Hormonal and neurochemical correlates of various forms of animal “aggression”

Psychon~ur~ndocrinology. Vol. 17. No, 6. pp. 537-551.

1992

0306-a530/92 SS.00+0.00 ©1993 Pergamon Press Ltd.

Printed in Great Britain

REVIEW

HORMONAL AND NEUROCHEMICAL CORRELATES OF VARIOUS FORMS OF ANIMAL "AGGRESSION" P. F. BRAIN 1 a n d M. HAUG 2 1Biomedical and Physiological Research Group, Biological Sciences, University College of Swansea, Swansea, Wales, United Kingdom, and 2URA 1295, Laboratoire de Psychophysiologie, Strasbourg, France (Received 12 June 1991; in final form 17 September 1991)

SUMMARY The majority of studies attempting to evaluate the roles of hormones and neurochemicals in "aggression" concern laboratory rodents, notably rats and mice, with fewer investigations on infrahuman primates. Studies suggest that situations used to assess aggression (e.g., social conflict tests, parental attack, predatory behavior, use of unavoidable electroshock) actually tap a diverse range of motivations whose functions include offense, defense and predation. It is also apparent that ethoexperimental techniques, i.e., those applying ethological methodologies and concepts to laboratory situations, have advantages in assessing the direct and indirect consequences of chemical treatments. In this review, the impacts of hormonal manipulation (by surgery and/or application) and varying neurotransmitters (studied in terms of regional changes and as consequences of drug treatments) on a variety of forms of behavior are assessed. Different tests do show varying responses to common weatments, confirming the heterogeneity of the available paradigms. A brief discussion is provided of which tests are likely to prove most relevant to clinical studies.

INTRODUCTION THE RELATIONSHIPSbetween aggressive behaviors and the chemical coordinating systems have been studied intensively. This is presumably because hormones are naturally-occurring compounds, and psychoactive (transmitter-influencing) drugs are perceived as providing possibly reversible therapies (certainly when compared to psychosurgery) for some clinical conditions that include hyper-aggressivenesss as a symptom. In contrast to studies on the influences of hormones and transmitters on sexual behavior, investigations of the chemical bases of aggression are still in their infancy. Studies have shown it difficult to generalize across species and test situations or to infer c o m m o n underlying mechanisms (Brain, 1979a; Miczek & Krsiak, 1981). It seems likely that these tests actually tap different mixtures of offensive, defensive, and predatory motivations. Brain (1981a) emphasized the complex interpla.y between endocrine glands and the variety of target tissues which is central to any investigation of hormonal Address correspondence and reprint requests to: Dr. P. K Brain, Biomedical and Physiological Research Group, Biological Sciences, University College of Swansea, Swansea, Wales SA2 8PP, U.K. 537

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involvement in aggression. It is certainly hard to assess the roles of hormones in aggression, because there are a great number of strong and weak correlations between a difficult behavioral concept (aggression) and an extremely complex and subtly integrated endocrine system (Brain, 1977). The same is certainly tree for the actions of neurotransmitters and neuromodulators on these behaviors. One of the current difficulties in assessing the impact of chemicals on agonistic behavior is that much of the accumulated literature is based on the traditional approaches of physiological psychology. Here, manipulations (generally pharmacological) of the endocrine and neural systems are usually attempted via combinations of surgery, implantation, and injection, and the consequences of the modification are related to aggression as determined in restricted situations where the animal has few options other than to attack or fail to attack. This is in contrast to the fertile developments in ethopharmacology, where a tradition of inclusive measurement of many aspects of behavior has been undertaken in animals who generally do not have the restrictions of the traditional laboratory tests for aggression. Brain (1989) strongly advocated the employment of ethoexperimental techniques (those that apply ethological methodologies and concepts to laboratory situations) in attempts to understand the roles of homaones and neurochemicals in agonistic behavior. It seems likely that such approaches will reveal more about how hormones and drugs influence behavior in complex, changing situations. They also provide some control over the possibility that the chemical effects on aggression are indirect, being mediated by facilitating a competing behavior (e.g., fear or exploration) or by simply sedating the animal. Obviously, clinically, one would wish to use treatments that would counter hostility while leaving most other behaviors intact. SYNOPSIS OF THE EFFECTS OF HORMONES ON AGONISTIC BEHAVIOR IN RODENTS Brain (1981a) suggested that all hormones can potentially alter some aspect of aggression in a particular species or a specific situation. These factors have very diverse actions and can change this behavior in a variety of ways. The most important hormones in the control of social conflict are undoubtedly the sex steroid secretions of the gonads and the adrenal cortices (reviewed in Brain, 1981a). Information on these relationships is, however, extremely diverse. Attempts to determine how such hormones influence behavior are generally guided by the sophistication of the techniques available to the investigator. These range from simple injection-behavioral response studies to attempts to correlate the translocations of the hormone into cell nuclei within precise he' al regions with the consequent behavioral changes. Sex steroids exert their effects on aggression via a variety of actions which will be considered individually.

