Selection for reduced aggressiveness towards man and dopaminergic activity in Norway rats

The brain dopaminergic system is involved in the process of long-term selection for reduced aggressive reaction towards man in Norway rats. The dopamine levels in the striatum as well as the nucleus accumbens with the tuberculum olfactorium were significantly lower in domesticated rats than in their wild counterparts. A substantial decrease was found in homovanillic acid level in the n. accumbens and tuberculum olfactorium. Specific binding of [³H]spiperone which labels D-2 dopamine receptors was higher in the mesolimbic structure of tame rats, whereas binding of [³H]SCH 23390 (D-1 receptors) was unchanged in this area. No substantial differences were detected in D-1 and D-2 binding in striatum. Apomorphine (0.3 mg/kg) elicited less locomotion in tame animals, reflecting a decrease of sensitivity of postsynaptic dopamine receptors. Tame rats showed fewer aggressive contacts in a foot-shock test than wild rats and the D-2 receptor antagonist sulpiride (25 mg/kg) significantly decreased the foot-shock aggression only in wild rats. Therefore, domestication, which diminishes defensive behavior and emotional reactivity of animals, is associated with decreases of dopamine level in the striatum, changed metabolism of dopamine in mesolimbic system, and an alteration in density and senstivity of D-2 receptors.     

Characterization of the discriminative stimulus effects of lorcaserin in rats

Lorcaserin is approved by the Food and Drug Administration for treating obesity and is under consideration for treating substance use disorders; it has agonist properties at serotonin (5‐HT)_2C receptors and might also have agonist properties at other 5‐HT receptor subtypes. This study used drug discrimination to investigate the mechanism(s) of action of lorcaserin. Male Sprague–Dawley rats discriminated 0.56 mg/kg i.p. lorcaserin from saline while responding under a fixed‐ratio 5 schedule for food. Lorcaserin (0.178‐1.0 mg/kg) dose‐dependently increased lorcaserin‐lever responding. The 5‐HT_2C receptor agonist mCPP and the 5‐HT_2A receptor agonist DOM each occasioned greater than 90% lorcaserin‐lever responding in seven of eight rats. The 5‐HT_1A receptor agonist 8‐OH‐DPAT occasioned greater than 90% lorcaserin‐lever responding in four of seven rats. The 5‐HT_2C receptor selective antagonist SB 242084 attenuated lorcaserin‐lever responding in all eight rats and the 5‐HT_2A receptor selective antagonist MDL 100907 attenuated lorcaserin‐lever responding in six of seven rats. These results suggest that, in addition to agonist properties at 5‐HT_2C receptors, lorcaserin also has agonist properties at 5‐HT_2A and 5‐HT_1A receptors. Because some drugs with 5‐HT_2A receptor agonist properties are abused, it is important to fully characterize the behavioral effects of lorcaserin while considering its potential for treating substance use disorders.     

Effect of stress on the behavior and 5-HT system in Sprague-Dawley and Wistar Kyoto rat strains

The effects of chronic novel stressors, for 21 days, on the behavior and the serotoninergic (5-HT) system in Sprague-Dawley (SD) and Wistar Kyoto (WKY) rats were studied. Open-field and forced-swim tests revealed a significantly greater behavioral depression in the WKY strain. SD rats showed a decrease in³H-DPAT binding to 5-HT_1A receptors in the hippocampus, whereas WKY rats revealed an increase in³H-DPAT binding in the hippocampus and hypothalamus. Stress did not appear to alter the binding of³H-DPAT to 5-HT_1A sites in the dorsal raphe or median raphe in either strains. SD rats revealed a modest increase in 5-HT transporter (5-HTT) sites in the cortex; WKY rats revealed a decrease in 5-HTT sites in the cortex and the hippocampus. Stress caused an increase in³H-CNIMI binding to 5-HTT sites in the dorsal and median raphe nuclei in both strains. The results suggest that the greater susceptibility to behavioral depression in WKY rats may account for the differential effects on 5HT_1A sites as well as 5-HTT sites in limbic regions and cell body area as compared to SD rats.     

