Neuropharmacological and related aspects of animal aggression

Prog. Nemo-P8@qhmMco~. , Vo1.2, pp.611-631. 1978. Pergamon Press Ltd., Printed in Great Britain

NEUROP IMRMACOLOGICAL AND RELATED ASPECTS OF ANIMAL AGGRESSION

ALEXANDER G. KARCZMAR: DANIEL L. RlCHARDSON’and GISELA KINDEL3 ‘Department of Pharmacology and 2p31nstitute of Neuropharmacology

Loyola University Medical Center Maywood, Illinois, U.S.A.

(Final form, October 1978)

Abstract

1. Various models of animal aggression are described and the differences between human and animal aggression are stressed. Various forms of aggression as they relate to a number of mice strains and genera are described in an attempt to link a specific “psychological” mouse profile with aggression. Several forms of aggression including those exhibited in in a pseudonatural habltat, maternal defense of the pups, isolation and footshock induced

aggression were investigated. These various forms of aggression were studied jointly with mouse behaviors such as exploratory, learning, locomotor and curiosity-dependent activities, as well as activities relatable to what can be defined as emotional behavior such as stress-induced activities and alcohol preference. A “flexible” prof 1 le characterized by high motor, exploratory and related activities and good learning capacity was correlated with various types of aggression including shock-induced and social aggresslon. An “emotional” syndrome was described as connoting poor learning capacity, interference with pertormance of “socially useful” activities in a pseudonatural habitat and tendency to alcohol preference; this syndrome was not associated with social or isolate aggression. The “flexibility” syndrome characterized particularly the CF-1 and C57BL/6J strains of mus Musculus, while the emotional syndrome characterized wild and less inbred mice types.

A review of the neuroanatomical and neurochemical basis of aggression is presented In a comparative manner revealing a “multitransmitter” control of aggression. The rodent types described differ greatly with respect to brafn levels of acetylchollne, choline acetylase, acetylcholinesterase, catecholamines and indoleamines and GABA.

The effects of drugs presumably acting via neurotransmitter mechanismsare discussed in an attempt to clarify the cholinergic and adrenergic control of various forms of aggression. The most consistent data suggest that the cholinergic system exerts profound influence on several forms of aggression, but discordant results are adduced as well.

Keywords : aggression-cholinergic-adrenergic-neurotransmitters-behavior-rodent-mice strains

Table of Contents

Abstract

1. Introduction

2. Background

PP

611

612

613 2.1 Definition of aggressive behavior 2.2 Diversity ot the forms of aggression and of the underlying factors 2.3 Animal vs human aggressive behavior

613 613 614

3. Comparative aspects ot rodent behaviors including aggression 614 3.1 Behavioral syndromes of related small rodent types 614

a. Flexible and affective behaviors (syndromes) 615 b. Models of animal (experimental) aggression 617 c. Relationships between aggression and the two behavioral syndromes 620

611

612 A. G. Karczmar

3.2 Neurochemlcal and neuroanatomlcal aspects of 3.3 Genetics and aggressive behaviors in rodents

4. General characteristics of aggression 4.1 Neuroanatomlcal and neurophysiologlcal findings

et al.

rodent behavior 620 621

622

4.2 Pharmacology of aggression.. The neurotransmltter mechanism a. Chollnerglc mechanism b. Catecholamlnerglc mechanisms c. Serotonerglc mechanism d. Other neurotransmi tters e. Neurotransmltter turnover and aggression

5. Conclusions

References

622 623 623 624 624 624 624

626

627

1. INTRODUCTION

The models of animal aggression that this paper 1s concerned with may be not related in any strict way to aggression in man. This is clearly apparent when one compares the defi- nitions of aggression as they appear in psychiatric and anthropologic versus ethologlcal wiltlngs. Such ethologists as Barnett (1967), Tinbergen (1953), or Lorenz (1966) refer to animal aggression as a stereotypic behavioral act, extremely homogenous and invariable for a particular species and in this particular sense appearing innate or instinctive. The ethologists define therefore aggression as a series of overt activities designed either to inflict wounds and death upon the adversary, to subjugate the latter, or to put it to flight. On the other hand, psychiatrists stress the affective, inner conflict or personality dis- order bases of aggression; thus, Rochlin (1973) equates aggression with “injured self- esteem” or with narcissism, as he states that there “is an indivisible bond between narcissism and aggression”, while Frown (1973) speaks of “peculiarly human” destructive aggression related to a malignant Oedipus complex and Freud’s “death instinct”. Still another viewpoint is reflected by anthropologists who emphasize culture or learning-dependent nature of aggression (Allan, 1972). Political and social scientists and historians may define aggression in a still different way.

The second point that we wish to raise is the variability and diversity of aggressive paradigms. In fact, this variability constitutes a common denominator between the psychiatrist and the ethologist. The psychiatrist may speak of outer or inner directed aggression and, in this latter case of suicide; he may speak of hostility, paranoia, rage outacting following frustration, etc. In the similar vein, the ethologist may speak of territorial aggression, defense of the young, predatory behavior, etc.. as well as of behaviors which may be related to aggression only In the dipole sense of relations; thus, flight and flght. or fear and aggression may constitute agonist-antagonist dipoles rather than various aspects of unltary aggressive behavior. Accordingly, we would like to accentuate the tenuous relationship and analogies between human and animal aggression by stressing in our present-

ation that animals exhibit various types of aggression; as these aggressions occur under differing conditions and within differing paradigms, they may be considered as corresponding to the cultural diversity of human forms of aggression.

First, various forms of aggression as they relate to a number of related mice strains and genera will be described. As these mice types represent a wide ethological and ecological specturm. it may be possible to relate various forms of aggression to other behaviors and link a specific “psychological mouse profile” with aggression.

Second, the neuroanatomical and neurochemical bases of aggression will be briefly reviewed. The comparative, inter-strain aspects of this matter can be only briefly referred to because of the paucity of the available data; however, the multitransmitter control of aggression emerges clearly from the pertinent investigations.

Finally, certain behavioral paradigms - stress and isolation - that may relate to man will be described and their neurochemical aspects explored.

Neuropharmacology and animal profiles of aggression 613

2. BACKGROUND

2.1 Definition of Aggression

It is relatively easy to define and describe animal aggression in terms of its visible characteristics; it is more difficult to pinpoint the underlying mechanisms and factors.

Aggression may be defined as an overt act the goal of which is either to eliminate, con- sume or cause the escape of, an opponent tiy inflicting organic damage upon the latter, or to induce the opponent to escape by non-contactual means, i.e., via a ritualized attack or threat (cf. Lorenz, 1966; Barnett, 1967). Either all participants - two or more - may be initially actively involved in the attack or threat, one ultimately becomlng the victor, or

only one is the attacker from the onset (Scott, 1948). While there are several forms and triggers of aggression (cf. below), the actual act is relatively slmllar in all cases, except when the trigger is constituted by predation, in which case certain overt signs present in other forms of aggression , such as autonomic changes and vocalization, are missing.

