Ethopharmacology: A historical perspective

Neurosclence& BwbehavtoralReviews.Vol 15, pp 439-.-445 o Pergamon Press plc. 1991 Pnnted m the U S A

0149-7634/91 $3 00 + 00

Ethopharmacology: A Historical Perspective MILO~ KR~IAK

Institute of Pharmacology, Czechoslovak Academy of Sciences, Albertov 4, 128 O0 Prague 2, Czechoslovakia

KR~IAK, M. Ethopharmacology. A htstorical perspecnve NEUROSCI BIOBEHAV REV 15(4) 439--445, 1991 --Ethopharmacology can be defined as the study of behavmral and other effects of drugs through the use of ethological concepts. The study of drug effects on natural acaon patterns (motor acts and postures hsted m ethograms), with respect to natural settangs and to behavior as a whole (all identifiable behaviors occumng dunng the measurement) represents the basic concepts of ethopharmacology. Although pioneers drew attention to the potential of the ethological approach in pharmacology in the early 1960s, the number of publications utihzing this approach has steadily grown only since the rmd-1970s In the 1980s, modern technology, such as wdeorecorders, rmcrocomputers and software, has been more widely applied in ethopharmacologlcal expenments, greatly facflaatmg the observation and quanutatave analysis of multiple data. Ethopharmacology is not "another" behavioral pharmacology, but an integral part of it Rather, a represents one of the tools which can be useful (and sometimes even indispensable) in achieving a better understanding of the behavioral effects of drugs It is to be hoped that it will be used m concert with other approaches m the future. History of ethopharmacology Concepts of ethopharmacology Aggressive behavmr Defenswe behavior

ETHOPHARMACOLOGY may be defined as the study of behavioral and other effects of drugs through the application of ethological concepts. The aim of the present paper is to review the origins, development and some perspectives of ethopharmacology.

Ammal models for screening psycholxoptc drugs

and postures, elaborated by Grant and Mackintosh (29) for small laboratory rodents, in the study of behavioral effects of drugs. Grant and Maclontosh's publication has become a "classic," since almost all lists of elements used in subsequent ethopharmacology experiments on common laboratory rodents have been based on this paper. The use of ethological concepts and methods in the laboratory study of behavioral effects of drugs on animal behavior was also advocated in the early 1960s by Ltit in Prague. Ltit emphasized the need for detailed and continual recording of all natural behavxoral patterns occurring dunng the experiment (52), as well as an approach which integrated ethology, behaviorism and higher nervous acuvlty (51). The configuralaon of the equipment he used for recording behavior (a keyboard coupled with an event recorder plus a film camera), and which he demonstrated as early as in 1963 in his lecture at the Second Internataonal Pharmacology Meeting in Prague (52), is in principle stall used in most contemporary ethopharmacology laboratories. The author of the present chapter owes a great deal to Josef L~it as well as to representatives of the Birmingham group, particularly Paul Silverman, for insptratlon and help in the study of drug effects on natural behavioral patterns and in appreciating important concepts of the ethological approach. The author was also fortunate to have been encouraged in his work by Hannah Steinberg and her co-workers during his stay at the Department of Pharmacology, University College in London in the late 1960s (43,44). These favourable circumstances greatly facilitated ethopharmacological investagation in our laboratory at the Institute of Pharmacology, Czechoslovak Academy of Sciences in Prague, which started in the 1960s (40) and has continued under modest conditions till now. The Birmingham group also had significant impact in other countries. The pioneering work of Sllverman respired Van der Poel (personal communication) in The Netherlands, who em-

APPLICATIONOF ETHOLOGICALCONCEPTSIN THE STUDYOF BEHAVIORALEFFECTSOF DRUGS

Natural Action Patterns Ethology is typically concerned with natural action patterns (motor acts and postures such as walking, attacks, escapes, sexual mounts). These natural action patterns, which are the behavioral elements of ethology, are listed in "catalogues" called

ethograms. The major credit for drawing attention to the utility of natural action patterns in the study of behavioral effects of drugs must be given to Michael Chance and his co-workers (Grant, Mackmtosh and Silverman) from the Ethology Laboratory, Uffculme Clinic in Birmingham. Chance advocated an ethological approach to the study of drug effects on behavior in his lecture given at the important Ciba Symposium in 1963 in London (16). This symposium, and particularly its proceedings edited by Steinberg (99), which incorporated various conceptual approaches to the study of behaworal effects of drugs, has become a landmark in the development of behavioral pharmacology (the term behavioral pharmacology is used here in its broader sense, connotative of the study of behavioral effects of drugs by various approaches). Soon afterwards, Sdverman (94-96) showed in a series of carefully done experiments that the study of drug effects on a great number of acts and postures occurring in rats during social encounters is not only feasible but also qmte instructive. Silverman was also the first to use a list of motor acts

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ployed the Grant and Mackintosh ethogram (29) m testing behavioral effects of antichohnergics, and who was among the first to use videotape recording for this kind of work (105). Subsequently, this method was introduced in the USA by Mlczek (59) and in the USSR by Poshlvalov (87). Miczek and Poshlvalov v~gorously and successfully developed ethopharmacology in their countries (Poshivalov, regrettably, only until his premature death m 1988). In Britain, the tradition of the Birmingham group has been maintained and further developed by Cutler (18). The testing of drugs on distinct natural behawor patterns, mstead of on some vaguely defined and poorly vahdated behaviors, represented a change of a great consequence for behavioral pharmacology. It might be compared with the shift from alchemy to the chemistry of elements. However, the identification of natural action patterns is based on observation, and there is still no consensus on some behavioral elements. Fortunately, modern technology, such as videorecorders, rmcroprocessors and methods of quantitative ethology, offer new tools and procedures whmh should assist in solving some of these problems [see below and a paper by Don& (26) in this issue]. The identification of natural behavioral patterns is a scientific topic of its own. However, it may not be sufficient to identify an element, but also to ascertain its position in the structure of behavior (24) as well as its kinematic aspects (2), i e , to learn about the element with respect to the higher and lower levels of its organization. Although the ongmal Grant and Mackintosh list of elements for small laboratory rodents (29) was later revised for mice (56), it is now generally felt that a revised "atlas" of natural behavioral acts and postures, particularly those occurring in mice and rats, is very much needed. It is to be hoped that descriptive studms of this kind will be elaborated and pubhshed m the nottoo-distant future, and that they will be as generally accepted as those pubhshed by Grant and Mackintosh in 1963 (29). Natural Sttuations