Serotonin metabolism and serotonergic receptors in Norway rats selected for low aggressiveness to man

Selection of Norway rats (24–27 generations) for low aggressiveness to man resulting in the loss of aggressive responding to handling markedly influences the brain serotonergic system. In “domesticated” Norway rats levels of serotonin in the midbrain and hypothalamus and 5-hydroxyindole acetic acid in the hypothalamus were higher than in non-selected aggressive rats. The activity of the key enzyme in serotonin biosynthesis, tryptophan hydroxylase, in midbrain of rats with genetically determined lack of aggressiveness to man was higher than in aggressive animals, although there was no difference in tryptophan hydroxylase activity in the hypothalamus. B_max and K_D of [³H]spiperone-specific binding in frontal cortex membranes were increased in tame rats. No significant differences in B_max and K_D were found between “domesticated” and aggressive rats in [³H]serotonin binding in the frontal cortex.     

Neuropharmacological aspects of adaptive pain inhibition in murine “victims” of aggression

This review outlines recent research on a subset of physiological responses in murine “victims” or aggression. In a typical resident-intruder paradigm, the detailed study of intruders has revealed that exposure to conspecific attack (and related stimuli) is associated with two forms of analgesia which appear to be integral components of the murine defensive repertoire. In response to intense/enduring attack, intruder mice display a profound, long-lasting and opioid-mediated analgesia. This reaction is highly correlated with defensive immobility and may function to reduce involuntary cues to further attack. In contrast, the inhibition of pain reactivity in mice tested immediately upon the display of defeat is less intense, shorter-lasting, non-opioid in nature and may function to facilitate active defenses such as escape. As this form of pain inhibition is also evident in intruders exposed to the scent of an aggressive male conspecific, a possible anticipatory defensive function linked to mechanisms of anxiety has been proposed. This hypothesis is supported by 1) the prevention of defeat analgesia by a range of antianxiety drugs (benzodiazepines, 5-hydroxytryptamine_1A [5-HT_1A] receptor agonists, and 5-HT₃ receptor antagonists) and 2) the effects of social defeat on behavior in the elevated plusmaze model of anxiety. These findings are discussed in relation to coping mechanisms in murine “victims” of aggression. © 1995 Wiley-Liss, Inc.     

Defensive reactions of “wild-type” and “Domesticated” wild rats to approach and contact by a threat stimulus

Selective breeding of wild rats over many generations on the basis of low or high defensive threat and attack to human approach and contact has produced highly polarized “domesticated” and “wild-type” animals. Because the selection procedure selectively involves these two defense patterns, and these clearly differ in the two groups, it is of interest to determine if other, nonselected, defensive behaviors to threat stimuli also change. “Domesticated” and “wild-type” rats of the thirty-fifth generation were run in a fear defense test battery (F/DTB) to systematically evaluate defensive behaviors to a variety of present threat stimuli. “Domesticated” rats showed reduced avoidance and slower flight speed to an approaching experimenter, reduced jump/startle response to handelap and dorsal contact, less vocalization and boxing to vibrissae stimulation or to an anesthetized conspecific, and reduced defensiveness to an attempted pickup by the experimenter. These results indicate that selective bi-directional breeding for defensive threat and attack to human approach and contact produces group differences in a variety of defensive behaviors, and in defensiveness to stimuli other than those on which the selection was based. © 1994 Wiley-Liss, Inc.     

The ontogeny of defensive reactions in the rat: Influence of the monoamine transmission systems

The effects of neonatal treatment of rats with the neurotoxins 5,7-dihydroxytryptamine and 6-hydroxydopamine on the ontogeny of the ultra sound vocalization and the immobility response were studied. The 5,7-dihydroxytryptamine treated rats showed reduced strength of both reactions indicating involvement of the serotonin system in their ontogeny. This hypothesis was supported by experiments with depletion of serotonin by para-chlorophenylalanine followed by replenishment with 5-hydroxytryptophan. The 6-hydroxydopamine treated rats showed normal defensive reactions, but displayed hyperactivity from their second week of age. The role of the dopamine system in the defensive reactions was studied by variations of the dopamine activity level by traditional tools: depletion by α-methyl-tyrosin followed by replenishment by l -DOPA; stimulation or inhibition of the dopamine receptors by apomorphine or haloperidol. The results suggested an inhibitory function of the dopamine system in both defensive reactions, antagonistic to that of the serotonin system.     