Having said this, it must be stressed that contrary to the relatfve homogeneity of the overt act, the causative factors underlying aggression are many, and they differ between species and various forms of aggression, or even from one intraspecies episode to another.

2.2 Diversity of the Forms of Aggression and of the Underlying Factors

Moyer (1976 a, b), Pradhan (1975), Reis (1975) and other described several forms of animal aggression as related either to their experlmental induction or natural causes and stimuli (see also Table 7). Thus, in a laboratory, aggression may be induced by fear, social isolation as well as overcrowding; iriitatlon by noxious stimuli such as footshock or an irritant drug; chemical or electrical stimulation or lesions of strategic brain parts; or, finally, by certain drugs and hormones (Moyer, 1976 a, b ; Thiessen, 1976; Valzelli, 1977, etc.). In the open field conditions or in a pseudo-natural habitat (“Mouse City”, Karczmar et al., 1973) additional types and causations of aggression appear, such as predation, mating competition, territorial defense, maternal aggression in defense of the pups, etc. All the pertinent paradigms, whether experimental or natural that induce these various forms of aggression are operationally quite specific;they were described in detail by several investigators (see Thiessen, 1976; Moyer, 1976 a, b; Pradhan, 1975; Karczmar et al., 1973).

It is clearly realized that the control of all these forms of aggression is multifactor- ial; experiential, psychological and environmental parameters are no less important than

hormones, neurotransmitters and second messenqers, brain centers and nuclei, and physiological functions (cf. Moyer, 1976 a, b). Yet, it is not possible today to define the parametric system involved In one or all forms of aggression. Nor is it possible to differen- tiate between the etiologies involved in the various forms of aggression, although this may be possible to a certain extent in the case of predatory versus non-predatory aggression. As pointed out above, these two types of aggression differ as to the overt act involved as well as with regard to their physiological characteristics and to type-specific chemical triggers (cf. Reis, 1974, 1975). On the other hand, non-predatory aggression includes several forms which are overtly similar; do these various forms of non-predatory aggression differ in parameters such as brain neurotransmitters and their turnover, hormone levels and environmental influences? The definitive answers are not available at this time, although these various forms of aggression appear in many experiments to differ; as Moyer (1976 a, b) points out, “a given manipulation may facilitate one kind of aggression, suppress another and have no effect on a third”. Unfortunately much of the available evidence appears to have anegdotal rather than causative meaning, the clarification of the latter being of obvious importance. For instance, what is the parametric meaning of the experiment demon- strating that isolation will not induce fighting in an isolation-sensltlve mouse straln when the paper towels are substituted as bedding for pine shavings (Bryson and Biahoff, 1975)7 As could be expected, possible involvement of neurotransmitter mechanisms in aggression was explored. An attempt to relate two forms of aggression, irritable and Isolatlon- induced, to turnover of cholinergic neurons is described in this paper. Changes in catecholaminergic and serotonergic system were also studied as possibly causative in isolation- induced aggression; the results are not definitive (cf. Pradhan, 1975; Valzelli, 1977;

Thiessen, 1976; cf. below, p. 13), and there is no evidence as to the neurochemical simil- arities or differences between, say, isolation or fear-induced aggression. The. only clear

614 A. G. Karczmar et at.

conclusion that may be reached Is that the phenomena in questjon are multitransmltter in nature (Karczmar, 1978).

Perhaps the comparative approach may be particularly heuristic. For several years many investigators (cf. Karczmar et al., 1973; Mandel et al., 1974; Thfessen, 1976) have been

engaged in a multi-disciplinary studies of related mice genera and strains, comprising several animal types. These animals differ widely in ecology and In behavior - both In their natural habitat and when tested in the laboratory. Furthermore, we (Karczmar and Scudder, 1967; Bourgault et al., 1963; Karczmar et al., 1973) and others established several neurochemical differences between the strains and genera in question. Altogether, it could be hoped that a parameter or a parametric system may be found that would explain

on a quantitative, biological basis the behavioral differences between these animal types, particularly with regard to aggression.

The present article describes certain aspects of this particular approach as employed in this laboratory with respect to a number of related stralns and genera of small rodents.

What we attempted to do was to describe not only aggression in its various forms but also other behavioral and, what appear to be “emotional” traits of these animals, in order to test whether a particular behavioral syndrome may comprise one or another form of aggression. Furthermore, we attempted to relate these syndromes to neurochemical and other biol-

ogical characteristics of the animal types in question. While the results seem encouraging, more work than presented here Is needed to reach definitive conclusions.

2.3 Animal versus human aggression

It was already pointed out (cf. 1) that at least certain types of human aggression may either not obtain among or not be recognizable in, animals. For instance, malignant, destructive aggression related to the “death instinct” (Frown, 1973) or narcissist aggression (Rochlin, 1973) may either not be exhibited by animals or when present, it may not be de-

finable as such. Yet, even this apparently self-evident caution may be not quite warranted: whereas some forms of human death instinct or narcissism may lead to suicide, under certain pathological conditions (such as chronic treatment with high doses of amphetamine) animals may inflict damage upon themselves (Karczmar et al., 1973). far-fetched.

Of course, this analogy may be

Similarly, wars and politically or societally motivated organized forms of mass aggression which characterize man are not readily analogized with animal aggression, particularly as man’s wars may involve now-a-days, no direct or even visual contact. Yet, organized animal aggression may exist as in the case of rodent aggression concomitant with migration (cf. Barnett, 1963) ; it is a moot question whether motivational aspects of this phenomenon

such as food, climate and population density are related to man’s wars.

On the other hand, certain forms of individual human aggression due to drugs, fear, irritation, threat or organic disease seem to be analogous to corresponding categories of animal aggression (cf. above, and Moyer, 1976 a and b). Slmilarly, the approach described in this article which concerns the behavioral syndrome or profile that may be related to aggression appears pertinent to human aggression, Mark (1969).

a strategy described also by Erwin and Altogether, this approach has as its purpose to establish individual animal

psychology and its neurochemical counterparts as they relate to aggression and render it predictable; hopefully, this approach may be relevant for the problems of human aggression.

3. COMPARATIVE ASPECTS OF RODENT BEHAVIORS INCLUDING AGGRESSION

3.1 Behavioral syndromes of related small rodent types

A wide number of behaviors can be quantitated in mice, rats and related small rodents forms (Karczmar et al., 1973). Some of these behaviors are tested by means of appropriate experimental paradigms (Table l), while others may be measured in natural or pseudo-natural habitats such as the Mouse City (Table 2, cf. Karczmar and Scudder, 1967, 1969; Karczmar et al., 1973; cf. also Clark and Schein, 1966 and Southwick and Clark, 1968). Some of the paradigms in question - such as tests of learnlng or of curiosity - are concerned with the response potential of the animals; altogether, the behaviors and activities measured seem to describe in detail actual as well as potential behavioral repertory.