Early Programming Effects of Sex Steroids The frequently recorded sex differences in aggressiveness (Brain, 1979b) in a variety of situations may reflect variations in the early patterns of endogenous sex-steroid secretion and/or adult production of hormones. Androgens have developmental effects in early life, when they alter the capacity of the animal to display social aggression in adulthood (Leshner, 1981). The presence of androgens in the mature animal is also a necessary condition for the display of this form of behavior. Dixson (1979) stated that the neural mechanisms which mediate patterns of sexual and aggressive behavior in rodents are profoundly masculinized and defeminized by the influences of androgens upon the developing brain. Male, or androgenized, genetically female rats (Rattus norvegicus) not only need higher doses of estrogen to produce female-typical sexual responses (e.g., lordosis) than do non-masculinized females (van de Poll & Van Dis,

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1977), but they also fail to respond to testosterone (T) by showing this behavior (van de Poll et al., 1978). The vast majority of studies in which neonatal hormone administration has been related to adult aggressive behavior have employed traditional aromatizable androgens (i.e., those which can be metabolized to estrogens in target tissues including the CNS), but some studies have also used non-aromatizable androgens (e.g., dihydrotestosterone) (Pomerantz et al., 1985). Male rats and house mice (Mus musculus) show a greater potential for social conflict than do their female counterparts, because endogenous hormone secretion by the testis occurs earlier than that of the ovary. The early surge of T changes the neural circuitry of male rodents from the female condition to that of the male. T-propionate treatment of neonatally castrated male (vom Saal et al., 1976) and female (Mugford, 1974) mice results in these animals' showing much higher incidences of fighting in adulthood than their counterparts treated with oil control injections. It seems reasonable to conclude that, in rodents at least, T plays an important role in the genesis and maintenance of some forms of aggressive behavior. Of particular relevance to the present account is the review by Whalen and Johnson (1990), which emphasizes that hormonally mediated sexual differentiation in mice influences which target animals will be attacked in adulthood. They suggest that, developmentally, hormones both organize and sensitize the brain. One should note, however, that even in rodents, some species and situations are characterized by no sex differences in Tmediated aggression, e.g., same-sex encounters in two strains of rats (van de Poll et al., 1981). The positioning of the fetus during intrauterine development is also an important source of variation in terms of the hormonal titers to which both male and female rat and mouse fetuses are exposed (cf. Vom Saal, 1991, for review). These studies have led to rather different conclusions than the pharmacological hormonal treatments referred to earlier. 2M females (those developing between two males in utero) are more aggressive than 0M females (those developing between two females in utero). 0M females are exposed to more estradiol (E2) and less T than their 2M littermates. Males are also behaviorally influenced by their intrauterine location, with 2M males being more responsive to T than their 0M counterparts. The early hormone dynamics are complex, involving actions at a variety of levels, metabolic conversions, and the impact of binding globulins. The differentiation of the "masculine" and "feminine" behavioral phenotypes even in the "simple" mouse is much more complex than was initially assumed. Hormones can influence the developing brain in mammals. For example, T and E2, reaching the nuclei of hormonally sensitive nerve cells during critical periods for sexual differentiation, activate some genes and suppress others. Androgens and/or estrogens (whether ultimately released by the testis or applied exogenously during the perinatal period) defeminize and masculinize the neural substrates controlling sexually dimorphic brain functions, perhaps permanently (Drhler et al., 1984). The development of this substrate starts in rats during late fetal life (Jacobson and Gorski, 1981) and depends on the hormonal environment during the critical or sensitive period of the sexual differentiation (Gorski et al., 1978). Sexual dimorphism of the brain has been demonstrated by several investigators, working with a variety of methods in different species. Several studies have extended our knowledge of the impact of androgens on neuroanatomy in a wide range of species (e.g., Arnold, 1980; De Jonge et al., 1990; Nordeen & Nordeen, 1990; Panzica et al., 1990; Yahr & Finn, 1990), confirming that hormones influence both synapse formation and the development of localized enzyme (e.g., aromatase) systems. Other investigators, employing immunofluorescence techniques and retrograde tracing, have demonstrated the existence of apparently behaviorally meaningful projections from steroid (androgen, estrogen, and progestin)-concentrating nuclei in a variety of neural areas to other areas of the