Although respect for natural settings m laboratory studies on the behavioral effects of drugs was appreciated somewhat later than that for observauons of natural action patterns, this concept has proved to be equally useful. For example, a comparison of some behavioral paradigms popular m testing antmggresslve activity of drugs in the 1960s (such as "footshock-mduced fighting") with the agomstlc behavior exhibited by rats in a seminatural colony situation has shown that the footshock-lnduced fighting reflects defensive rather than aggressive behavior (5) Aggressive behavior occumng in another popular test, the "isolationinduced fighting" paradigm, was initially interpreted as a behavioral disorder reduced by individual housing [the 'hsolatlon syndrome," (104)]. However, from an ethological viewpoint, such behavior would not appear to be abnormal, at least so far as the mouse is concerned, as territorial ammals, male mice tend to be "behaviorally isolated" m that they do not tolerate mature conspec~fics on their territory (11). Thus the natural aggressive reaction of the mature male mouse to a strange male conspeclfic, which is mostly suppressed by " n o r m a l " (but artificial) group-housing of a large number of male mice, may actually be recovered by mdwldual housing These elegant studms were only prodromes to much greater prosperity of this concept in the 1980s, which can be exemplified by investigations of "defeat" analgesm by Rodgers, Miczek and their co-workers. Although it had been known since 1976 that footshocks and some other stimuli could elicit analgesm in laboratory rats (91), a presumed role of natural sumuh m "stress-analgesm" was virtually unknown at the beginning of the 1980s. However, ingenuous and extensive experimental investigation of nociceptlon after exposure of mice to mtraspecific

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conflict (and to some other natural threatening stimuli) revealed the existence of two forms of analgesic reaction. One is induced by extended exposure to attack and is mediated by oploid mechanisms (64,65) The other is nonoplold, can be induced by a mere exposure to the scent of an aggressive male conspecxfic and appears to be related to anxiety/fear (90). This problem, investigated also by other research groups, is reviewed in more detail elsewhere in this issue (92). Respect for natural situations is also crucial in the search for laboratory settings which will evoke required behavioral elements reliably enough and at an appropriate baseline for testing drug effects. This can be well demonstrated by the recent development of novel para&gms of defensive behavior in several laboratories. For instance, Blanchard and Blanchard (7) have elaborated a model of ant~predator defensive behavior in laboratory rats (elicited by confrontations with cats) for testing potentially anx~olytlc drugs. Th~s model is based upon an extensive investigation of the wide range of defensive and other behaviors of wild rats m a visible burrow system Another recent example of employing natural stimuli in evoking antipredator defensive behavior is the work of Hendne (32) on murine reactions to the calls of owls Finally, it should be emphasized that bnngmg natural behavxors m the laboratory (6,7) is a far more difficult task than acquiring skills in recognizing &stmctwe behavioral acts and postures Behavior as a Whole

Although the study of the entire behavioral repertoire within a given test represents one of the cornerstones of the ethopharmacological approach (25), a fact stressed by its pioneers (15,52), this concept has been largely overlooked to date. Nevertheless, It is important for several reasons. Firstly, as Dixon has repeatedly emphasized (21, 24, 25), no one component of behavior can be understood without reference to the dynamic structure of behavior as a whole Some behavioral elements, occumng m different behavioral contexts, may have different "meanings " For instance, some components of self-grooming can be understood as &splacement activity (presumably reflecting tension) m the context of opposing act~vlties, or as a "comfort" behavior during relatively quiet intervals. The analysis of the linkage between natural elements of behavior, for instance by dendrograms or Markov models, is dealt with in more detail elsewhere [e.g., (13,30)]. However, if drug effects are ascertained on elements of the ethogram only, wxthout reference to the behavioral context in which they occur, then the information obtained may be insufficient and even misleading; rather like attempts to understand a language only with respect to word frequency. This point has recently been &scussed in full (24). Secondly, evaluation of all identifiable behavioral elements occurring dunng the test increases the chance of detecting unexpected drug effects. This is particularly important in screening for potentially useful or dangerous effects of drugs or chem:cals. Moreover, a broad repertoire of behavioral elements gives a sound basis for behavioral &fferentiations between a large number of psychotropic drugs. This possibility had been discussed in the early 1970s (39) and was later extensively validated (37, 38, 45, 46, 76). Multiple measures can also be advantageous in the assessment of behavioral differences between drugs with respect to variations in their effects on receptor subtypes, etc. Thirdly, information on changes in concomitant behaviors may be valuable for assessing the selectivity of drug effects on the behavior in question. For example, comparison of the changes in defensive upright posture with other activities involving upright movement but occurnng m another behavioral context