Table 1

Quantifiable behaviors of small rodents that may be related to aggression

Mouse City behaviors Autonomic responses (defecation) Response to stress Brain excitability Alcohol preference Sleep

REMS sws

Photometer activity Exploratory “reflex” Motor activl ty

Wheel cage activity Curiosity Diurnal rhythms Learning

For the description of the quantification of these behaviors cf. Karczmar et al. (1973) and Thiessen (1976).

Table 2

Behaviors measured in Mouse City

Exploration Digging Stereotypic behavior Sleep Contactual behavior Aggression

Attacking Being attacked

Carrying objects ingest ion Sexual behavior Grooming

Self Others Being groomed

For methodology, see Karczmar et al. (1973).

a. Flexible and affective behaviors

As a number of mouse strains and small rodent types are scored for the occurence and intensity of these various behaviors, it becomes apparent that the animal types that score high with respect to certain activities score low with respect to some other actlvlt- ies (Table 3; cf. Karczmar et al., 1973).

Table 3

Comparison of relative occurrence of various behaviors of several rodent types

Behaviors Rodents

Exploratory CF-1 C57 Micr. Per.Ba. Per.C. ““o” Onych. Perog . , reflex Rhei thro.

Whee 1 Per.C. Per.Ba. Micr. I IHo’ I c57 CF-1 Perog .

activity “C I ty” CF-1 I IHo’ 1 c57 Onych. Per.Ba. Micr.

Explor. “C i ty”

s tereotypy Per.Ba. ~~Mo~~ c57 CF-1 Micr. Onych. “City”

aggression CF-1 c57 “,,o,l Onych. Micr. Per.Ba.

nice listed in the order of decreasing frequency or intensity of the given behavior. C57, CF-1 and “MO” Mus musculus C57Bl/6J, CF-1 and “Missouri” respectively. Per. Ba. and Per. C.: Peromyscus manlculatus Bairdii and Colorado, respectively. Rheithro.:Rheithrodontomys. Micr.:Microtus Ochrogaster.


In fact, we have noticed at the onset of these studies (Karczmar and Scudder, 1567) that certain behaviors are closely linked; they are either present or absent as a syndrome in a particular strain of mice. For instance, wheel cage activity and stereotypic behavior in the Mouse City seem coupled; similarly, mouse strains tend to exhibit jointly good learning capacity and high level of exploratory activity as measured in the Mouse City or in the photoactometers. Conversely, as the occurrence of these behaviors is evaluated across the various strains and rodent types, the presence of certain activities excludes that of others (Tables 3-5). For instance, the rodent strains exhibiting high degree of stereotyped

activity whether measured in the Mouse City or by means of the wheel cages showed little exploratory activity in the Mouse City or in the photo-actometers. On the other hand, the exploring strains showed good avoidance and learning behavior (Table 4: Karczmar et al., 1973: Karczmar and Scudder, 1967, 1363 a). It could be of course expected that exploration is conducive to learningm while, conversely,

conditioning (Karczmar and Scudder, 1363 a). stereotypic motor behavior may interfere with

The two sets of mutually exclusive behaviors are shown in Tables 4 and 5 with respect to two mouse strains that are characterized by one or the other set.

Table 4

“Flex1 bi 1 i ty” score

Behaviors CF-1 C 57 B1/6J

“C i ty” exploration 1 0 Photoactometer exploration

(exploratory reflex) 1 0 Learning (avoidance) 1 0 Curiosity (visual and facti le) 1 0 “city” carrying 1 0 Aggression (total) 1 0

6 0

CF-1 and C5781/6J mice were compared with regard to behaviors listed at left; “flexible” behavioral syndrome characterizes mice that exhibit high scores in these behaviors. Symbols/ and 0 indicate the strain that scored high and low, respectively, in the test for the behavior In question.

Table 5

“Emotional” score

Behaviors CF-1 C 57 B1/6J

Total daily activity Wheel cage Freezing Contactual behavior Grooming Stereotypic behavior Defensive behavior

Isolate “C i ty” Maternal

Discontinuity of lear Alcohol preference

0 0 0

ning 0 0


CF-1 and C57B1/6J mice were compared with regard to behaviors listed at left; “emotional’ behavioral syndrome characterizes mice that exhibit high scores in these behaviors. Symbols/ and 0 indicate the straln that scored high and low, respectively, in the test for the behavior in question; defensive behaviors correlates inversely with aggressive behaviors (see Table 8).

It is tempting to assign value judgments to these two “syndromes” or “psychological prof i les”. Antropomorphically, we classified these two groups of behavior or “syndromes” as denoting “emotional” versus “flexible” behavior, our connotation of the “emotional” syndrome being its tendency to interfere with learning and with the performance of apparently useful tasks in the Mouse City (Karczmar and Scudder, 1969; Scudder et al., 1969); the

Tables 4 and 5 show that these two syndromes characterize CF-1 and C57B1/6J strains of M. musculus, respectively. Some of the behaviors in question were similarly classified by others. It is consistent with this concept that several stress situations including footshock, increase or induce autonomic discharge and defecation - a behavior generally recog- nized as emotional (Hall and Lindsay, 1934; Lieblich and Guttman, 1968; Lindzey, 1951; Karczmar et al., 1977; Poley and Royce, 1970,1973; Sprott and Staats, 1975) - as well as increase intensity or frequency of other “emotional” behaviors (Table 6), preventing at the same time purposeful activity. It must be added finally that the strains exhibiting highly “emotional” behavior are frequently wild mice and rodent types: in this case, the “emotional” profile may have life preserving value in the natural but not in the laboratory habitat (Karczmar and Scudder, 1969 a,b; Scudder et al., 1969).

Table 6

Effect of repetitive foot shock on Mouse City behaviors of CF-1 mice

Behavior 0

Number of Shocks.

5 10 60

Exploration Freezing Contactual

behavior Grooming

self Aggression Defacation

9.15 + 0.24 8.35 + 0.28* 7.83 + 0.25* 7.48 c 0.26** 1.30 f 0.04 1.39 + 0.11 2.90 f 0.46+* 2.10 + 0.40

0.97 f 0.15 1.99 +_ 0.27” 2.43 f 0.57”” 2.10 + 0.21

1.28 f 0.11 1.45 f 0.10 1.57 * 0.11* 2.03 i o.ii** 30.8 +- 5.30 39.2 A 6.40 39.5 +- 8.0 28.60 f 6.50

+ -I-+ u

The numbers refer to average frequency of behaviors in question per mouse f SE (* p < 0.05; ** p < O.Ol)during 30 min of testing; ++, + and - indicate high, present or

absent defecation, respectively.