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brains of adult male and female guinea pigs and rats (Corodimas & Morrell, 1990; Don-Carlos & Morrell, 1990; Lisciotto & Morrell, 1990; Poulain et al., 1990). Indeed, Warembourg et al. (1989) demonstrated that some neurons may have receptors for more than one hormone. These studies show that the impact of hormones on the brain is likely to be complex, subtle and wideranging. It is highly probable that some of these complexities are laid down in perinatal development. Influences of Sex Steroids on Aggressive Motivation The repeatedly demonstrated effects of hormones on the motivation of behavior implies that these chemicals have direct actions on the CNS. Brain (1977) reviewed the lines of circumstantial evidence for such actions on the brain. In terms of information applicable to the sex steroids, it has been suggested that: 1) Some steroid treatments cause morphological and/or receptor population changes in neural structures. 2) Sex steroids are sometimes more behaviorally effective when the hormone is placed in particular neural loci. 3) Neural regions commonly accumulate specific behaviorally active steroids. This accumulation is usually detected by autoradiographic examinations of brain sections. Major concentrations of neurally located sex steroids are found in the hypothalamus, the preoptic area, and the septum. The particular regions of the rodent brain that accumulate androgens are the medial preoptic nucleus, periventricular nucleus, paraventricular nucleus, septal region, medial amygdaloid nucleus, and ventral premammillary body. The binding characteristics of neural regions that concentrate these steroids can be altered by administering the hormones in early life, which changed the organism's behavioral potential. Several studies have shown that such processes occur in birds, rodents, and primates (e.g., Balthazart et al., 1990; Blaustein et al., 1990; Michael & Bonsall, 1990). 4) Steroids alter neuronal activity in particular regions of the CNS (Datta, 1986). 5) Hormonal changes may be correlated with alterations in localized turnover rates of a range of neurotransmitters (Versteeg et al., 1980; Hiemke et al., 1985; Ottinger & Balthazart 1987; Barclay & Harding, 1988). In some cases, changes in these biogenic amines have been related to certain forms of aggressive behavior in rats and mice (cf. Damna, 1978, for review). The difficulties in using different animal tests to assess the impact of hormones on aggression are illustrated by the following review of studies on the impact of common manipulations on behavior in different tests: Sex Steroid Influences on Performance On Tests of Aggression in Swiss Albino Mice Endocrine manipulations were applied to Swiss mice bred and housed under highly controlled conditions (Brain, 1981a) and given the opportunity to express their aggression in a wide range of laboratory tests said to measure aggression. Treatments were of differing duration and doses of hormone. Docile, anosmic male "standard opponents" were used in many of these studies (Brain et al., 1981a). Steroids, where used, were obtained from Sigma Chemicals (Poole, UK) and dissolved (after solubilisation) in myristic acid isopropyl ester (also from Sigma). The materials were injected into the animals' thigh muscles. Effects of Gonadectomy on Tests of Aggression in Swiss Albino Mice Nine-week-old Swiss mice were bilaterally gonadectomized or sham-operated under ether anesthesia 1, 2, or 4 wk prior to behavioral assessment in tests involving:

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1) social conflict in individually housed (for 3 wk) males; 2) social conflict in reproductively experienced (for 3 wk) males (used in Brain, 1983); 3) electroshock-induced attack in individually housed (for 3 wk) males (parameters described in Brain et al., 1981b); 4) electroshock-induced attack in reproductively experienced (for 3 wk) males; 5) parental defense in lactating females (Svare, 1981); and 6) attack on lactating intruders by individually housed (for 3 wk) females (Haug, 1980). The findings have been reviewed in Brain et al. (1983) and reveal that all durations of prior gonadectomy significantly depressed social conflict and electroshock-induced attack in individually housed males only. No other effects were evident, with the exception that the longest duration of prior gonadectomy increaseds attack by females on lactating intruders. It also has been confirmed that castration of males induces them to attack lactating intruders (Haug et al., 1986a, 1986b).