ETHOPHARMACOLOGY. A HISTORICAL PERSPECTIVE

( e . g , exploratory rearing) in the same animal and setting, seems to provide a more relevant (as well as more economic) measure of behavioral selectivity of drug action (37). This procedure, originally used by Silverman in 1965 (94), has been adopted in a number of later studies [for review (61)]. Shortening of the time spent in a particular activity must be accompanied by prolongat~on of time spent in other act~vmes, and th~s can be revealed through "time-budget" analysis, a useful procedure introduced m the 1980s (106). When testing drug effects on behavior during social encounters, it is advisable to obtmn sufficient data on the behavior of the untreated partner of the drugged test animal. This is because the behavior of the test ammal can be indirectly influenced by behavioral (or other) changes induced m partners as a consequence of the drugged state of the test animal. The problem of indirect effects of drugs on behavior dunng social encounters has been repeatedly discussed, mostly as a potential source of "artifact" [e.g., (14, 24, 36, 39, 61)]. However, such indirect changes might lead to new information about social behavior as well as drug action (43). For instance, diazepam has been found to enhance the aggression-releasing action of male mouse urine which, in turn, rendered the drugged mice more susceptible to attack (22). The study of drug effects on behavior as a whole is obviously laborious. Moreover, the resultant extensive database gives rise to problems of data presentation. Instead of presenting all data obtained (including nonsignificant results) m complex tables, it seems more appropriate to present only the most sigmficant aspects of the data; much the same as do anatomists, who do not show all the preparations they have inspected, but only those that best illustrate their findings. MEASUREMENT AND ANALYSIS OF BEHAVIOR IN ETHOPHARMACOLOGY

The technological development of equipment used for the measurement and analysis of drug effects on behavior by ethopharmacologists has been enormous: from a pencil and a sheet of paper, through "home-made" keyboards connected to counters (in the 1960s), to contemporary rmcrocomputers and videorecorders. Indeed, recent advances in the latter represent a real blessing for the further development of ethopharmacology, which is so heavily dependent on detailed recording by observation and quantitative analysis of multiple data, and fulfills wishes anxiously expressed in the early 1970s (39). Currently, hardware-software systems specially adapted for ethopharmacologlcal studies are commercially available, such as the "PC-Protocol" for most exacting studies (48) or "'The Observer" for more routine work (74) A more complete review of equipment of this kind ts presented elsewhere in this issue (26). Nevertheless, the "classical" tool represented by a pencil and a sheet of paper can still be useful. For instance, for those who would like to try the ethological approach in pilot experiments before investing m sophisticated equipment, and in the training of students in observational skills. The species-specific behavioral patterns, which are m the focus of ethological interest, are very complex not only in terms of space, 0.e., in their topography), but also in terms of time, (Le., m their duration, intervals and sequences). Whereas a human observer is mostly well able to recogmze elements hsted in the ethogram, he is much less able to capture their temporal structure. To gain the latter information, various quantitative ethological methods are being developed. Thus distribution of the durations of behavioral elements or intervals between them can be assessed and simply summarized by frequency histogram or log-survivor plot. For example, amphetamine (but not dmz-

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epam or alcohol) has been found to alter the intervals separating consecutwe attacks (60). Addiuonal information can be extracted from analysis of behavioral sequences, for instance by Markov chain statistics (30) or dendrograms (13). A number of ethopharmacological groups have been working on this topic [e.g., (13, 27, 47, 70, 75, 88)], but it would be beyond the scope of the present review to go into detail on this topic. Thus while the "classical" ethological analysis of behavior was mostly quahtative, based (for instance) on analysis of topographical relations between components of a particular pattern (102), contemporary ethological analysis is largely quantitative. Quantitative tools to analyze the temporal pattern of behavior fulfill some basic requirements of pharmacological research' they are sensitive to low doses of some but not all drugs; they yield reliable information from relatively small groups of subjects being examined for a hmlted period of time. These methods appear useful not only in clearly differentmtlng drug effects on behavior, but also in identifying patterning mechanisms as potential primary targets of drug action (60). NONPHARMACOLOGICAL SCOPE OF ETHOPHARMACOLOGY

Ethopharmacology, as follows from its name, is an interdisciphnary field. Its scope is therefore not hmited to drugs, but is open also to other closely related topics. In fact, the term "'ethopharmacology" has gained popularity only since 1982 when it was first used in a printed form (21); earher, the term "pharmacoethology" was equally popular [e.g., (109)]. Thus ethopharmacology and pharmacoethology represent two sides of the same coin. Obviously, ethopharmacologlsts must first select and "prepare" a particular behavior for their study. In the 1960s and 1970s, the major research focus was on exploratory behavior [e.g., (40, 42, 44, 52)] and aggressive behavior (5, 10, 38, 41, 43, 59, 87) while, in the 1980s, defensive behaviors and distress calls have become popular areas for investigation. Older models of aggressive behavior (such as the isolation-induced aggression or footshock-induced fighting paradigms) were reappraised, and new paradigms convenient for testing drug effects developed. An excellent example of such development is the "maternal aggression" paradigm [aggressive behavior exhibited by lactating mice (77, 81, 101)]. Another example (infanticide in nuce) is included in this issue (82). Surprisingly, sexual behavior has remained outside the main stream of ethopharmacology/pharmacoethology even though ethograms of the sexual behavior, e.g., of the rat (58), and much other necessary information has been available for quite some time. However, some papers (69,108) included in this volume are devoted to this topic. Although one of the first ethologlcally based models of defensive-escape behavior ("timid" mice, i.e., males exhibiting defensive-escape behavior during encounters with nonaggressive strange male conspecifics) was introduced for drug testing m the mid-1970s (37), major interest by ethopharmacologlsts m defensive behaviors (such as antipredator defensive behavior or attackreduced defenswe behavior associated with analgesia as mentioned above) is of more recent origin. The model of timid mice, which provides a broad spectrum of agonistic defensive-escape behavior [including defensive postures, protean (erratic) jumping and fleeing, alert postures or freezing as well as defence calls] has been extensively tested for drug effects (46), but sttll awaits a thorough nonpharmacologlcal analysis. One of its main advantages is its relative robustness against md~rect effects of drugs (mediated by social interaction as noted above) m contrast to defensive behavior induced by attacks (21,25). While the low incidence of timid animals in some mouse strains represents a