One of the behaviors classified as “emotional”, alcohol preference (cf. Table 5), may require additional comment. Mice strains differ conspicuously in their alcohol consumption; when offered a choice, mice of certain strains prefer even concentrated alcohol solutions to water, and in fact, they will seek out the former even when presented in an adverse situation (Kahn, 1969). As shown in detail elsewhere (Karczmar et al., 1978), alcohol preference and alcohol-seeking behavior are linked with emotional activities listed in Table 5 and with stress susceptibility of the strains in question; speculative explanation of such a coupling was offered at length elsewhere (Karczmar et al., 1978). It should be added that individual, intrastrain differences in alcohol behavior are also present and may be related to affective

behavior and stress.

b. Models of animal (experlmental) aggression

As we attempt to relate the two syndromes to aggression, the various forms of the latter should be recalled (see Section 2.2). The many types of animal aggression (Moyer, 1976 a and b; Pradhan, 1975; Table 7) include several models of experimental aggression, as the latter may be induced by footshock, isolation, and stimulation of various brain areas, etc.

as well as several aggression types exhibited in the natural habitat and/or Mouse City such as the defense of the pups, territorial defense and predatory aggression (muricidal activity

618 A. G. Karczmar ef cd.

of certain “Killer” rats presumably represents the laboratory counterpart of this latter behavior).

Table 7

Types of rodent aggression

City aggression (ecological aggression)

Territorial defense (attacking strangers)

Fear Isolate aggression Predatory aggression

(niuricide)

Defense of pups

Irritable Withdrawal-induced (morphine abst-

inence syndrome) Foot-shock induced Induced by brain stimulation Hierarchic

Various forms of aggression exhibited in the open field or pseudonatural habitat (Mouse City), or induced experimentally. For the behaviors listed and their measurement, see Karczmar et al. (1373), Karli (1956) and La1 (1575).

It is of interest that aggressive rodent types exhibit high level of aggression with respect to at least several aggressive paradigms (Table 8).

Table 8

Comparison of various forms of aggressiveness of small rodents

Aggression

Taxon “C i ty” Isolate

Intratax. Intertax. Maternal defense

Mus must. CF-1 1 1 1 4 Mus must. C57 Mus must. “MO.” : : : 2 Micro. ochro. 4 6 4 3 Peromys. man. B. 2 Dnychom. leuco.

i : 1

The numbers refer to comparative status of the 6 strains with respect to the four forms of aggression listed,1 and 6 denoting the most and the least aggressive mouse, respectively.

In the case of the rodents represented in the Table, the domestic M. musculus strains show marked aggression in several tests. It is of interest that M. musculus CF-1 is highly aggressive upon isolation, both in intra- and intergeneric tests, as compared to certain wild strains as well as to M. musculus “MO.“, a comensal, i.e., M. musculus that “went wild’! This reflects the fact that aggression characterizes several inbred laboratory strains rather than rodent types that learned to exhibit discretion in their wild habitat (Karczmar et al., 1373). Yet, a rodent may not exhibit similar degree of aggressiveness in all tests - for instance, laboratory Mus strains exhibit little maternal defense and little predatory activity as compared to the wild rodents such as Onychomys (cf. Table 8). It should be added that extensive inbreeding of the laboratory mouse, M. musculus, led to development of non-aggressive strains, rather specialized in their behavioral repertories (Crispens. 1373; Denenberg, 1965; Van Abeelen, 1966; Sprott and Staats, 1575).

Many investigators (Wasman and Flynn, 1962; Rels, 1975; Pradhan, 1975) classified several forms of aggression as “emotional” or “affective”, as contrasted with p;ed;t;l;z ;x;;z;s;;;; they suggested that autonomic activation, vocalization, etc., character ze


not the latter (Reis, 1374, 1975; Reis et al., 1973; cf. also Moyer, 1568, 1576). While it is generally agreed that there may be a distinction between affective and predatory aggression, the type of aggression evoked by a given experimental paradigm is not always clear. Whereas predatory aggression seems to be elicited by certain odors, by the stimulation of lateral hypothalamus and by the presence of an appropriate prey and the affective aggression occurs upon medial hypothalamic stimulation, yet, the classification of such forms of aggression as isolation-induced as affective (Reis et al., 1973; Reis, 1975) may not be valid. The interesting point in this context is that the “emotional” mice strains such as C57B1/6J (Table 5) are relatively non-aggressive whether in pseudonatural habitat of Mouse City (see

also Southwick and Clark, 1568) or following isolation. whi ie certain “non-emotional” strains such as M. muscuius CF-1 show high degree of aggression.

Table 9

Relationship between “flexibility” and “emotional” characteristics, and various forms of aggression of small rodents

Taxon

Aggression

Maternal Isolate

“Fiexi bi 1 i ty” “Emotion” “C i ty” defense Intratax. Intertax.

Mus must. CF-1 1 4 1 4 1 1 Mus must. C57 2

2 2

Mus must. “MO.” i 1

5 : 2

Micro. ochro. 2 z Peromys. man. B. 4 5 : t

Onychom. Leuco. 5 1 5 1 5 z

The small rodents were ranked as to their “flexible” and “emotional” behavior and as to several forms of their aggressivity. Ranking was based on “emotionaiity” arid “flexibility” scores (Table 4) recorded for these rodents, the frequency of Mouse City aggression (Table 6). frequency and latency of isolation-induced fighting (Table 12) and latency of defense response (see Karczmar et al., 1973).

Furthermore, following the footshock stress, the “affective” behavior but not aggression,

is intensified (Tables 6 and 10; this post-shock behavior must be distinguished from intra- shock behavior; paired rodents fight during application of intense high frequency footshock;

Tedeschi et al., 1959). Conversely, isolation has little effect on “affective” and stereotypic behaviors measured in the Mouse City or by means of the wheel cage test.

Table 10

Effect of repetitive foot shock on “City” and cage aggression of CF-1 mice

Shocks 0 5

“City” Aqgression

20 60

Frequency of fights Ave. f S.E.

ho. of aggressive mice (>lO fighting episodes)

Ave. S.E.