Effects of Daily Injections of T on Tests of Aggression in Swiss Albino Mice As above, groups of 12, 9-wk-old animals were bilaterally gonadectomized and given daily injections with 0, 25, 50, or 100 I.tg T. The groups generally received their treatments for 7, 14 or 28 days, with the commencements of injection being staggered so that all animals could be assessed behaviorally 31 days after surgery. Because the reproductively experienced males did not show castration-induced decrements of attack in the first experiment, only individually housed (for 3 wk) animals were used in tests of social aggression and tests involving unavoidable electroshock. Parental defence was assessed in animals after 7 or 14 days of treatment only, because such behavior seldomly occurs after this time. The data for these studies have been presented in Brain and Kamis (1985). Seven days of treatment with only the highest dose of T augmented attack by individually housed mice on "standard opponents". All doses of T facilitated this behavior when the treatment duration was 14 or 28 days. In a similar fashion, 50 or 100 ug per day of T augumented electroshockinduced attack in animals given 7 days of hormonal treatment; increasing the treatment duration to 14 or 28 days resulted in all doses being effective. With both 7 and 14 days of treatment, only the highest (100 lag/day) dose of T depressed parental defense. T also has been shown to inhibit attack by castrated males on strange lactating intruders (Haug et al., 1986a, 1986b). Effects of Daily Injections of E2 on Tests of Aggression in Swiss Albino Mice Identical treatment groups to those used in the T study were used, with the exception that animals received 0, 0.I, 0.5, or 1.0 lag E2 per day. The data for these studies have been presented in Kamis (1983) and Kamis and Brain (1986). All doses of E2 for all treatment durations significantly augmented social aggression in gonadectomized, individually housed animals compared to their control-treated counterparts. Similar, but more impressive, effects were evident for electroshock-induced attack. All doses of E2 suppressed parental defense by ovariectomized female mice, whether the treatments were administered for 7 or 14 days. E2 also has been shown to inhibit attack by castrated males, but not by intact females, on strange, lactating intruders (Haug et al., 1986a, 1986b). Effects of Daily Injections of 5~- Dihydrotestosterone (DHT) on Tests of Aggression in Swiss Albino Mice This study was identical in design to those presented above, with the exception that animals received 0, 50, 100, or 200 gg DHT per day. The data for these studies have been presented in

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Kamis (1983) and Kamis and Brain (1985). The 100- and 200qag-per-day doses of DHT augmented social aggression in castrated (4 wk earlier), individually housed males. All doses of DHT elevated such behavior when treatment durations were 14 or 28 days. In a similar fashion, only the 200 gg dose of DHT augmented electroshock-induced attack in castrates given 7 days of replacement therapy; increasing the treatment duration to 14 or 28 days resulted in all doses being effective. No dose of DHT influenced parental defense in ovariectomized females, whether the treatment was given for 7 or 14 days. DHT (and dehydroepiandrosterone) inhibited attack by castrated males on lactating intruders. DISCUSSION Earlier studies (Brain, 1981b; Brain et al., 1983) confirmed that predatory forms of attack, e.g., locust killing by mice, and attack on an inanimate target while confined in a narrow tube, do not tap the same motivations occurring in the dyadic encounters used in the more recent tests. The rationale for using this range of endocrine manipulations was based not only on the initial assumption that androgens "control" aggression (cited in the Introduction), but also on suggestions that testicular androgens are neurally converted to estrogenic metabolites before exerting their effects on aggressive motivation in male mice (cf. Brain, 1983, for review). This extension of the aromatization hypothesis (Naftolin & Ryan, 1975) to include aggression is based on findings that, in murine social aggression encounters involving castrated subjects, estrogens are more potent than androgens in terms of restoring or maintaining such behavior, anti-estrogens are more effective than anti-androgens in blocking sex steroid-replaced attack, and aromatase inhibitors (preventing conversion of T to E2) block the actions of T but not of E2. The only contradiction to the hypothesis has been the consistent finding that even exceptionally pure DHT (which cannot be aromatized to an estrogenic metabolite) augments the level of social aggression in castrates. Perhaps both T metabolites are effective. The studies reviewed above also confirm that not all expressions of aggression, even those that seem similar, are equally responsive to the effects of manipulation of sex steroids (extending claims made on the basis of using different genotypes, e.g., Jones & Brain, 1987). Some forms of attack, e.g., social aggression and electroshock-induced attack in individually housed mice, are systematically depressed by gonadectomy and can be restored by treatment with comparatively low doses of T, E2, or DHT. As suggested by Brain (1983), E 2 is the most effective hormone of the three. There is some evidence that certain "female" kinds of aggression are influenced in a diametrically opposite fashion by sex steroids. Gonadectomy may augment attack on lactating females by resident females and males (Haug et al., 1981, 1986a, 1986b), and such attack can be suppressed by T (in both males and females) or E2 (in males only). Treatment of gonadectomized females with T or E2 (but not with DHT) suppressed parental defense in response to intruder males. The use of intact male stimulus animals also strongly indicates that estrogen directly increases aggressiveness in mice - - all the rodent studies in which estrogens suppressed aggression depended on treating both intact subjects with these steroids, perhaps altering their stimulus effectiveness as targets for attack). It should be emphasized, however, that all the above generalizations are based on studies of a limited number of genotypes of the laboratory mouse. Although the mouse is, by far, the most utilized laboratory animal in studies of aggression, it seems important to establish whether these findings hold for other species, especially for infra-human primates and man.

