Neural control of predatory aggression in wild and domesticated animals.

The neural mechanisms of predatory aggression in laboratory animals were investigated in a variety of rodents and members of the order Carnivora. Experimental enhancement of brain serotonin (5-HT) blocked killing behavior in rats, mice, mink and silver foxes, indicating that there is a 5-HT inhibiting mechanism of predatory aggression in animals of different species. Suppressed killing behavior, at least in some strains of mice, does not depend for expression on the inhibitory effect of the brain 5-HT system, but is caused by the low tonus of the system activating predatory behavior. Long-term satiation of mink increased the level of 5-hydroxyindole acetic acid in the lateral hypothalamus and amygdala and enhanced the latency of predatory aggression. It is suggested that 5-HT represents a dietary responsive endogenous factor regulating predatory behavior in carnivores. Selection of Norway rats over many generations for tamed behavior towards man (domestication) leads to an increase in level and turnover of 5-HT in the midbrain and hypothalamus, but does not change predatory aggression. Substantially reduced defensive behavior of domesticated rats is thus unconnected with the neural mechanism of predatory aggression.

Long-term behavioral and neuronal cross-sensitization to amphetamine induced by repeated brief social defeat stress: Fos in the ventral tegmental area and amygdala.

Repeated exposure to stress induces cross-sensitization to psychostimulants. The present study assessed functional neural activation during social defeat stress-induced sensitization to a subsequent amphetamine challenge. Social defeat stress was induced in intruder rats during short confrontations with an aggressive resident rat once every third day during the course of 10 days. Rats received d-amphetamine injections (1 mg/kg, i.p.) 17 or 70 days after the first social defeat stress exposure. Amphetamine administration induced a significantly higher frequency of locomotor activity in stressed animals than in handled control rats, which was still evident 2 months after the last social stress exposure. Immunohistochemistry for Fos-like proteins was used to detect activated neural profiles in the striatum, nucleus accumbens (NAc), prefrontal cortex, amygdala, and ventral tegmental area (VTA). Repeated social defeat stress significantly increased Fos-like immunoreactive (Fos-LI) labeling 17 days after the start of stress exposure in the prelimbic and infralimbic cortical regions, NAc shell and core, medial, central and basolateral amygdala, and VTA, which probably represented the expression of chronic Fos-related antigens. Amphetamine augmented stress-induced Fos-LI labeling 17 days after the first stress episode in the dorsal striatum, NAc core, and medial amygdala, reflecting a cross-sensitization of Fos response. Amphetamine challenge 70 days after social stress exposures revealed sensitized Fos-LI labeling in the VTA and the amygdala. These data suggest that episodes of repeated social stress induce a long-lasting neural change that leads to an augmented functional activation in the VTA and amygdala, which might represent a neurobiological substrate for long-lasting cross-sensitization of repeated social defeat stress with psychostimulant drugs.

Role of genotype and dopamine receptors in behaviour of inbred mice in a forced swimming test.

The role of genotype in the effects of selective D1 and D2 dopamine agonists and antagonists on behavioural despair (Porsolt's test) was studied. Mice of nine inbred strains showed significant interstrain differences in duration of immobility. The influence of dopaminergic drugs was assessed in six strains characterized by different levels of swimming activity. SKF 38393 (10 mg/kg), an agonist at D1 dopamine receptors, increased swimming activity, while the D1 antagonist SCH 23390 (0.2 and 0.5 mg/kg) reduced it, the effects being genotype dependent. The involvement of D2 dopamine receptors in the regulation of mouse behaviour in the forced swimming test was not so evident; the D2 agonist bromocriptine (10 mg/kg) produced no significant effect. The D2 agonist quinpirole (2.5 mg/kg) increased immobility in the majority of the mouse strains studied, while in CBA mice it resulted in a marked reduction of immobility. The D2 antagonist sulpiride (20 mg/kg) decreased immobility and increased active swimming only in two strains. The present results suggest a different role for D1 and D2 dopamine receptors in the regulation of swimming in the mouse.

Zolmitriptan--a 5-HT1B/D agonist, alcohol, and aggression in mice.