30.08 f 5.3 39.2 f 6.4 39.5 + 8.0 28.6 i: 6.5

4.2 f 0.7 2.5 + 0.5 3.0 f 0.8 2.3 + 0.6*

“Cage” (isolate) aggression

Percentage of fights 13.3 11.0 6.6 11.1

“Mouse City” aggression was recorded as frequency of fighting episodes during 30 min. “City” studies and as frequency (percentage) of fighting episodes in the course of 45”-


‘!round robin” encounters (Karczmar and Scudder, 1969 b) .

c. Relationships between aggression and the two behavioral syndromes

The relationship between aggression and either “affective” or “flexible” behavior can be additionally clarified by juxtopposing the scores for “affective” and “flexible” behavior with the various aggressive behaviors of two selected mice strains (Tables 4 and 9). It can be seen that CF-1 mice which exhibit high exploratory activity and exploratory re-

flex as well as other parameters of “flexibility” show also marked aggressions of several types; conversely, C97B1/6J mice exhibiting high degree of stereotypic and wheel cage activity show little aggressive behavior. Altogether, when the six mice types illustrated in

Table 9 are arraigned in the order of decreasing frequency or intensity of “flexible” and several aggressive behaviors, it appears clear that the “flexible”, domesticated Mus strains show more aggression - except for the defense of the pups - than the wild mice (Table 3). It is of interest that Onychomys, a predatory mouse, exhibits low aggressive scores, although Onychomys mothers defend their pups vigorously (Table 9). Comparable data relating field activity and aggression were presented by others (Southwick and Clark, 1968). A work of caution must be saiu I,, this context. A particular neuroanatomical mechanism underlying a behavioral syndrome may be developed phylogenetically in an animal series, hence the relationship suggested here; however, another phylogenetic “strategy” may appear in another series of animal types. Obviously, the relationship in question will not obtain across the two animal series. Pertinent data are being obtained at this time in our laboratories.

Another aspect that deserves attention in this context is the individual, intrastrain difference in behavior including aggression. With some strains such differences are extensive; they may be related to their genetic heterogeneity (Bovet et al., 1969; Oliverio et al., 1972) or to developmental (‘&udder et al., 19671, experiential factors. It may be generalized that exploring, dominant and “flexible” mice of any strain may be also aggress- fve (Clark, 1962; Clark and Schein, 1966; Southwich and Clark, 1968; Ginsburg and Allee, 1942; Scudder et al., 1969; Karczmar et al., 1973). An interesting sideline in this context is the question of alcoholism. Alcohol-aversive mice exhibit marked aggression as compared to alcohol attracted mice whether on intra- or interstrain level (Karczmar and Scudder, 1974) . As already stated, alcohol-aversive mice may be also characterized by their “flex- i ble” behavior* thus, drinkers were found among emotional (Karczmar et al., 1977), or re-

gressive, non-&minant mice (Kahn, 1975). In fact, unfavorable behavioral experience such as repeated defeat seemed to convert initially aggressive, alcohol-aversive mice into drinkers (Karczmar and Scudder, 1974). Other investigators also stressed the non-adaptive effect of defeat experience (Scott, 1948).

3.2 Neurochemical and Neuroanatomical Aspects of Rodent Behavior

Ultimately, the behavioral profiles of aggression, the relation between aggressive and other behavioral traits, and the comparative aspects of this relationship depend on the neuroanatomical and neurophysiological organization of the pertinent brain areas as well as on the neurochemical and neurotransmitter characteristics. These two subjects will be reviewed in more detail subsequently; at this time, a brief comment pertinent for the comparative aspects of the present context will suffice.

The rodent types discussed in this article differ markedly as to the gross anatomy of their brain and neurotransmitters. The sizes of several brain parts of nine Mus and related small rodent strains were measured in this laboratory (Karczmar et al., 1973; Betti, 1969) : while major size differences were found, no clear cut relationship could be found between the sizes of the possibly pertinent structures such as hypothalamus, hippocampus or neocortex and the behavioral and aggressive characteristics of the rodent types in question; in-depth investigation of the comparative neuroanatomy and neurophysiology of the rodent types is needed in this context.

Rodent types described here differ greatly with respect to the levels of several neurotransmitter and related enzymes. Brain levels of acetylcholine. choline acetvlase, acetylcholinesterase, catecholamines and indoleamines and GABA (Karczmar et al., 1973; Tunnicliff

et al., 1973.1976: Al An1 et a1.,1970; Mandel et al.,1974; Mandel et al., 1978) vary widely between the rodent types in question; the differences become particularly prominent when brain parts such as the hypothalamus, telencephalon and pons-medulla (Karczmar et al., 1973; Eleftheriou. 1974) rather than whole brain are investigated. Among 13 small rodent


types studied in this laboratory the Mus strains which included the highly aggressive M musculus CF-1 were characterized, compared to other small rodents, by relatively low levels of acetylchoiine and of serotonin and intermediate levels of norepinephrine and dopamine (Karczmar et al., 1973). In the context of the behavioral differences between the rodent types in question the wide range of their neurotransmitter levels appears to be meaningful. In fact, the marked differences in drug response, seizure susceptibility, etc. exhibited by the strains in question were related to the differences in their neurotransmitter characteristics (Richardson et al., 1972; Karczmar, 1974; Maynert et al., 1975). However, the levels

of neurotransmitters may be not as pertinent as their turnovers as the latter reflect the activity of the neurons of the various neurotransmitter systems. Unfortunately, only preliminary data are available on scnne of the strains in question; they appear to be quite inconsistent. DBA/2J and SEC/ReJ strains exhibiting high learning capacity and certain other traits indicative of “flexibility” as per our terminology, were characterized by Mandel et al. (1974) as exhibiting higher choline acetylase levels and thus, possibly, higher acetylcholine turnover values as compared to poor learners; however, Ho and Kissfn (1975) found no differences of choline acetylase activity between these strains and Tunicliff et al. (1973) obtained inverse relation between locomotor activity and choline acetylase concent-

ration in 7 mice strains. A strain of rats characterized by good learning capability and high motor activity differed little with respect to norepinephrine and dopamine turnover, compared to a less well “endowed” strain (Ray and Barrett, 1975)) whereas Tunicliff et al. (1973) found a positive relation in 7 mice strains between MAO and catechol O-methyltrans-

ferase (COMT) on the one hand and learning and motor activity on the other. However, Segal et al. (1972)found an inverse relationship between midbrain tyrosine hydroxylase activity and spontaneous motor activity in six rat strains. Ray and Barrett (1975) found also that active, fast learning rats exhibited higher turnover of serotonin and greater increase in the catecholamine turnover following stress compared to the poor learners. Furthermore, those Sprague-Dawley rats that exhibited high intra-species aggression were characterized by high serotonin turnover (Daruna and Kent, 1976). However, as will be seen later, serotonergic neurons may be concerned with blockade of aggression.