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Pituitary-Adrenocortical Influences on Performance on Tests of Aggression in TO Strain Albino Mice One should not assume that the only hormones that have powerful effects on some forms of aggressive behavior in rodents are gonadal steroids. Brain and Haug (1990) reviewed the effects of treating mice with 200 ~tg dexamethasone, a synthetic, adrenal-suppressing glucocorticoid (Organon), 4 IU long-acting ACTH (Cortrophin/Zn, Organon), or appropriate control solutions on fighting in many of the situations used for the sex-steroid studies. The results were as follows: 1) Acutely administered dexamethasone and ACTH elevated social conflict. The fact that these hormones have the same effect suggests that the effect is brought about by glucocorticoids (ACTH by stimulating corticosterone release and dexamethasone by intrinsic properties). The effect was much more obvious when aggressiveness was induced by individual housing rather than by mating activity, a factor which simply may be related to the initial level of fighting behavior. 2) ACTH, but not dexamethasone, reduced parental defense in female mice. 3) Dexamethasone, but not ACTH, significantly increased attacks by castrated males on lactating intruders. However, this synthetic glucocorticoid had only a slight, non-significant effect on behavior in sham-operated residents (perhaps mediated by decreases in endogenous androgen levels). This account considers agonistic behavior. It is worth mentioning that, although androgens and/or their products are strongly implicated in certain forms of aggression, avoidance of attack, which also is part of the spectrum of activities that make up agonistic behavior, is much more influenced by ACTH and the adrenocortical hormones (Leshner, 1983). INFLUENCES OF HORMONES ON SOCIALSIGNALSFOR AGGRESSION A comparative approach to social communication has revealed the great variety of signalling methods used by different species. The endocrine system can serve as a "go-between" in such social communication. Kelley (1981) has described three ways in which endocrine mediation may be involved in social signalling:

Effects of Hormone on Perception Perception refers to the processing of sensory input by the CNS (Gandelman, 1981). It is important to distinguish between the processing of information that is involved in the perception of an individual relationship in a given situation and the mechanisms involved in the elaboration and execution of a behavioral "project". Perception is frequently assessed in routine clinical examinations. This is less due to an identified need to collect specific information on this important area of human performance than to the clinically outmoded notion that the perceptual apparatus is particularly liable to brain damage (cf. Thomas et al., 1981, for review). It is conceivable that hormones also alter perception in humans, accounting for some behavioral changes. Indeed, an animal's hormonal status can affect its perception of stimuli, which can act as social signals. Hormones can be regarded as acting on situational factors by altering the perception of signalling between conspecifics (Brain, 1983). Evidence for hormonal involvement in perception has been obtained for all the major sensory systems.