RATIONALE: Zolmitriptan is an anti-migraine agent with action at 5-HT1B/D receptors. It penetrates into the central nervous system and, like other 5-HT1B/D agonists, its pharmacotherapeutic profile may include significant anti-aggressive effects. OBJECTIVES: To examine whether zolmitriptan has potential anti-aggressive effects by studying two kinds of aggressive behavior in mice--species-typical and aggression under the influence of alcohol. A second objective was to study whether pre- or post-synaptic receptors mediate these anti-aggressive effects. METHODS: Initially, the anti-aggressive effects of zolmitriptan were studied in male CFW mice during 5-min resident-intruder confrontations. To confirm the 5-HT1B receptor as a critical site of action for the anti-aggressive effects, the zolmitriptan dose-effect determinations were repeated after pretreatment with GR 127935 (10 mg/kg, i.p.). In further experiments, mice were treated concurrently with alcohol (1.0 g/kg, p.o.) and zolmitriptan (1-30 mg/kg, i.p.) in order to compare the effects of this agonist on species-typical and alcohol-heightened aggression. Finally, mice were infused with the neurotoxin 5,7-DHT (10 microg) into the raphé area to eliminate somatodendritic and presynaptic autoreceptors. The anti-aggressive effects of zolmitriptan (17 mg/kg, i.p.) or CP-94,253 (10 mg/kg, i.p.) were assessed 10 days after the lesion, and levels of 5-HT and 5-HIAA were measured in the hippocampus and prefrontal cortex. RESULTS: Zolmitriptan exerted behaviorally specific anti-aggressive effects. The reduction in aggression was antagonized by GR 127935, indicated by a rightward shift in the dose-effect curves of zolmitriptan, showing the specificity for the 5-HT1B receptors. Zolmitriptan also decreased alcohol-heightened aggression with equal efficacy. The anti-aggressive effects of CP-94,253 and zolmitriptan remained unaltered by 5,7-DHT lesions that depleted cortical and hippocampal 5-HT by 60-80%. CONCLUSIONS: Zolmitriptan proved to be an effective and behaviorally specific anti-aggressive agent in situations that engender moderate and alcohol-heightened levels of aggression. These effects are potentially due to activation of post-synaptic 5-HT1BD receptors.

Social defeat stress increases expression of mu-opioid receptor mRNA in rat ventral tegmental area.

Prompted by previous studies linking social defeat stress to changes in opioid antinociception, we evaluated the expression of mu-opioid receptor (MOR)-encoding mRNA in selected rat brain areas as a function of this type of stress. Because opioids mediate significant regulatory activities of brain dopamine neurons, dopaminergic loci in the ventral tegmental area (VTA) and substantia nigra (SN) were selected for analysis. Within 30 min after social defeat stress, the level of MOR-encoding mRNA, as detected and quantified by in situ hybridization histochemistry, increased in the lateral VTA and this increase was present for at least 6 h. In contrast, defeat stress was without effect on the expression of MOR-encoding mRNA in the SN. These data suggest that stress-induced alteration of MOR-encoding mRNA expression in the VTA may be involved in the consequences of social defeat stress.

Behavioral sensitization to cocaine after a brief social stress is accompanied by changes in fos expression in the murine brainstem.

The objective of the present study was to determine how c-fos gene expression in brainstem structures after a brief episode of social defeat stress is related to behavioral sensitization to cocaine challenge. Social stress was defined as defeat in a brief confrontation with an aggressive resident mouse and subsequent 20-min exposure to the resident's threats behind a protective screen. Mice were treated with cocaine (40 mg/kg, i.p.) immediately or 1 week after social defeat stress. Fos-like immunoreactive (Fos-LI) cell nuclei were analyzed in the ventral tegmental area (VTA), dorsal raphe nucleus (DR), periaqueductal grey area (PAG) and locus coeruleus (LC). One episode of social stress induced behavioral sensitization to cocaine as indicated by an augmented locomotor response to a challenge injection 7 days after a single defeat. In naive mice, social stress markedly increased the number of Fos-LI nuclei in the DR, PAG and LC, but not in the VTA. Similarly, cocaine administration resulted in a significantly increased number of Fos-LI nuclei in the same areas. Administration of cocaine immediately following social defeat significantly reduced the number of Fos-LI nuclei in the DR, PAG and LC. Cocaine-induced Fos expression returned in the PAG and DR, but not in the LC, 1 week after social stress. In conclusion, the present results suggest that the presence of brainstem Fos be related to the ability to express stress-induced behavioral sensitization to cocaine.