Defensive behavior of laboratory and wild Rattus norvegicus

Analysis of the defensive behaviors of wild rats to an inescapable approaching threat stimulus (the experimenter) indicated a pattern of freezing to distant stimuli, giving way to vocalization, jumps, and jump-attacks at shorter defensive distances. Comparisons of the defensive reactions of wild-trapped and laboratory-bred wild rats to a variety of threatening stimuli, in escapable as well as inescapable situations, indicated that the two wild strains were similar and consistently more defensive than laboratory rats to both human and conspecific threat stimuli. These results thus suggest that the defensive behaviors of rats have been substantially reduced during the process of domestication, with relatively little of this reduction being attributable to housing in standard laboratory conditions.     

The effects of negative reinforcement for irritable aggression on resident-intruder behavior

This experiment demonstrated that rats trained to display elevated levels of shock-induced aggression in a negative reinforcement paradigm displayed more boxing behavior than yoked control groups in a later test in which intruder rats were placed in the home cage of resident rats. Resident or intruder status did not affect the influence of the negative reinforcement procedure on the observed resident-intruder behavior of trained animals; however, naive intruders paired with trained residents displayed increased defensive behavior, suggesting that negative reinforcement for shock-induced aggression affected the behavior of these residents.     

A fixed interval schedule in which the interval is initiated by a response

The fixed interval schedule described requires the animal to initiate every time interval by making a response on a bar other than the one on which it is reinforced. This response, R_A, demarcates the postreinforcement pause (S^R-R_A interval) from the fixed interval pause (R_A-R_B interval) so that these pauses may be measured separately. Twelve rats and three monkeys, working in two-bar Skinner boxes, were trained and stabilized on this schedule. The resulting performances, presented for individual animals, are analyzed in terms of (1) the relative frequencies with which the animal waits various lengths of time between consecutive responses, (2) the relative frequencies with which various rates of responding appear, (3) the change in response rate throughout the fixed interval, (4) the average length of the postreinforcement pause, (5) the relative frequencies with which the animal waits different lengths of time between the R_A and the first R_B, and (6) the average inter-response time as a function of the rank order in the fixed interval of the inter-response time. The joint interpretation of the several measures taken leads to the following conclusions: 1. The probability of an R_B increases throughout the fixed interval. 2. The increase is discontinuous at the first R_B, at which point the probability increases sharply. 3. The frequency distributions of R_A-R_B pauses exhibit three discrete types of behavior with no intermediate cases. 4. The (main) mode of R_A-R_B interval length usually occurs just below the fixed interval requirement.     

Fear and aggression in the rat

The effect of fear on two types of aggression in rats was investigated by adding a cat stimulus to a colony in which the dominant male was attacking an intruder (offensive aggression), or, to a tube test situation in which defensive biting was measured before and during tail shock. The cat completely abolished offense in the colony; when the cat was presented and removed before a strange rat was placed in the colony, attack on the intruder was also reduced. In contrast, defensive biting was unchanged or even slightly potentiated by the presence of the cat, demonstrating a separation of the effects of fear on offensive and defensive aggression.     