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Effects of Hormones on Signal Generation Hormones also may alter the probability of the production of signals that serve social functions. The most frequently modified signals are somatosensory, olfactory, visual, and auditory. For example, androgens and estrogens have major effects on olfactory social communications in both rodents and infra-human primates (Brain et al., 1987). Changes in Hormonal Status of the Receiver as a Consequence of Experience There is good evidence that signals expressed by the behavior of conspecifics can alter the functioning of their recipient's endocrine system. Behavior produces endocrine changes in a variety of bird species (e.g., Lehrman, 1965; Silver, 1983). Harding (1981, 1989) presented several examples of this kind of interaction in hamsters and birds. Brain (1990) reviewed the evidence that fighting and, especially, subjection to defeat can produce wide-ranging repercussions in the endocrine systems of rodents, which vary with time. Consequently, there is an interactive relationship between hormone production and agonistic behavior. Although the mechanisms for involvement of particular hormone systems in agonistic behavior may vary from species to species (e.g., infra-human primates generally do not respond to estrogens in the same way as do rodents), it is obvious that there is a wide range of activities that are considered aggressive. One should recognise that it is improbable that there is a physiology common to all such behaviors. Hormones potentially change many elements of social interactions and have complex time-courses for their actions. Metabolic conversions of hormones (e.g., androgens to estrogens) should at least be considered, i.e., compounds do not necessarily act in the form in which they are administered. The relationship between hormones and behavior is interactive in that, not only do hormones change behavior, but behavioral experiences also influence the organism's endocrine profile. SYNOPSIS OF THE INVOLVEMENT OF NEUROTRANSMITTERS ON AGONISTIC BEHAVIOR IN RODENTS One of the most interesting, as well as challenging, aspects of research on aggression has been the correlation of such behavior with putative central neurotransmitter mechanisms. However, such correlation is complex, because aggressive behaviors are heterogeneous and there are many putative central neurotransmitters, often with associated sub-populations of binding sites. Consequently, only intermale social conflict, attack on lactating females, and parental defense in lactating females (all spontaneous behaviors) will be considered in this section, and only qtaminobutyric acid (GABA) and serotonin (5-HT) will be explored in detail.

Intermale Social Conflict In most studies dealing with this form of aggression, mice are rendered aggressive by individual housing. GABA has been correlated with behavior by both whole brain and regional measurements in animals exhibiting or not exhibiting aggressive responses. In addition, a pharmacological approach has been used, i.e., drugs related to GABA being administered as tools to modify aggression. Earley and Leonard (1977) found that the concentration of brain GABA was inversely related to the degree of aggressive behavior exhibited. Aggressive, individually housed mice had reduced GABA levels in some brain areas (such as striatum, hippocampus and amygdala) compared to much less aggressive grouped animals. Lower levels of GABA also were found in the olfactory bulb and striatum of isolated, highly aggressive mice compared to their counter-

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parts exhibiting low levels of aggressive responses. Pharmacological studies of the GABAergic system confirmed the role of this neurotransmitter in the inhibitory control of male social conflict in mice: Administration of aminooxyacetic acid (AOAA) and ~,-acetylenic GABA (GAG), both of which increase neural GABA in mice, concomitantly suppress the aggressive response, generally in a dose-dependent manner (Da Vanzo & Sydow, 1979). Administration of GABA-T (GABA-transaminase), nDPA (sodium n-dipropylacetate, a GABA agonist), and NCS3 ([R,S] nipecotic acid amide, an inhibitor of GABA uptake) all inhibited aggressive responses in Swiss (Simler et al., 1982) and isolated, aggressive DBA/2 (Puglisi & Mandel, 1980) mice. However, the behavioral effects of some GABA derivatives seem at times to be a consequence of inhibiting other transmitters, e.g., dopamine (Allikmets et al., 1980). GABA is not the only neurotransmitter capable of exerting an inhibitory control over social conflict in male mice; 5-HT seems to play a similar role: Nearly every pharmacological manipulation of 5HT neurotransmission; e.g., administration of PCPA (which inhibits tryptophan hydroxylase and blocks 5-HT synthesis) and of storage-depleting agents and receptor antagonists more-or-less specifically decreases isolation-induced aggression (Miczek & Donat, 1989). As is the case with GABA, 5-HT has very complex relations with other neurotransmitters, such as dopamine (Haney et al., 1990) and other catecholamines (Leonard, 1984). This account will be limited to GABA and 5-HT, because it would be too time-consuming to deal with all the varied transmitters, these transmitters have been the most heavily investigated in aggression studies, and they are the only compounds whose effects have been assessed on all the models of murine aggression presented above. Attack by Mice on Lactating Intruders The roles of GABA and 5-HT have been investigated in a form of aggression where isolated or group-housed female or castrated male mice strongly attack intruding, lactating females. Very low levels (in intact and spayed females, as well as in castrated males) or a total disappearance (intact males) of attack on lactating intruder~ were noted after treatment with n-DPA (Haug et al., 1980). However, this suppressed fighting was not correlated with an increase in GABA, at least in some brain areas. GABA levels were increased in the hypothalamus, olfactory bulb, and amygdala of the highly aggressive male castrates compared to their less-aggressive, intact (sham-operated) conspecifics. Similar findings were obtained in a subsequent study where the relationship among aggression toward lactating intruders, gonadectomy, and brain GABA levels was examined in different inbred strains of mice (C57, C3H, and CBA). The most aggressive C57 castrates had significantly higher levels of GABA in the aforementioned brain areas, whereas such a change was not evident among animals of the C3H and CBA strains, which showed low baseline levels of aggression towards lactating intruders (Haug et al., 1984). In the most recent study, muscimol hydrobromide (MU), a GABA-agonist, and NCS3 were administered intraperitoneally in a range of doses to intact (sham-operated) or gonadectomized male and female Swiss strain mice before they encountered (for 15 min) unfamiliar lactating intruders (around day 14 after parturition). The gonadectomized and the sham-operated, intact animals were surgically manipulated one month before the administration of drugs and testing. The single dose of MU was given precisely 10 min before the encounter with the intruder, and the NCS3 was administered 30 min before the test. Each dose of the two substances suppressed the number of biting attacks on intruder females in both males and females, irrespective of their gonadal condition (Figs. 1 & 2). Although the treatments were able to increase the latencies to first biting attack in both intact males and females, they had no such effect on the gonadectomized animals of either sex (Figs. 3 & 4).