Strain differences in clonidine-induced aggressiveness in mice and its interaction with the dopamine system.

The influence of a genotype of inbred mice on the aggressive behavior induced by clonidine and the role of dopamine D1 and D2 receptors in that behavior were studied. Clonidine in a dose of 10 mg/kg evoked a strong aggressiveness in BALB/c, DBA/1, and CC57Br mice and an intermediate response in C57BL/6J, Albino Swiss, and CBA mice, whereas DD, A/He, and C3HA/y mice did not show any aggressive behavior. Apomorphine significantly potentiated the clonidine-induced aggressiveness in C57BL/6J mice. In Albino Swiss mice, SK&F38393 as well as quinpirole augmented the aggressive behavior evoked by clonidine. The clonidine-induced aggressiveness was blocked by SCH23390 and cis-flupentixol but not by (-)-sulpiride. In aggressive mice, the binding of [3H]SCH23390 was decreased in the limbic forebrain, whereas the binding of [3H]spiperone was not changed. The obtained results indicate that the potency of the clonidine-induced aggressiveness depends upon genotype of mice; moreover, the presence of a physiological function of D1 receptors is necessary for its occurrence.

Dopamine D1 and D2 receptor ligands modulate the behaviour of mice in the elevated plus-maze.

To further our understanding of the potential role of dopamine in mechanisms of anxiety, the effects of four dopamine receptor ligands were examined in an ethological version of the murine elevated plus-maze test. The D1 receptor partial agonist, SKF 38393 (2.5-20.0 mg/kg), had minimal behavioural activity in this test, whereas the selective D1 receptor antagonist, SCH 23390 (0.025-0.2 mg/kg), had dose-dependent but behaviourally nonspecific effects. Quinpirole (0.0625-0.5 mg/kg), a D2 receptor agonist, had no effects at low doses but severely disrupted locomotion and exploration at the highest doses tested. In marked contrast to the lack of effect or nonspecific effects seen with the other ligands tested, the D2 receptor antagonist, sulpiride (2.5-20.0 mg/kg), produced an unambiguous anxiolytic-like profile under present test conditions. Although none of the doses tested adversely affected general activity, clear antianxiety effects were observed on both traditional and novel (i.e., risk assessment) behavioural measures. Data are discussed in relation to the relative importance of D1 and D2 receptor mechanisms in plus-maze anxiety, and the need to further assess D2 involvement through the use of more selective compounds.

Role of genotype in brain dopamine metabolism and dopamine-dependent behavior of mice.

In mice of eight inbred strains--BALB/c, AKR/J, DBA/2, CBA, C57B1/6, DD, CC57Br, and C3H/He--brain dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in striatum and nucleus accumbens with tuberculum olfactorium, the structures of two main dopaminergic systems--nigrostriatal and mesolimbic--were determined. In both dopaminergic regions, no strain effect on either dopamine or DOPAC levels was found, while for HVA content a highly significant hereditary determination was shown. Influences of selective D1 and D2 dopamine receptor agonists--SK&F 38393 and quinpirole, respectively--as well as that of a mixed D1/D2 agonist, apomorphine, on general locomotor activity and stereotypic climbing were studied. By that, marked genotypic differences in dopamine-dependent behavior and dopamine receptor sensitivity were observed. Although both SK&F 38393 (5 mg/kg) and apomorphine (0.25 mg/kg) decreased locomotion, the effect being genotype dependent, in all strains of mice quinpirole (2.5 mg/kg) proved more potent in locomotor inhibition. SK&F 38393 (10 mg/kg) induced climbing, but 2.5 mg/kg apomorphine in most strains was much more effective. At the same time, quinpirole (up to 8 mg/kg) failed to induce this behavior. This suggests the crucial role of D1 receptors in the generation of climbing, attracting, at the same time, attention to the importance of D1/D2 interaction. The observed drastic interstrain differences in dopamine receptor sensitivity demonstrate the essential role of genotype in the effects of dopaminergic drugs.