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problem, about 40 percent of singly housed randomly bred mice constantly show this behavmr in some laboratories (19, 37, 45, 46). The 1980s witnessed a marked revival of interest in the study of ultrasomc signals in laboratory animals (66), phenomena that had already been investigated m the 1960s [e.g., (73)]. Attention has focused mainly on distress vocalization evoked (for example) by separation of pups from mothers m rats (28, 31, 34), mice (3,71) and chickens (54,80), separation in adult monkeys (72), or by exposure to attack [defensive ultrasonic calls: for review (7)]. Most of these studies were carded out with respect to the development of new models for testing anxiolytlc drugs. When studying behavioral effects of drugs by the ethological approach, knowledge about the brain mechamsms underlying etholog~cally derived behavmral categories and elements can be helpful. One of the first reviews on brain mechanisms of agonlstlc behavior with respect to ethological categories was pubhshed by Adams (1). The role of hypothalamic structures in elic~ting various patterns of attack in rats by electrical stimulatmn has been systematically mvesigated by Kruk [reviewed in this issue (49)]. Furthermore, Depaulis (20) has recently reviewed different patterns of defensive behavmr elicited by chemical stimulation of the periaqueductal gray in the rat. PHARMACOLOGICALSCOPEOF ETHOPHARMACOLOGY Although the ethological approach has distract potential m the development of novel vahd measures for the prediction of anx~olytic, antidepressant, antipsychotic (and many other conventionally wanted neuropsychotropic activities m drugs), the main v~rtue of th~s approach hes m the provision of measures for unconventional, truly novel activmes of drugs. Indeed, the ethological approach is closely related to the "cnterion behavior" strategy which tests whether a drug is able to influence a pamcular behavior in a particular way (as opposed to the "criterion drug" approach testing whether a drug ~s able to produce effects s~mtlar to those exhibited by a prototype drug prone to generate "me-too" drugs) which was embodied m the proposals of Russell m the early 1960s (50,93). For example, this perspective can lead to questions such as: "Is there a drug which is able to inhibit aggresswe behavmr completely and selectively (without inhibiting other components of behavmr)?" This kind of reasoning has led to a vigorous search for selectwe antmggresswe drugs, and to the related d~scovery of compounds such as DU 27725, fluprazme (DU 27716) and eltoprazine (DU 28853) (9, 75, 79) which have striking antlaggressive potency at nonsedauve doses. The term "seremcs" (9) has been corned for this novel class of psychoactwe agent. Another intriguing question, recently raised by Dixon (24), concerns the issue as to whether there are drugs which are able to increase soctable behavmr through a dtrect action. Dixon (24) proposed the term "socmtrop~cs" for th~s hypothetical category of drugs. Since impairment of sociability occurs in many psychiatric d~sorders, this concept has potentially important clinical implications. Of course, most centrally acting drugs affect several aspects of behavmr m ways that often cut across distinctions made by ethological classification However, the goal is not to find an "absolutely" selective drug, but a reasonably selective and effectwe drug. The growing awareness of the utihty of the ethological approach in searching for new drugs has led to the increasing particlpatmn of ethopharmacologists m psychopharmacological drug screening in several pharmaceutical firms (first m Sandoz and Duphar). As for the testing of well-established acttv~t~es of psychotropic drugs (such as anxiolytic, antidepressant and antlpsychottc

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THREE-YEAR PERIODS FIG 1. Growth of hterature on ethopharmacology. Based on original articles, pubhshed abstracts, book chapters and reviews. profiles), the ethological approach has thus far been mainly employed in the evaluation of anxiolytic action. While various agonistic and antipredatory defensive behaviors, as well as ultrasonic calls, have been mostly specific for anxiolytics (3, 4, 28, 46), findings obtained with the stretched attend posture test (35,85) have been contradictory. However, predictive validity for anxiolytic activity of drugs based on their effects on a single behavioral element is usually very hmited (46). It is therefore advisable to assess anxmlyt~c potential on a wtder spectrum of behavmral activities, not least because this increases the posslbihty of differentiating between various kinds of anxiolytlcs. To date, the ethological approach has not been employed extensively for the detection of antidepressant or antipsychotic activity, although behavioral changes induced (for example) by chronic exposure to socml stress (33) or disorders of social communication, respectively, might be convenient and could be detected by ethological analyses. The increased aggressive behavmr observed m rats after chronic, but not acute, antidepressant drug treatment illustrates an attempt to utilize natural behavmr as a measure of antidepressant efficacy [reported in this issue (68)]. Although the ethological approach could also be of use in the study of drug dependence, it has been little exploited so far. However, the Blanchards (8) and Wolffgramm (107) have shown that dommance-subordmauon has a significant influence on alcohol consumption and dependence m rats. The uuhty of ethological methods m behavioral toxicology (98) and behavioral teratology (12) have been recently reemphasized, but they are comparatively rarely used for this purpose (53). Although the ethological approach could be especially useful in the study of psychotropic drug effects in humans, and ethology has been used to analyze certain nonverbal features of psychiatric patients (23, 24, 83, 84), such techniques have only rarely been used in human psychopharmacology (103) GROWTHOF ETHOPHARMACOLOGYAND ITS RELATIONTO OTHER APPROACHESIN BEHAVIORALPHARMACOLOGY It IS possible to differentiate several periods in the development of ethopharmacology. The first period (in the early 1960s) could be characterized by publication of papers by pioneers who showed the potential of such methods (16,94). A relatively long latent period followed (m the late 1960s and the early 1970s), when only a few researchers were active in the field, and new pertinent publications occurred rarely [e.g., (43, 86, 97, 105)]. Since around the mid-1970s, however, the number of publications employing the ethological approach in testing drug effects

ETHOPHARMACOLOGY: A HISTORICAL PERSPECTIVE

has begun to increase steadily, and the field has passed into a period of manifest growth (Fig. 1). Trends in ethopharmacology research appear to be similar to those in drug discrimination research, where rapid growth also began only after a longer period of relative inactivity (100). Whilst both these branches of behavioral pharmacology are still m the period of rapid growth, ethopharmacology is about 10-15 years younger, and is less advanced. Indeed, the number of ethopharmacological publications per year is currently about 5 times lower than that of papers m drug discrimination (100) or kindling (17) research. If the above developmental periods of ethopharmacology can be ontogenetically compared with conception, the embryonic phase (the latent period), the fetal phase (the period of manifest growth) and birth (marked by gettmg tts name m 1982), then ethopharmacology ~s now m its early infancy. Indeed, ethopharmacology is not yet mature enough to have a generally accepted terminology, neither has it its own textbook, journal, society or research instltuttons. However, ethopharmacological symposia have been held, first during the meetings of the Internatmnal Society for Research on Aggression in the early 1980s, later also at the meetings of the European Behavioral Pharmacology Society. Proceedings from some of these symposia have been pubhshed (62, 63, 78) and, together with the proceedings of this