3.3 Genetics and Aggressive Behavior in Rodents

Genetic control of aggression is well documented for animals (cf. Thiessen 1976) and, on less general basis, for man (Money and Ehrhardt, 1972; Jervik et al., 1973). It is well known that, among small rodents, inbreeding techniques may be used to obtain or increase aggression (Craig et al., 1965; Lagerspetz, 1961; Lagerspetz and Lagerspetz, 1971). Two such strains C57B1/6J and CF-1 (for the pedigree of these strains see Green, 1968) were used in the present study: as in the case of other investigations (Southwick and Clark, 1966, 1968; Bourgault et al., 1963; for other references, cf. Thiessen et al., 1976) we found that the mice of these strains are highly aggressive (cf. Table 8). In the case of other mice genera and types studied at this time inbreeding was not carried out to a degree sufficient to establish the relationship, if any, between the genetic make-up and aggression, The genera such as Peromyscus or Microtus (cf. Table 8) may be considered as having

a genetic pool which is not homogeneous for aggression but which is balanced in a way such that their aggressive characteristics are relatively stable under testing conditions; to an even greater extend this is true for the wild mouse type. mus Musculus Missouri (“MO.“; Table 7). In the case of these mice types there is considerable interplay between nature and nurture (Barnett, 1972); for instance, Onychomys is a desert form living in arid conditions of Arizona; consequently, it may exhibit herbivorous or omnivorous habits depen- ding on conditions and it may readily exhibit predatory and other forms of aggression under certain circumstances (Clark, 1962; Karczmar et al.. 1973). This then points out to the environmental and other factors - such as diurnal rhythms or hormonal influences - that may overshadow or mask the genetic control of aggression. Yet, certain behavioral characteristics, presumably genetically controlled, may increase even in the field conditions, the genetic homogeneity related to aggression. For instance, when dominant and non-dominat male are released onto female populations in field conditions, mating homogeneity will result as only dominant males will mate; this may result in a genetically relatively pure population exhibiting high degree of territorial defense and aggression (Selander and Yang, 1970; Horn, 1974).

Similarly, genetic control underlies neurochemical differences exhibited by various rodent genera (cf. Karczmar et al., 1973; Eleftheriou, 1974; Mandel et al., 1974; Thiessen,

1976). In fact, rodent types can be inbred for the selection of neurochemical parameters such as bioamine levels and turnover(Mande1 et al., 1974; Everett, 1973). It is of particular interest that, in such cases, the genetic factors that control bioamine kinetics may


also be linked with specific behaviors; in such cases, the genetic control of behavior operates presumably via the pertinent neurochemical mechanisms. This appeared particularly clear in the case of genetic regulation of seizure threshold (Everett, 1973; Karczmar, 1974) and, perhaps in that of certain other behaviors (Mandel et al., 1974; Mandel et al., 1978). Frequently, however, inbreeding produces a breakdown of the original relation between a given behavior and its neurochemical concomitants. For example, inbreeding of C57Bl/By mice for high levels of hypothalamic norepinephrine (Eleftheriou,l974) may select out the gene or genes regulating aggression, as we have found that these mice do not exhibit isolation- induced aggression which is characteristic for the parent strain (Richardson and Karczmar, unpublished). This phenomenon may explain why a strain exhibits in different laboratories differing degrees of aggression (as for instance Balb-c strain, cf. Vale et al., 1971 and Southwick and Clark, 1966), as this variation may depend on the degree of inbreeding of the strain used by the various investigators.

Altogether, while the genetic control of certain forms of aggression as well as of certain neurochemical parameters is well established, it is difficult at this time to validate the hypothesis that a parallel change in aggression and in specific neurochemical characteristics may occur upon genetic manipulation; in fact, results contrary to readily adduced (Goldberg et al., 1973; Karczmar et al., 1979). What cates the matter independently of the problem of the genetic coupling istry and aggression, is that the neurochemical profile of aggression defined today.

4.GENERAL CHARACTERISTICS OF AGGRESSION

4.1 Neuroanatomical and Neurophysiological Findings

such concept can be additionally compli- between neurochem- cannot be readily

The main brain sites involved in various forms of aggression are limbic areas including prepyriform cortex and olfactory bulb, hypothalamus, and certain efferent midbrain and brainstem areas such as tegmentum and median forebrain bundle (for review, cf. Flynn, 1972; Pradhan, 1975; Moyer, 1976; Myers, 1974). On the whole, aggression depends on and can be facilitated or initiated by, the stimulation of hippocampus, amygdala, anterior, posterior and lateral hypothalamus, stria terminals and ventromedlal midbrain tegmentum. As recently proposed (Karli, 1972; Pradhan, 1975), aggression 1s mediated by a descending pathway oriq- inating wlth the limbic hfppocampal-amygdaloid system and related cortical areas_(cingulate cortex), coursing down lateral hypothalamus, and ending with the efferent structures such as median forebrain bundle and ventral and ventromediai tegmentum. Modulatory and inhibit- ing influences are exerted via olfactory bulb and pre-pyriform cortex upon the lateral hypothalamus (Paxinos, 1975) and via the mesencephalic central grey or periventricular system upon the median forebrain bundle and the tegmentum. Also the caudate exerts inhibitory influences (Hull et al., 19671, possibly via the caudate loop and its limbic connections (Buchwald et al., 1961).

It must be pointed out that the systems in question are not solely concerned with aggression. Thus, caudal and septal stimulation may cause arrest of ongoing behavior whether the latter is aggressive or not (Karczmar, 1976, 1977). Similarly, hypothalamic structures are also concerned with motor activities directed at ingestive and energy conserving behavior (Myers, 1974). while amygdala is involved in a number of ingestive, social and maternal activities(Gloor, 1975). Finally. these and related cortical structures such as temporal lobe are also concerned with sexual activity (Karczmar, 1975a, b; 1976).

It was already mentioned that several limbic sites may control differentially defensive,. predatory, and affective aggressive activities. In fact, not all sites of the limbic system are concerned with emotional behavior and affective aggression as could be expected on the basis of concepts of Papez (1937) and MacLean (1970). For instance, certain hypothalamic sites evoke predatory rather than affective stimulation (Flynn, 1972), various nuclei of amygdaia may be concerned differentially with irritable, predatory or affective aggression (Ursin and Kaada, 1960; Moyer, 1976). whereas temporal lobe and its reciprocal connection with the iimbic system may relate to fear and defensive mechanism as well as to affective rage (Mark et al., 1969). Final iy, it should be emphasized that the above findings are not relevant to animals only: particularly the contribution of amygdala and temporal lobe to human affective and aggressive reactions is well known (Kluver and Bucy, 1939; Gloor. 1975).


4.2 Pharmacology of Aggression. The Neurotransmitter Mechanisms.

This discussion of pharmacology of aggression is restricted to drugs acting presumably via neurotransmitter mechanisms. The well-known relation of steroid hormones to aggression - and to sexual behavior - and, the pharmacology of antiaggressive drugs such as benzo- diazepines will be not reviewed (Moyer, 1576).

a. Cholinergic mechanism

Cholinergic agonists and antagonists exert dependable and consistent aggressive effects when applied to the limbic and related structures described above. In fact both “affective” and predatory types of aggression could be elicited by localized appliiation of cholinergic, particularly muscarinic, agonists and anticholinesterases (Table 11).