Dopaminergic brain system in the quaking mutant mouse.

Quaking mice (qk/qk), autosomal recessive mutants with central nervous system dysmyelinization, characterized behaviorally by abnormal locomotion and tremor, are found to have altered brain dopaminergic system parameters, in comparison with phenotypically normal heterozygous littermates. Dopamine metabolism is enhanced in structures of both nigrostriatal and mesolimbic systems, as revealed by increased metabolites content (that of homovanillic acid in striatum and concentration of 3,4-dihydroxy-phenylacetic acid in nucleus accumbens with tuberculum olfactorium) along with unchanged neurotransmitter levels in qk/qk mice. D1 and D2 receptor analysis via radioligand binding using [3H]-SCH 23390 and [3H]-spiperone, correspondingly, showed an increase of D2 receptor density with decreased affinity to D2 ligand in striatum of mutants: both Bmax and Kd were markedly higher. D1 and D2 receptor sensitivity in the quaking mouse was also altered. Stimulation of D1 receptors by a highly specific agonist SKF 38393 (2.5 and 5 mg/kg) decreased locomotor activity only in mutants, but not in controls. In contrast, qk/qk were less sensitive than phenotypically normal qk/+ mice to a selective D2 dopamine receptor agonist, LY 171555 (quinpirole, 1 and 2.5 mg/kg). The alterations found in the brain dopaminergic system of qk/qk mice may be responsible for the behavioral expression of this neurologic mutation.

Behavior, adrenocortical activity, and brain monoamines in Norway rats selected for reduced aggressiveness towards man.

Wild Norway rats were selected over 20 generations for reduced aggressiveness towards man. Selection for this characteristic was accompanied by many physiological changes. Although neophobia was significantly inhibited, and irritable aggression reduced by selection, no changes were revealed in mouse-killing behavior or in intermale aggression. The mean level of 5-hydroxyindole acetic acid in the hypothalamus as well as serotonin (5-HT) content in the hypothalamus, the midbrain and the cortices was higher in the 'domesticated' than in aggressive rats. Mean hypothalamic norepinephrine (NE) level also tended to be higher in the 'domesticated' animals. The resting corticosterone level and the response of the hypothalamic-pituitary-adrenocortical axis to an emotional stressor or intracerebroventricularly administered 5-HT or NE were decreased in domesticated rats compared to their aggressive counterparts. It is suggested that the diminution of the hypothalamic-pituitary-adrenocortical function as a result of selection for domesticated types of behavior depends, at least partly, on changes in brain monoaminergic systems.

Experimental studies on genetically determined predisposition to catatonia in rats as a model of schizophrenia.

To check experimentally the hypothesis of schizophrenia being a manifestation of extremely low threshold of hypnotic (catatonic) type of reaction, changes of some neurophysiologic and neurochemical systems in rats with a genetic predisposition to catalepsy were compared to analogous changes found so far in schizophrenia or chronic amphetamine intoxication considered nowadays as the most adequate pharmacological model of schizophrenia. It is found that in rats predisposed to catalepsy the threshold of audiogenic seizures is elevated; the activity of tryptophan hydroxylase in striatum is higher in rats predisposed to catalepsy genetically and due to a chronic methylphenidate intoxication as compared to control animals; noradrenaline content and noradrenaline/dopamine ratio is lower in the diencephalon of rats predisposed to catalepsy than in controls; cataleptic rats have a higher content of homovanillic acid in N.accumbens , and a higher frequency of inversion of hemispheric asymmetry as estimated by levels of dopamine and dioxyphenylacetic acid in N.accumbens and caudate nucleus, than normal rats; MAO-B/MAO-A ratio is higher in the brain stem of cataleptic than normal rats. The effects of haloperidol and apomorphine on motor activity of cataleptic and normal animals point to a higher sensitivity of postsynaptic dopamine receptors in the former. Conditioned avoidance reaction is formed slower, but preserved longer in rats predisposed to catalepsy. Blood serum of wild rats predisposed to akinetic catatonic reactions, unlike the serum of normal wild rats, inhibits the electric activity of snail neurons. The above indicated changes are analogous to those known to be present in schizophrenia and/or chronic intoxication with amphetamine or its pharmacological analogues, which witnesses in favour of the proposed hypothesis.