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Ethopharmacology Conference (actually the first meeting devoted exclusively to the field), they provide additional mformation for those who are stimulated to discover more about this exciting field of research. Furthermore, for the interested reader, the conceptual development of ethopharmacology is reviewed in a number of excellent articles [e.g., (16, 21, 24, 39, 57, 61, 67, 89)]. Finally, it should be stressed that ethopharmacology is not "another" behavioral pharmacology, but an integral part of it. The ethological approach represents one of the tools which can be useful, and sometimes even indispensable, for a better understanding of behaworal effects of drugs. So far, different approaches to the study of behavmral effects of drugs have been developed largely independently and have been largely preoccupied with themselves. This phase has probably been necessary, rather like when one learns to play a musical instrument. It is to be hoped that, in the future, the individual approaches will be mature enough to seek and enjoy the study of behavioral effects of drugs m concert with the others. ACKNOWLEDGEMENT I wish to thank Dr John Rodgers for his kind help with the draft manuscnpt of th~s paper

REFERENCES I Adams, D B Brain mechanisms for offense, defense, and subrmssmn Behav Brain ScL 2 201-241, 1979 2 Adanl, N., Kiryatl, N.; Golam, I. The descnptmn of rat drug-reduced behavmr: Kinematics versus response categories Neurosci Bmbehav Rev 15.455-460, 1991 3 Benton, D , Nastm, K The influence of psychotroplc drugs on the ultrasomc calhng of mouse pups. Psychopharmacology (Berhn) 95 99-102, 1988 4 Blanchard, D C , Blanchard, R J Effects of ethanol, benzodtazepmes and serotomc compounds on ethophannacolog~cal models of anxiety In" McNaughton, N , Andrews, G , eds Anxiety Dunedm Umverslty of Otago Press, 1990 188-199. 5 Blanchard, R J , Blanchard, D C Aggressive behavmr m the rat Behav Bml 21:197-224, 1977 6. Blanchard, R. J., Blanchard, D C Antlpredator defenswe behaviors in a visible burrow system. J Comp. Psychol. 103 70-82, 1989 7. Blanchard, R J , Blanchard, D C , Rodgers, J , Wetss, S M The chamctenzatmn and modelhng of annpredator defensive behawor. Neurosc~ Bmbehav Rev 14 463-472, 1990 8 Blanchard, R J., Hon, K ; Tom, P , Blanchard, D C Sooal structure and ethanol consumptmn m the laboratory rat Pharmacol Bmchem Behav 28437--442, 1987 9 Bradford, L D , Ohvler, B , van Dalen, D , Schlpper, J Seremcs The pharmacology of fluprazme and DU 28412. In Miczek, K A , Kruk, M R , Ohvler, B , eds Ethopharmacology aggressmn research New York: Alan R. Llss; 1984:191-207 10 Brain, P F Study on the 4-10 ACTH fractmn on ~solatmn-mduced mtermale fighnng behavmur m the albino mouse Neuroendocnnology 10 371-376, 1972 11 Brain, P F What does mdwldual housing mean to a mouse9 Life So 16"187-200, 1975 12 Brain, P. F., Ajarem, J. S , Petkov, V V The unhty of ethological assessments of munne agomsuc mteracnons in behavtoral teratology" The foetal alcohol syndrome In Ohvler, B , Mos, J., Brain, P B , eds Ethopharmacology of agomstlc behavmur m animals and humans Dordrecht. Martmus Nijhoff Pubhshers, 1987 110-121. 13 Brain, P F ; Jones, S E ; Brain, S., Benton, D Sequence analys~s of socml behawour illustrating the acnons of two antagomsts of endogenous opmtds. In Miczek, K A , Kruk, M R , Ohvler, B., eds Ethopharmacology aggressmn research New York Alan R Llss, 1984 43-58

14 Brain, P F , Szmon, V M.; Martmez, M Ethopharmacologlcal studies on the effects of antthormones on rodent agomsuc behavmr with especial emphasis on progesterone Neuroso Blobehav. Rev 15 521-526, 1991 15 Chance, M R A Resolutmn of socml conflict mammals and man In de Reuck, A V S., Kmght, J , eds Clba foundation symposmm on conflict m society London J. A Churchdl, 1966 16--35 16 Chance, M R A , Sdverman, A P The structure of social behavlour and drug acUon In Steinberg, H., de Reuck, A V S , Kmght, J , eds Animal behavmr and drug action London- J A Churchrll; 1964'65-82. 17 Corcoran, M E. Conmbutlons of Graham Goddard to kmdhng. Neuroscl Biobehav Rev 13 251-252, 1989 18. Curler, M G Changes m the social behavlour of laboratory mace during admamstratlon and on withdrawal from non-ataxlc doses of ethyl alcohol. Neuropharmacology 15 495-498, 1976. 19 D'Amato, F. F ; Castellano, C Behaworal effects of morphine m mace Role of experimental housing Pharmacol Bmchem Behav 34 361-365, 1989. 20 Depauhs, A , Bandler. R.; Vergnes, M. Charactenzatmn of pretentonal penaqueductal gray matter neurons medmtmg mtraspec~flc defensive behavmrs m the rat by m~cromjectmns of kamlc aod Brain Res 486"121-132, 1989 21. Dixon, A. K Ethopharmakologle Em neuer Weg zur Untersuchung des Elnflusses von Med~kamenten auf das Verhalten Thangel 21.95-105, 1982. 22 Dixon, A K A posszble olfactory component m the effects of dlazepam on socml behawor of mace Psychopharmacology (Berhn) 77 246-252; 1982 23 Dixon, A K , Flsch, H U., Huber, C , Walser, A Ethological studies mammals and man" Their use m psychmtry Pharmacopsychmtry 22 44-50, 1989 24 D~xon, A K , Fisch, H U., McAlhster, K. H Ethopharmacology A bmloglcal approach to the study of drug-reduced changes in behavmr Adv Stud Behav. 19'171-204, 1990 25. Dixon, A K , Kaesermann, H. P. Ethopharmacology of flight behavlour In Ohvler, B., Mos. J , Brain, P B., eds Ethopharmacology of agomstlc behavmur in ammals and humans Dordrecht Marunus Nljhoff Pubhshers; 1987 46-79 26 Domit, P Measuring behavmur The tools and the strategies Neuroso Bmbehav Rev. 15 447-454, 1991 27. Fernfmdez-Espejo, E , Mn-, D Ethological analysis of the male