Table 11

Relation between several forms of mouse aggression and neurotransmitters

Type of aggression Action and interaction of neurotransmitters

A. Affective or ACh (Ag) -- NE (Ant) dipole; paradoxical ACh following isolation turnover phenomena

DA as Ag (paradoxical effects of DOPA and

6-OHDA) 5-HT as Ant GABA as Ant

B. Predatory ACh (Ag) -- NE (Ant) dipole 5-HT as Ant

C. Irritable DA as Ag

Ag=Agonist; Ant=Antagonist. The data refer generally to the effects on aggression (Ag=agonist. Ant=antagonist) of intracerebral injection of serotonin (5-HT) or serotonergic

drugs, norepinephrine (NE) and dopamine (DA) or dopaminergic drugs, acetylcholine (ACh) or choiinomimetic drugs, and GABA or gabaminergic drugs (see Pradhan, 1975 and Karczmar, 1978).

Conversely, several types of aggression could be blocked by localized as well as systemic application of anticholinergics, generally of atropinic rather than curaremimetic type; in some cases, however, curaremimetics also produced a response (in animals not pretreated

with cholinergic agonists) that could be construed as inhibition of endogenous aggressive drive (Decsi and Karmos-Vorszegi, 1363; Romaniuk et al.. lq73a, b; Yoshimura and Ueki, lq77; for further references, cf. Allikmets. 1974; Pradhan, 1975; Myers, 1974; Reis, 1974; Valzelli. 1971. 1374a, b; Karczmar, 1376, 1977). The agonistic effects in question ras- embled or were identical with, those produced by electric stimulation of the pertinent limbic structures (Allikmets, 1974; Baxter. 1967: Pradhan, 1975: Myers, 1974). It should be

added that, besides eliciting various forms of aggression cholinergic agonists facilitated muricidal behavior (McCarthy, 1966; Avis, 1974) and isolation-induced aggression (Karczmar and Scudder. 1969 b; Karczmar et al.. 1973), while atropinics given intracerebrally (particularly into hypothalamic regions) or systemically blocked isolation-induced and muricidal aggression, as well as several forms of electrically-elicited aggression.

In view of inhibitory influences on aggression that could be induced by electric stimulation of the septum and certain hypothalamic areas, it is of interest that such actions were generally not induced by localized application of cholinergic agonists to these structures. However, isolated instances of block of aggression following septai appiic- ation of chollnergic agonist (Sodetz. et al., 1967); Moyer, 1968) or following septal lesions (Stark and Henderson, 1972) were reported. Also, cholinergic agonists and anticholinesterases induced sometimes biphasic actions (Karczmar and Scudder, 1363). Further- more, cholinergic agonists may block aggression elicited by dopaminergic stimulation (Gianutsos and Lal, 1977). It should be also pointed out that the caudate, the olfactory lobe and the periventricular grey, areas involved in inhibition of ongoing behavior, were

not studied with respect to the effect of cholinergic agonists on aggression.

624 A. G. Karczmr et at.

Altogether, much evidence may be adduced in support of Myers’ (1974) comment that the aggression-related amygdalo-fugal trajectory which includes several limbic structures, the fornlx being the key pathway, may be preponderantly cholinergic.

b. Catecholaminerglc mechanisms

Catecholaminergic actions on aggression were studied in less detail and the results are inconsistent (Table 11). At hypothalamic sites, catecholamines and related drugs blocked

cholinergfcally Induced aggression or rage (Decsi, 1969). They seem to have inconsistent effects on predatory behavior (Bandler, 1971; Horowitz et al., 1965; Reis, 1974). although the majority of investigators consider noradrenergic agonists as blocking predatory behavior. Even more inconsistent effects were those on foot-shock or isolation-induced aggression (Pradhan, 1975; Karczmar, 1977, 1978). Dopaminergic agonists may exert more consistent actions (Table 11); dopaminergic agonists such as apomorphine and amantadine, and L-dopa with or without MAO inhibitors produced or facilitated spontaneous aggression and facilitated isolation-induced aggression (Senault, amlnergic antagonists (Myers, 1974; Pradhan,

1971), these effects being antagonizable by dop- 1975); L-dopa and dopaminergic agonists exerted

similar effects in man (Rizzo and Morselli, 1972). It must be, however, pointed out that DOPA and dopaminergic agonists may induce irritability (Everett, 1961, 1975) rather than predatory aggression or-aggression resembling that induced by isolation and directed, teleologically, at animal objects. I ndeed, in the pseudonatural habitat of the Mouse City, DOPA alone or DOPA with an MAOI inhibitor inhibited the spontaneous aggression (Karczmar and Scudder, 1969 ; Karczmar et al ., 1973). In fact, under these circumstances, catecholaminergic and dopaminergic agonists induced stereotypic behavior that interfered with motiv- ation for or overt expression of, aggression.

c. Serotonergic mechanism

The effects on aggression of localized brain administration of serotonin or serotonergic agonist and antagonists were not studied extensively. Applied to the amygdala, serotonin did not induce aggression in the cat (Allikmets et al., 1969). When serotonin was given systemically or when its levels were increased by appropriate pharmacological maneuvers, the muricidal activity and irritability (induced for instance by DOPA administration) were blocked (Pradhan, 1975). Conversely, inhibition of serotonin synthesis by PCPA facilitated footshock-induced fighting; however, this was not an unanimous finding (Pradhan, 1975). Similarly, effects of PCPA on isolation-induced fighting and on other forms of aggression were not consistent. Altogether,however, the available data suggest that serotonin acts as inhibitor of aggressive activities (Sheard et al., 1977) including ethological aggression; the administration of the serotonin precursor, 5-hydroxytryptophan, decreased Mouse

City fighting and this effect was potentiated by pretreatment with MAO inhibitors, these anti-aggressive phenomena being accompanied by increased brain serotonin levels (Karczmar et al., 1973; Richardson, 1971).

d. Other neurotransmitters

That other transmitters related substances may also affect aggression becomes progress-

ively apparent. GABA is one such substance, (Table 11; Brody et al., 1969).

as it inhibited footshock-induced aggression

e. Neurotransmitter Turnover and Aggression

On the whole, these results may suggest that cholinergic and dopaminergic activation may’ be related to aggression, noradrenergic neurons may be less involved in control of aggression and that serotonergic and, possibly, gabaminergic activities are inhibitory to aggression (Pradhan, 1975; Reis, 1974; Aliikmets. 1974). Accordingly, turnover of the neurotrans-

mitters should exhibit appropriate changes in suitable paradigms. Unfortunately, insuffic- ient data are available at this time; sometimes the pertinent-results are inconsistent with the expectations.

Perhaps most dependable data are those concerning the turnover of serotonin. Isolation decreased serotonin turnover in brain parts and in the whole brains of mice: this effect was not noticed in the strains of mice that do not show isolation-induced aggression (Garattini et al., 1967; Valzelli et al., 1974a, b; Valzelli, 1977). Muricidal activity was related to decreased serotonin turnover and decreased tryptophan hydroxylase activity (o.c.); it was


induced by inhibition of serotonin synthesis (Miczek et al., 1375). Yet, it must be pointed out that procedures used to evaluate serotonin turnover were not most approprlate, and that certain data (Kostowski and Vaizelli, 1974; Modigh, 1973, 1374) are not consistent with the findings reported; for instance, lesions of central serotonergic pathwa

r s abolished rather

than increased, post-isolation aggression (Kostowski and Vaizeili, 1374 .