Role of dopamine receptors in the regulation of aggression in mice; relationship to genotype.

The interline differences in the manifestation of aggression evoked by stimulation was studied in mice of eight inbred lines, and the role of different types of dopamine (DA) receptors in its manifestation was investigated. Aggression was assessed in a test involving the effect of a weak electrical stimulation through the floor of the cage. A significant relationship to the animals' genotype was demonstrated, and low-aggression (C3h/He, DD, BALB/c, and AKR) and high-aggression (CBA, DBA/2, and CC57Br) lines could be distinguished on the basis of the level of aggressivity. The mixed agonist of DA receptors, apomorphine, in a one-time administration activated aggressivity in the low-aggression mice. The selective stimulation of D2-receptors with bromocriptine substantially increased the evoked aggressivity in the low-aggression mice; the blockade of D2-receptors by sulpiride decreased or prevented the manifestation of aggressivity in the high-aggression lines. At the same time, the selective D1-agonist SKF 38393 and the selective D1-antagonist SCH 23390 did not exert a substantial influence on evoked aggressivity. Evidently the D2-receptors play a key role in the control of aggression evoked by stimulation, which constitutes a model of affective aggression.

[Genotypic differences in the metabolism of brain dopamine and in the dopamine-dependent forms of behavior in mice]. / Genotipicheskie razlichiia v metabolizme dofamina mozga i dofaminzavisimykh formakh povedeniia u myshei.

Metabolism of dopamine in striatum and the dopamine-dependent forms of behaviour of 6 inbred mice were studied. Interstrain significant differences were shown in the level of dopamine metabolite, homovanillic acid (HVA), as well as in locomotor activity and climbing produced by injection of dopamine agonist apomorphine. Significant negative correlation between the level of HVA in striatum and spontaneous locomotor activity was found. Different levels of HVA and significant behavioural differences were discovered in two similar strains--BALB/c and CC57BR. According to its behavioural characteristics, DBA/2 should also be considered among the most interesting.

[Genetic analysis of predator aggressiveness in mice]. / Geneticheskii analiz agressivnosti khishchnika u myshei.

The character of inheritance of mouse predatory aggression towards crickets and locusts was investigated. The percentage of aggressive animals in the group and the latency of attack were indices of aggression. The hybridological analysis included obtaining reciprocal F1 and F2 hybrids and backcrosses of CBA and DD mice lines exhibiting polar parameters in predatory tests. Examination of hybrids and backcrosses showed that the high level of aggressiveness is dominant. Sex differences in aggression were seen neither in parent strains, nor in hybrids, reciprocal effects being also absent. The results of the hybridological analysis indicated that the predatory aggressions are under control of a small number of genes with a pronounced dominant effect. As a result of diallele analysis in three strains of mice, BALB/c, C57BL/6, DD and all combinations of first generation hybrids, it was found that almost all hybrids exhibited greater aggressiveness than that of parent strains or that it was similar to the indices of highly aggressive parents. Analysis of a strain combinative ability showed that the genotypic component is conditioned by a specific combinative ability, the influence of the total combinating ability and of the reciprocal effects being not significant. It was once more confirmed that the predatory aggression in mice is inherited as a high level dominancy of aggression and genes influencing its manifestation are localized in autosomes.

[Effect of a single-locus mutation of the silver-blue color allele in mink on the dopaminergic system of the brain]. / Vliianie odnolokusnoi mutatsii allelia serebristo-goluboi okraski norok (PP) na dofaminovuiu sistemu mozga.

The peculiarities of dopamine metabolism and dopamine receptors in the brain of homozygous silver-blue (pp) minks were examined in comparison with wild-type (PP) minks. A pp mutation was found to affect the dopamine turnover in corpus striatum, which is one of the major dopaminergic brain structures. In silver-blue minks, increased dopamine catabolic enzyme activity monoamine oxidase type B (MAO B), together with the decreased level of dopamine and the tendency for the level of the metabolite 3,4-dihydrophenyl acetic acid to increase, were demonstrated in this brain region. No significant alterations in the level of another dopamine metabolite, homovanillic acid, or in D1 and D2 receptor density were shown. In the midbrain and hippocampus, an elevated level of MAO B activity was detected. We found no modifications in receptor properties, nor in dopamine turnover in a mesolimbic dopamine structure, the nucleus accumbens. We propose that the primary effect of pp mutation is an increase in MAO B activity resulting in dopamine turnover alterations and probably in dopamine-dependent behavior (pleiotropic cascade).