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rat's SOCloagonlstlc behavior m a resident-intruder paradigm Aggress Behav 16 41-55, 1990 Gardner, C R Distress vocahzatlon ,n rat pups A s~mple screening method for anxlolytlc drugs. J Pharmacol Methods 14 181187, 1985 Grant, E C , Mackintosh, J H A comparison of the socml postures of some common laboratory rodents. Behavlour 21 246-259; 1963 Haccou, P , K r u k , M R,Meells, E , v a n Bavel, E. D T , W o u t erse. K M , Meells. W Markov models for socml mteracaons Analysis of electncal sumulatmn m the hypothalam~c aggression area of rats Atom Behav 36 1145-1163, 1988 Hard, E , Engel, J , Lmdh, A S Effect of clomdme on ultrasomc vocahzatton m preweanmg rats J Neural Transm. 73 217-237, 1987 Hendne, C A., Ned. J C Exposure to the calls of predators of mice activates defenswe mechanisms and inhibits consummatory behavlour m an inbred mouse strata Neuroso Bmobehav Rev 15 479-482, 1991 Hoist, D , yon Physlolog~e SOZlaler Interaktlonen-Sozmlkontakte und ~hre Auswirkungen auf Verhalten SOWle Fertd~tat und Vatahtat von Tupajas Phys~olog~e Aktuell 3 189-208, 1987 Insel, T R , Hill, J L , Mayor, R B Rat pup ultrasomc ~solatlon calls Possible medmtmn by the benzodmzepme receptor complex Pharmacol Blochem Behav 24 1263-1267, 1986 Kaesermann, H P Stretched attend posture, a non-socml form of ambivalence, is sensitive to a conflict-reducing action Psychopharmacology (Berlm) 89 31-37, 1986 Kr~lak, M Behavmral changes and aggressw~ty evoked by drugs m mice Res Comm Chem Pathol Pharmacol 7 237-257, 1974 Kr~mk, M Tim~d singly-housed m~ce Their value m prediction of psychotroplc acuvlty of drugs Br J Pharmacol 55 141-150, 1975 Kr~lak, M Effects of drugs on behav~our of aggressive m~ce Br J Pharmacol 65 525-533, 1979 Kr~lak, M , Borgesov~i, M Drugs and spontaneous behavlour Why are detaded studies stall so rare `) Act~v Nerv Suppl (Praha) 14 285-293, 1972 Krgmk, M , Jankfi, I Effect of 6-azaundlne and 6-azacytldlne on exploratory activity in rats Actw Nerv Suppl (Praha) 6.201-202, 1964 Krg~ak, M , Jankfi, I The development of aggressive behavior in m~ce by isolation In Garattlm, S , Sigg, E B , eds Aggressive behav~our Amsterdam Exerpta Medlca Foundation, 1969 101105 Krglak, M ,Jankfi, I Measurement of pharmacological depression of exploratory activity m mice A contrthut~on to the problem of time-economy and sensmwty Psychopharmacologm 21 118-130, 1971 Krg~ak, M , Steinberg, H Psychopharmacolog~cal aspects of aggression A review of the literature and some new experiments J Psychosom Res 13 243-252, 1969 Kr~lak, M , Steinberg, H , Stolerman, I P Uses and limitations of photocell activity cages for assessing effects of drugs Psychopharmacologm 17 258-274, 1970 Kr~ak, M , ~ulcov~t, A Dlfferentml effects of six structurally related benzod~azepmes on some ethological measures of t~mldlty, aggression and locomotion m m~ce Psychopharmacology (Berhn) 101 396--402, 1990 Kr~lak, M , ~ulcov~i, A , Donht, P , Toma~ovh, Z , Dloh~.kov~i N , KosaL E , Ma~ek, K Can socml and agomst~c interactions be used to detect anx~olytlc actlv~ty of drugs`) In Miczek, K A , Kruk, M R , Ohvler, B , eds Ethopharmacology aggression research New York Alan R L~ss, 198493-114 Kruk, M R Mathematical methods and representatmns in ethological aggression research Leiden Ethopharmacology Group, Department of Pharmacology, Leiden Umvers~ty, 1985 Kruk, M R , Geuze, R PC-Protocol Gronmgen Gamma, 1990 Kruk, M R Ethology and pharmacology of hypothalam~c aggression m the rat Neuroso B~obehav Rev 15 527-538, 1991 Kumar, R Ammal models for screening new agents A behav~oural view Br J Chn Pharmacol 3(Suppl I) 13-17, 1976 L~tt, J Motivation from the point of v~ew of the reflex theory, be-