The data concerning norepinephrine appear to be even less conclusive. Norepinephrine turnover was found to be increased in “killer” compared to normal rats; it was elther not affected or decreased by isolation (Goldberg et al., 1973; Vaizelll, 1974a, 1977; Pradhan, 1975) * The turnover of dopamine In aggressive animals was not studied extensively; Modigh (1373, 1574) reported that isolation increased dopamine turnover. Finally, GABA turnover

and binding may be attenuated in aggressive as compared to non-aggressive mice (DeFeudis et al., 1576; Earley and Leonard, 1977). and GABA kinetics may be inversel,y related to and- rogens in the pertinent tests (Eariey and Leonard, 1577).

In view of the consistent and dependable agonist action of choiinergic drugs on manyforms of aggression(vide supra), the relation between acetylcholine turnover and aggression be-

comes particularly interesting.lsolation did not affect markedly choline acetyiase (Consoio and Valzelii, 1570) and may actually decrease acetylchoiine turnover (see Table 12, cf. also Karczmar, 1376) and the relation between acetyicholine synthesis and murlcidal behavior seems inconsistent (compare Ebei et al., 1373; Yoshimura and Ueki, 1377). In this laboratory we were interested in this context in coupling of isolation and footshock stress. it was already pointed out that following the footshock stress spontaneous aggression is not induced or facilitated among aggregated mice whether caged or placed in the Mouse City habitat; however, we found that isolation-induced aggression is potentiated by subsequent footshock stress whether tested in caged mice or in the Mouse City (Table 12). Thus, the appropriate effects of these two paradigms, used single and in combination, on acetyicholine turnover would constitute a potent argument in favor of the relationship between acetyicholine turnover and aggressive states.

Table 12

Effects of isolation and stress on aggression, acetylcholine levels and turnover

Fighting latency Percent fights ACh levels Turnover of ACh Paradigm in % of controls

Ba 1 b-c- C57B1/6 B lb- C57Bl Ba 1 b- in X of -01s

c57ei CF-1 By BY CF-1 caBy /6By CF-1 -c-By /6Bv

Balb- C57Bl CF-1 c-Bv /f&v

Controls

‘;:::z; 100 100 100

>300 >600 >600 8 0 0 t7.5 A4.95 -18.99 100 100 100

3 weeks isol- 95.24 133.72

ation 82+20 587~1.1 ~600 95.5 4.5 1.1 f 4.4 + 5.2 - 76.59 89.40 -

“Stressed” Aggre- gatesc6' 109.15 112.33 102.5 shocks) 270+38 *600 >600 13 0 o f 4.24 f 7.43 +4.47 48.83 82.78 157.90

“Stressed” Isolates (3 weeks Isolation 80.24 129.06

+60 60+15 466k34.3 412t282 100 29 21 k4.56 f 6.4 - 69.24 84.07 - shocks)

Acetylcholine was measured by the method of Haubrich (1373) following microwave oven sacrifice (Stavinoha and Weintraub, 1974: Stavinoha et al., 1973). choline was calculated as described by Jenden et al. (1974).

The turnover of acetyl- For methods employed in mea-

suring fighting latency and frequency (percent fights). see Karczmar et al., 1573, Karczmar et al.. unpublished.

626 A. G. Karczmar et al.

The two paradigms, when combines, facilitated aggression of ,the aggressive (in the Mouse City or following isolation) CF-1 mouse strain and induced it in the case of two non- aggressive strains (Balb-c-By and C57Bl/6By); yet, there was no parallelism between aggressive behavior on the one hand and the change in acetylcholine levels or turnover on the other. In fact, the turnover decreased with either paradigm in CF-1 and Balb-c-By strains (it increased following stress in C57Bl/6By mice; Table 12). It is of interest in this

context that the decrease of the turnover and the synthesis of acetylcholine by hemicholln- iums was associated with increased aggressiveness of rats (Freeman et al., 1975). Severa 1 other inconsistent results pertinent in this context were reviewed recently (Karczmar, 1976) .

5. CONCLUSIONS

It is apparent from this review that related animal forms differ widely as to several forms of aggressive activities that they may exhibit. It is also apparent that these differences are genetically controlled, as obvious from inter-strain investigations of related forms and of the results of crossover studies. Furthermore, related rodent forms vary widely with regard to several neurotransmi tters; the differences in question are also genetically determined (Everett, 1975; Mandel et al., 1974; Mandel et al., 1978).

It is further obvious that when related animal forms exhibit high level of aggression, the latter constitutes a component of a general profile or behavioral syndrome exhibited by the animals in question. As shown mainly by studies carried out in pseudonatural habitats, high motor, exploratory and food-related activities as well as good learning capacity compose one such syndrome (“flexible” prof i le) , the mice in question exhibiting high level of several types of instrumental and societal aggression; other paradigms show also a relationship between sexual and aggressive activity (Karczmar, 1975a). This coupling between ingestive and sexual activity on the one hand and certain types of aggression on the other

may be of special interest. Another syndrome, termed “emotional’ or “affective” , is not associated with the same types of aggression, although it may be linked with predatory aggression. That this relationship between a given behavioral syndrome and aggression may obtain for some related animal types but not for others was emphasized.

The findings show also that a number of limbic areas (amygdalo-fugal pathway) and also related cortical and mesencephalic structures are involved in aggression; it is consistent with the concept presented above that these structures are also involved in energy conserv- ation and ingestion (Myers, 1974; Myers and Wailer, 1975) and in sexual behavior (Karczmar, 1977, 1978). Unfortunately, characteristics of synaptic organization and circuitry that may underlie genetic differences between aggressive activities of related rodent forms are not known at present. That neurotransmitters also constitute the basis of the differences in question is strongly suggested by the data presented. Yet, inconsistencies are abound; even in the case of the cholinergic system which is clearly implicated in several forms of aggression and which is an important component of the amygdalo-fugal pathways (Myers, 1974) paradoxical findings could be adduced. Altogether, the importance of cholinergic system for a behavioral profile that includes several forms of aggression is consistent with the specific characteristics of the CNS role of the cholinergic system; this concept was reviewed elsewhere (Karczmar, 1975b, 1976, 1977, 1978; Karczmar and Dun, 1978).

Acknowledgements

Published and unpublished investigations carried out in these laboratories and referred to in this paper were supported in part by National Institutes of Health Grant NSO6455, and GM77. and the VA Grant 4830.

Inquiries and reprint requests should be addressed to: Dr. A.G.Karczmar Department of Pharmacology Loyola University Medical Center 2160 S. First Avenue Maywood, Illinois 60153, USA


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Neuropharmacological and related aspects of animal aggression

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