[Selection vector and ontogenetic development of behavior under domestication of wild Norway rats]. / Vektor otbora i ontogeneticheskie zakonomernosti formirovaniia povedeniia pri deomestikatsii serykh krys.

Hereditary variation in rates of ontogenetic formation of exploratory behavior, glucocorticoid functions, and neurotransmitter systems in wild Norway rats during selection for absence of defensive response towards humans (domestication) is demonstrated. Interrelated shifts in the development of behavior and neurohormonal systems are shown. A comparison of the data obtained with the results of domestication of another species-silver fox-suggests that equally vectorized selection of animals belonging to different taxa produces equally directed changes of their regulatory systems.

[The effect of the pleiotropic action of single-locus (pp) and dual-locus (aapp) mutation of mink fur color genes on serotonin metabolism in the brain]. / Vliianie pleiotropnogo deistviia odnolokusnoi (pp) i dvulokusnoi (aapp) mutatsii genov okraski norok na metabolizm serotonina v mozge.

Specific features of serotonin (5-hydroxytryptamine, 5-HT) metabolism were studied in the brain of mutant sapphire minks, homozygous at genes determining silver-blue and Aleutian fur color (ppaa), and silver-blue minks (pp) in comparison with the standard-colored minks (++/++). In the midbrain of sapphire mutants, the activities of tryptophan hydroxylase (TPH) and monoamine oxidase (MAO), key enzymes of 5-HT biosynthesis and catabolism, were significantly higher; an increase in the 5-HT level was statistically nonsignificant due to considerable variation in this parameter; and the level of 5-hydroxyindole-3-acetic acid remained unchanged. A similar increase in TPH and MAO activities was also found in the midbrain of silver-blue pp minks, suggesting that activation of key enzymes of 5-HT metabolism in sapphire aapp minks is associated with the mutant alleles pp.

[Disorder of catecholamine synthesis in early ontogeny and hypophyseal-adrenal cortical function in adult rats]. / Narushenie sinteza katekholaminov v rannem ontogeneze i sostoianie gipofizarno-adrenokortikal'noi sistemy u vzroslykh krys.

The effects of daily intraperitoneal (150 mg/kg of body weight) injections of alpha-methyl-dl-tyrosine (MT), an inhibitor of tyrosine hydroxylase, on the 2nd to 4th, 5th to 7th or 10th to 12th days of life on the pituitary-adrenal function and brain adrenaline level in 3 to 4-month old rats were studied. MT treatment on the 5th to 7th days resulted in a decrease of noradrenaline content in hypothalamus and midbrain and chronic decrease of basal corticosterone level in blood, its diurnal fluctuations being preserved. MT injections on the 10th to 12th days were accompanied by a decrease of the basal corticosterone level, but the brain noradrenaline level remained unchanged. A study of pituitary-adrenal stress reactivity of adult rats has revealed no specific MT effect. A conclusion was drawn that the MT treatment applied exerted a long-term effect, predominantly, on the regulation of tonic corticosterone secretion.

[The effect of the S1A-receptor agonist ipsapirone on behavior types in wild and domesticated rats]. / Vliianie agonista S1A-retseptorov ipsapirona na nekotorye vidy povedeniia dikikh i domestitsirovannykh krys.

Selective agonist of 1A subtype of serotonine receptors ipsapirone inhibited manifestation of affective kinds of aggression in wild and domesticated rats. Administration of ipsapirone (10 mg/kg) decreased the number of aggressive attacks of wild and domesticated rats in the test of shock-induced aggression and blocked manifestation of defensive reaction to the experimenter in wild rats. Neophobia in wild rats decreased under the influence of ipsapirone. At the same time ipsapirone did not change mouse-killing behaviour either in wild or in domesticated rats. Probably, 5-HT1A receptors the aggressive regulate reaction, which are parts of the complex of defensive behaviour of the wild animals.