havlonsm and ethology (in Czech) s Fyslol 13 316-331, 1964. 52 L~it. J The spontaneous exploratory reactions as a tool for psychopharmacological studies A contribution towards a theory of contradlctory results m psychopharmacology In. Mlkhel'son, M Y a , Longo, V G , Votava, Z , eds Pharmacology of condmomng, learnmg and retention Oxford Pergamon Press, Praha Czechoslovak Medical Press, 1965 47---66 53 Lavlola, G , Blgnaml, G , Alleva, E Interacting effects of oxazepam m late pregnancy and fostenng procedure on mouse maternal behavior Neuroso Blobehav. Rev. 15 501-504, 1991. 54. Lehr, E Distress call reactivation in isolated chicks A behavioral indicator with high selecavlty for antidepressants. Psychopharmacology (Berhn) 97 145-146, 1989 55 Lister, R G Ethologtcally-based animal models of anx,ety disorders Pharmacol Ther. 46 321-340; 1990 56 Mackintosh, J H Behavtour of the house mouse Symp Zool Soc Lond 47337-365, 1981 57 Mackintosh, J H , Chance, M R A , Sllverman. A P The contnbutmn of ethological techmques to the study of drug effects In: Iversen, L L , Iversen, S D , Snyder, S H , eds. Handbook of psychopharmacology vol 7 New York Plenum Press, 1977335 58 Madlafousek, J , Hllfi~ik, Z Sexual behavlour of the female laboratory rat Inventory, patterning, and measurement Behav~our 43 129-174. 1977 59 Miczek, K A Intraspectes aggression m rats Effects of d-amphetamine and chlordlazepoxlde Psychopharmacologia 39"275-301, 1974 60 M~czek, K A , Haney, M , Tidey, J., Vatne, T , Weerts, E , DeBold, J F Temporal and sequentml patterns of agomstlc behavior Effects of alcohol, anxlolyt~cs and psychomotor stimulants. Psychopharmacology (Berhn) 97 149-151, 1989 61. Mlczek, K , Kr~mk, M Drug effects on agomsttc behavior. In Thompson, T , Dews, P , eds Advances in behavioral pharmacology vol 2 New York. Academic Press, 1979"87-162 62 M~czek, K A., Kr~mk, M Ethopharmacology of socml confhct and commumcatmn Anxmlyttcs, antidepressants, antlpsychot~cs, and analgesics (Symposmm introducuon) Psychopharmacology (Berhn) 97 141, 1989 63 MJczek, K A , Kruk, M R , Ohvler, B Ethopharmacology aggression research New York Alan R. Llss, 1984 64 Mlczek, K A , Thompson, M L . Shuster, L Oplold-hke analgesm in defeated mice Soence 215 1520-1522, 1982 65 Miczek, K A , Thompson, M L., Shuster, L. Analgesm followmg defeat m an aggressive encounter Development of tolerance and changes m opiold receptors Ann. NY Acad Scl 467 14--29, 1986. 66 M~czek, K A., Tornatzky, W , V~vmn, J Ethology and neuropharmacology Rodent ultrasounds In Ohwer, B , Mos, J., Slangem J , eds. Ammal models m psychopharmacology Basel. BIrkhauser, In p r e s s 67 M~czek, K A , Wlnslow, J T Psychopharmacologlcal research on aggressive behavmr In Greenshaw, A J , Dounsh, C T., eds Experimental psychopharmacology New York Humana Press, 1987 68 Mitchell, P J , Fletcher, A., Redfern, P H Is antidepressant efficacy revealed by drug-reduced changes m rat behavlour exhibited dunng socml mteractlon`) Neuroscl Blobehav Rev 15 539-544, 1991 69 Mos, J., Logten van, J , Bloetjes, K , Ohvler, B The effects of tdazoxan and 8-OH-DPAT on sexual behavlour and ultrasomc vocahzatlons m the rat Neuroscl Blobehav. Rev 15 505-510, 1991 70 Mos, J , Ohvler, B., van der Poel, A M Modulary actions of benzodmzepme receptor hgands on agomstlc behavmr Physml Behav 41 265-278, 1987 71 Nastm, K , Benton, D., Brain, P F , Haug, J The effects of 5-HT receptor hgands on ultrasomc calhng in mouse pups Neuroscl Biobehav Rev 15 483-487, 1991. 72 Newman, J D Ethopharmacology of vocal behavior m primates In Todt, D , Goedelong, P , Symmes, D , eds Pnmate vocal commumcauon Berhn Spnnger-Verlag, 1988 146-153 73 No.rot, E Ultrasounds and maternal behavior m small rodents Dev Psychoblol 5 371-387. 1972 74 Noldus, L P J J The Observer, base package for the IBM PC.

ETHOPHARMACOLOGY' A HISTORICAL PERSPECTIVE

75.

