Se&man, M. E. P. 135-145 (1976) /. Exp. Psychol.: General 1,3-46 37 WEMar, P. (198s) Dcpmrior: A Psycho10 Brown, Cf. W. in Connmmitypsychiatry biological Syntws, Wiley (Bennett, D. H. and Freeman, H., eds), R. M., Bowers, W. J., 38 Zachwko, Churchifl-Livingtone (in press) Kokkinidis. L and Antsman, H. (1983) 11 Lewinsohn, P. M. (1974) in The PrvBehar. B&I Rex. 9,129-141 chology of Dcpnssiofl: Coiitcnpora~ 59 Wfllner, P., ToweE, A., Sampson, D., Theory and Rwwch (Friedman, R. J. Muscat, R. and E@tokMoua, S. (1987) and Katz, M. M., eds), pp. 157-185, Psychophannwkgy 93,3!&364 Winston/Wiley 40 WiEner, P. et al. (1%9) Bchau. Phana12 Soubrfe, P. (19%) Bchau. Brain Sci. 9, col. 1, 8590 319-364 41 ToweU, A., Muscat, R. and Witfner, P. 13 Willner, P. (1989) in Bchauioural (1987) Rychophannacafgy 92,262-264 Phar~nacology of 5HT (Bevan, P., Cools, 42 Wiifner, P. (19B9)in Rychaactfuc Drugs: A. R. and Archer, T., eds), pp. 157-175, Tolcrancc and SndlftrNsrr (EmmettEdbaum 14 Fawcett, J., Clark, D. C., Scbeftner, W. A. and Gibbons, R. D. (19B3) Arch. 43 Muscat, R., Sampam, 0. and WElner, P. Gn. Prychiuty 40,79-&l (19%) Bid. psychfafry28,223-229 15 Klein, D. F. (1974) Arch. Gcn. Psuchiatry 44 Broekkamp. C. L, Garr@u, D. and I _ 31,447-454 Uoyd, K. G. (1990) PharmacoL Biochcm. Bchm. 13.643&46 16 Wil!ner, P., Sampson, D., Papp, M., Phillips, C. and Muscat, R. (1991) in 45 Wiflner, P., &meat, R., plpp, M. and Anitnul Models of PsychiatrfcDisorders Sampson, D. (1991) in The Mesofhnbic (Vol. 3) (Soubrie, P., ed.), pp. 71-99, Dopuminc System: Frvn Motfuaffon lo Kargcr Action (Willner, P. and S~hd-KNEW, 17 Allen, M. C. (1976) Arch. Gen. Psychiatry J., eds). pp. J87-410, Wii 33,1476-147E 46 WiUner, P., Gokmbfowaka, K., Kfimek, 18 Weissman, M. S. and Paykef, E. S. (1974) V. and Muscat, R. PsychohfoloBy(in The Depressed Woman: A Study of Social Pm@ Relutioaships,University of Chicago 47 Papp, M., WiUner, P. and Muscat, R. PnXS Psychopbumnwdogy (in press) 19 Kennett, G. A., Chaouloff, F., Marcou, 48 Zachatiro, R. M. and A&man, H. (1991) M. and Curzon, G. (19%) Brain Rn. 382, in The MesoffmhfcDopaminc System: 416-421 From Motfoaffoa to AC&I (Wflbter, P. 20 Dourish. C. T.. Corka. 2.. Williams. and Scbeef-Kruger, J., eds), pp. 411-442, A. R. and lversen, S. D. (lk) J. Psyche: WilPV . .--, rrhrrmacof.3.3BP 49 Mouret. J., LeMoine, P. and Minuit, M. 21 AnesbenseL~C.S. and Stone, J. D. (1982) (19B7) C. R. Acad. Scf. S&c ffl 305, Arch. Ccn. Psyrhiafry39,1X?-13% Ml-3% 22 Shanks, N. and Anisman, H. (19B6) M Def Zompo, M., Bo&atta, A., Bernardi, BehaD. Ncurosci. 102,8%-%5 F.. Burrat, C. and Corsfnl, C. U. (1990) 23 Zacharko, R. M., Lalonde, G. T., Kasian, in Dopaatiuc and Met&l Deprksion M. and Anisman. H. (19B7) Bmitt Res ((+a, C. L. and Serra, C., eds), pp. 426. W-168 177-154, Pergamon
of depression provide clinically relevant information. However, it is important to recognize that research using animal models of psychopathology also makes a direct contribution to the development of behavioural neuroscience, and is therefore of value in its own right, outside the clinical context.