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MU MU NCS3 NCS3 0,50 0,75 125 250 mg/kg mg/kg mg/kg mg/kg CASTRATEDMALES

FIc. 1: Effects of saline control (NACL), musctmol (MU), and nipecotic acid amlde (NCS3) on mean (hatched area) number of biting attacks by intact or castrated male mice on lactating intruders. The blocks Indicate the standard deviations, and each category is actually separate. Mean number of biting attacks 60

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MU MU NCS3 NCS3 0,50 0,75 125 250 mg/kg mg/kg mg/kg mg/kg INTACTFEMALES

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F~o. 2: Effects of saline control (NACL), muscimol (MU) and nipecotic acid amide (NCS3) on mean (hatched areal number of biting attacks by intact or ovariectomized female mice on lactating Intruders. The blocks indicate the standard deviations, and each category Is actually separate. Experiments also were performed to investigate the role of 5-HT in aggression towards lactating intruders by residential female mice (Haug et al., 1990). The attack response could be suppressed by some 5-HT-modulating substances, e.g., the 5-HT1A agonist 8-OH-DPAT, suggesting that the 5-HTIA receptor subtype plays a role in the control of this aggressive behavior.

Parental Defense by Lactating Females Neurochemical studies also have been performad on parental defense (maternal or postpartum aggression) in female rats and mice. Qureshi et al. (1987) reported that cerebrospinal fluid GABA levels increased when females lived with their pups but decreased when the pups were removed for a few hr. In other studies, parental defense was found to be reduced after females were given the GABA receptor-blocker bicuculline (Hansen & Ferreira, 1986). Several lines of evidence also have prompted the exploration of the role o f 5-HT in parental defense d i s p l a y e d b y rats and mice. T h e y include the facts that studies have ruled out the

HORMONALANDNEUROCHEMICALCORRELATESOFAGGRESSION Mean latency to first bite 8OO 7O0 6OO 500 400 3OO 2O0 100 0 NACL MU MU NCS3 NCS3 0,50 0,75 125 250 mg/kg mg/kg mg/kg mg/kg

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MU MU NC.,S3 NCS3 0,50 0,75 125 250 rng/kg mg/kg mg/kg mg/kg CASTRATEDMALES

FIG. 3: Effects of saline control (NACL), muscimol {MU}, and nlpecotic acld amide (NCS3) on mean (hatched area} latency to first bite (in sec) by intact or castrated male mice on lactating intruders. The blocks Indicate the standard deviations, and each category is actually separate.