76

77

78

79

80

81

82

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User's manual, version 2.0 Wagemngen Noldus Informataon Technology, 1990 Ohvler, B Selectwe anti-aggressive properties of DU 27725 Ethological analyses of mtermale and temtonal aggression an the male rat Pharmacol Baochem Behav 14(Suppl 1)61-77, 1981 Ohvler. B , van Dalen, D Social behavior m rats and mice An ethologlcally-based model for differentiating psychoactive drugs Aggress Behav 8 163-168, 1982 Ohvler, B , Mos, J A female aggress.on paradigm for use m psychopharmacology' Maternal agonlstac behavlour m rats. In Brain, P F , Ramfrez, J M , eds Cross-dlsclphnary studies on aggression Spare Pubhcatlons de la Umversldad de Sevalla 1986 73111 Ohvler, B , Mos, J , Bram, P B . eds Ethopharmacology of agorustic behavlour m ammals and humans Dordrecht Martmus Najhoff Pubhshers, 1987 Ohvler, B . Mos, J , van der Heyden. J , Schlpper, J , Tulp, M , Berkelmans, B , Bevan, P Serotonerglc modulation of agomstlc behavlour In Ohwer, B , Mos, J., Brain, P B , eds Ethopharmacology of agomstlc behavlour mammals and humans Dordrecht Martmus Nuhoff Pubhshers, 1987 162-186 Panksepp, J , Herman, B , Conner. R , Bishop, P , Scott, J P The biology of social attachments Opmtes allevmte separataon dlsU'ess Blol Psychiatry 13 607-618, 1978 Parmlgmm, S , Brain, P F , Mamarda, M , Brunom. V Different patterns of biting attack employed by lactating female mice (Mus domestwus) m encounters with male and female conspecafic intruders J Comp Psychol 102 287-293, 1988 Farmlgmnl, S , Palanza, P Fluprazme inhibits mtermale attack and infanticide, but not predation, an male mice Neurosc~ B,obehav Rev 15"511-513, 1991 Pedersen, J , Lwolr-Petersen, M F , Schelde, J T M An ethological approach to autism An analysas of visual behavlour and interpersonal contact m a child versus adult anteractlon Acta Psychmtr Scand 80 346-355, 1989 Pedersen, J , Schelde. J T M , Hanmbal, E , Behnke, K , Nielsen, B M , Hertz. M An ethological descnptaon of depression Acta Psychmtr Scand 78 320-330, 1988 Pollard, G T , Howard, J L Effects of chlordlazepoxade, pentobarbital, busptrone, chlorpromazme, and morphine m the stretched attend posture (SAP) test Psychopharmacology (Berhn) 94 433434. 1988. Poole. T. B Some studaes on the influence of chlordtazepoxade on the social interaction of golden hamsters (Mesocrwetus auratu~) Br J Pharmacol 48 538-545, 1973 Posh~valov, V P Pharmacological and psychophystologacal analys~s of aggressive behavaour under condmons of zoosocml anteractlons (m Russian). In Valdman, V A , ed Psychopharmacology of behavlour Leningrad First Pavlov Medical Institute, 1974 6082 Poshlvalov. V P , Khodko, S T Mathematical description and experimental pharmaco-ethologacal analysis of ammal mtraspeclfic agomsUc behavior In. Maczek, K A , Kruk, M R.. Ohvler, B , eds Ethopharmacology aggress*on research New York Alan R Llss, 1984 59-80 Rodgers, R J Effects of benzodlazeplne and 5-HT receptor hgands on aggression and defense an animals In Rodgers, R J , Cooper. S J 5-HT.A agomsts, 5-HT 3 antagonists and benzodmzepmes Their comparative behavioral pharmacology Chlchester J Wiley and Sons, an press

445

90 Rodgers, R J., Randall, J I Situational-dependence and differential medlatton of analgest~c reactions to conspec~fic attack m mace In" Ohvler, B , Mos, J , Brain, P B , eds Ethopharmacology of agomst~c behav~our m animals and humans Dordrecht Marunus Nljhoff Publishers, 1987 80-93 91 Rodgers, R J , Randal, J I Environmentally-reduced analgesia Satuauonal factors, mechamsms and slgmficance In Rodgers, R J , Cooper, S J . eds Endorphms, opiates and behavloural processes Chachester Wdey, 1988-107-142 92 Rodgers, R J , Shepherd, J K , Don~t, P Differentaal effects of novel hgands for 5-HT receptor subtypes on nonopaold defensive analgesia m male mace Neuroscl Btobehav Rev 15 489-495, 1991 93 Russell, R W. Behavaoral research m prechnlcal psychopharmacology Issues of design and techniques; US Pubhc Health Servace Pubhcatlon No 968, 1962 94 Sdverman, A F Ethologacal and statistical analysis of drug effects on the socml behavtour of laboratory rats Br J Pharmacol 24 579-590, 1965 95 Sdverman, A P Barbiturates, LSD, and the socml behavlour of laboratory rats Psychopharmacologm 10 155-171, 1966 96 Sdverman A P The social behavlour of laboratory rats and the action of chlorpromazme and other drugs Behavlour 27 1-38, 1966 97 Sdverman, A P Behavlour of rats gwen a "smoking-dose'" of nicotine Atom Behav 1967-71, 1971 98 Sdverman, A P An ethologist's approach to behavioral toxacology Neurotoxlcol Teratol. 10 85-92, 1988 99 Steinberg, H , de Reuck, A V S , Knight, J , eds Ammal behavlour and drug action London J A Churchill, 1964 100 Stolerman, I P , Rasul, F , Shine, P J Trends m drug dlscnmanataon research analysed with a cross-indexed blbhography 19841987 Psychopharmacology (Berhn) 98 1-19, 1989 101 Svare, B Psychobiological determinants of maternal aggressive behavior In Slmmel, E C , Hahn, M E , Waiters, J K , eds Aggresswe behavior Genetac and neural approaches Hdlsdale Lawrence Erlbaum Assocmtes, 1983 129-146 102 Tmbergen, N Comparative studies of the behavlour of gulls (Lartdae) A progress report Behavlour 15 1-70, 1960 103 Troasa, A , Paslm, A , Bersam, G , Gnsptm, A , CaanL N Is nonverbal behavaour dunng antervaew a vahd index of amprovement in depressed patients '~ Psychopharmacology (Berlin) 101 $58, 1990. 104 Valzelh, L The 'qsolatlon syndrome" m mice Psychopharmacologm 31 305-320, 1973 105 Van der Poel. A M , Remmelts, M The effects of antlchohnerglcs on the behavaor of the rats m a sohtary and a socml situation Arch Int Pharmacodyn Ther 189394-396, 1971 106 Wmslow, J T , Maczek, K A Socml status as determinant of alcohol effects on aggressave behawor m squirrel monkeys (Salm~rt sctureus) Psychopharmacology (Berhn) 85 167-172, 1985 107 Wolffgramm, J An ethopharmacologlcal approach to the development of drug addiction Neuroscl Biobehav Rev 15 515-519, 1991. 108 Yoshlmura, H , Kamura, N Ethopharmacology of copulatory dasorder induced by chronic socml conflact m male mice Neuroscl Biobehav Rev 15 497-500, 1991 109 Yoshlmura. H , Ogawa, N Pharmaco-ethologlcal analysis of agorustic behavaor between resident and intruder m~ce Effect of antlcholmergac drugs Jpn J Pharmacol 32'111 I-1116, 1982