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MU MU N C S 3 NCS3 0,50 0,75 125 250 mg/kg mg/kg mg/kg mg/kg

OVARIECTOMIZEDFEMALES

FIG. 4: Effects of saline control (NACL), muscimol (MU}, and nipecotic acid amide (NCS3} on mean (hatched area) latency to first bite (in sec} by Intact or ovariectomized female mice on lactating intruders. The blocks indicate the standard deviations, and each category is actually separate. involvement o f suckling-induced changes in adrenal, ovarian, and pituitary (especially prolactin) hormones, suckling is known to profoundly alter 5-HT function in postpartum rodents (Svare 1983), and 5-HT has long been implicated in sexual and aggressive behavior in a variety of mammalian species. Olivier et al. (1987) found that 8-OH-DPAT suppressed the attack response by lactating females. This finding is in line with the demonstration that this drug possesses central 5-HT1A agonist properties (Hjorth et al., 1982) and provides further support for an inhibitory role of central 5-HT in the mediation of aggressive behavior. Detailed behavioral analysis, taking into account a broader repertoire of activities, indicates large differences between 5-HT-modulating drugs. Olivier et al. (1987) suggested that almost all agonists o f the 5-HT1B, mixed 5-HT1A/ 5-HTIB, and mixed 5-HT1/5-HT 2 types inhibit maternal aggression in a dose-dependent manner, some having a non-specific behavioral profile. The mixed 5-HTI/5-HT 2 agonist quipazine, for example, suppresses aggression and social interest but increases the time the animals spend in

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inactivity. The 5-HT1A/5-HT1B agonists RU 24969 and DU 28853, as well as the weak, putative 5-HT1A/5-HT1B agonist fluprazine, suppress maternal aggression while concomitantly increasing social activities, exploration, care of pups, and inactivity. A number of points can be made in connection with these neurochemical studies: 1) Each form of aggression involves more than one neurotransmitter. Thus, one should consider the balance among transmitters; i.e., each behavior has a complex multi-transmitter profile. 2) Measurement of endogenous concentrations of these substances in the brain may be of little significance (e.g., the increase of GABA in only some brain areas of castrated aggressive male mice). Their turnover rates should be considered, and analyses should be performed in appropriate brain areas rather than in whole brain, as was frequently done in earlier studies. 3) Correlations among each form of aggression, the hormonal state of the animals, and their neurochemical profile should be systematically studied. SYNTHESIS It is obvious that a wide range of behaviors receive the label aogressmn in infra-human animals and our own species. This diversity suggests that different animal models do not easily represent the human behaviors that are focus of this account. Rather, they serve to elucidate the involvement (or potential involvement) of particular physiological factors in mechanisms that increase or reduce the probability of eliciting behaviors in specific environments. One might, for example, speculate that predatory responses will prove revealing vis-a-vis psychopaths (since both activities are characterised by low levels of emotional arousal) and that defensive behavior will have relevance for the activities characteristic of many disturbed individuals (since aggression in clinical settings frequently appears to be a consequence of increased fearfulness). Studying examples of offensive, defensive, and even predatory behavior seems more likely to increase our understanding of the range of human activities that receives the label "aggression" than does concentrating on offense alone. Furthermore, at present, the influence of hormones and/or neurochemicals on behavior can be truly evaluated in detail only in animal studies. Acknowledgements: Supported in part by a project d'Accord Interuniversitaire (DCRI) between Strasbourg and Swansea. REFERENCES Allikmets LKH, Polevoi LG, Tsareva TA, Zharkovski IAM (1980) Dopaminergic component in the action mode of gamma-aminobutyric-acid derivatives and structural analogs. FarmakolToksikol (USSR) 42: 603606. Arnold AP (1990) Hormonally induced synaptic reorganization in the adult brain. In: Balthazart J (Ed) Hormones, Brain and Behaviour in Vertebrates, Vol 1. Karger, Basel, pp 82-91. Balthazart J, Foidart A, Surlemont C, Harada N (1990) Preoptic aromatase in quail: behavioral, biochemical and immunocytochemical studies. In: Balthazart J (Ed) Hormones, Brain and Behaviour in Vertebrates, Vol 1. Karger, Basel, pp 45-62. Barclay SR, Harding CG (1988) Androstenedione modulation of monoamine levels and turnover in hypothalamic and vocal control nuclei in male zebra finches. Brain Res 459: 333-343. Blaustein JD, Olster DH, Delville Y, Nielsen KH, Tetel MJ, Turcotte JC (1990) Hypothalamic sex steroid hormone receptors and female sexual behavior: new insights from immunocytochemical studies. In: Balthazart J (Ed) Hormones, Brain and Behaviour in Vertebrates, Vol 2. Karger, Basel, pp 75-90. Brain PF (1977) Hormones and Aggression, Volume 1. Eden Press, Montreal.

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