Manipulations of vasopressin alter aggression differently across testing conditions in monogamous and non‐monogamous Peromyscus mice

Differences in the distribution of arginine vasopressin (AVP) and a subtype of AVP receptors, the V_1a receptor, may explain dissimilarities in social behavior of monogamous and non‐monogamous rodents. Intracerebroventricular infusions of AVP and a V_1a antagonist were used in sexually naive males of two mouse species, the monogamous and highly aggressive California mouse (Peromyscus californicus) and the non‐monogamous and less aggressive white‐footed mouse (P. leucopus), to begin testing the interaction between the social system of a species and the effects of AVP on aggression. Two testing conditions, the resident‐intruder aggression test (R‐I) and the neutral arena aggression test, were used because they may differ in function and underlying biological mechanisms. In the R‐I test, administration of the antagonist lengthened attack latencies in California mice. In contrast, blocking V_1a receptors did not alter attack latencies in the R‐I test in white‐footed mice or in the neutral arena aggression test in both species. AVP also did not alter aggression in either species in either behavioral test. Overall, these results suggest that AVP may be more likely to be associated with offensive aggression as measured in the R‐I test than with neutral arena aggression and that the effects of AVP manipulations may differ between monogamous and non‐monogamous rodents. Aggress. Behav. 31:000–000, 2005. © 2005 Wiley‐Liss, Inc.     

Effects of serotonin-mimetic drugs on mouse-killing behavior

Muricidal behavior induced in rats by social isolation or by olfactory bulb ablation was blocked following IP administration of serotonin (5–HT) agonist 8-OH-DPAT and 5-MeODM and by 5-HT uptake inhibitors, fluoxetine and indalpine. Among uptake inhibitors, although fluoxetine has a higher IC₅₀ and a higher Ki, it is apparently more efficient than indalpine. The 5-HT agonist, 8-OH-DPAT, acting at a putative 5-HT_1A receptor, appears more efficient on muricidal inhibition than 5-MeODM, at a much lower dosage. It is highly probable that 5-HT_1A receptor rather than 5-HT_1B is involved in the antimuricidal effect of serotonin-mimetic drugs. Since 5-HT mimetic drugs blocked mouse-killing behavior of bulbectomized rats, we suggest that in the sequence of events in muricidal inhibition 5-HT circuits participate after gabaergic modulation from olfactory bulbs.     

Effects of septal-forebrain lesions on maternal aggression and maternal care

Septal-forebrain lesions significantly increased the defensive reactions of lactating Long-Evans rats (n = 13) relative to nonlesioned control females. The lesions greatly enhanced defensive behaviors on a number of standard tests (e.g., responsiveness to humans and anesthetized conspecifics) while abolishing aggression toward intruding male conspecifics. The lesions also produced a striking disruption in maternal behavior as evidenced by absence of nest building, reduced litter weights, failure to retrieve, lick, or nurse pups, and increased cannibalization. While these results cannot be interpreted as indicating that maternal aggression is equivalent to offense, they are congruent with such a view. Certainly they are not supportive of a view that maternal aggression is primarily defensive. The lesion-induced abolition of maternal attack may have resulted from an inhibition of offensive tendencies by heightened defensiveness and/or reduced pup stimulation. There was no evidence that the lesion-induced impairment in maternal behavior resulted from a failure to sequence the individual behavioral acts comprising maternal behavior. Rather, all features of maternal care seemed to be greatly attenuated.     

Enhanced defense in adult rats deprived of playfighting experience as juveniles

In an earlier study we found that shock-elicited defensive aggression was intensified in rats that had been deprived of playfighting as juveniles. The three experiments reported here extend this phenomenon to the more naturalistic intruder/resident paradigm for eliciting defense. Rats were reared from 20 to 50 days in one of three conditions: in pairs or in isolation with or without 1 hour of daily playfighting experience. They were rehoused in small groups at 50 days, when the frequency of play is beginning to wane, in order to eliminate the effects of ongoing isolation at the time of testing. They were tested for defense at 80 to 100 days by being placed in a resident's cage for 10 minutes. Our main finding was that play-deprived animals spent significantly more time immobile after they had been attacked than did animals of the other two groups. The increased immobility associated with playfighting deprivation is not caused by baseline differences in emotionality such as those elicited by a novel environment (Experiment 1), the presence of a strange animal (Experiment 2), or nonsocial aversive stimuli (Experiment 3). Furthermore, play-deprived rats were not more reactive when pinched with forceps to stimulate a bite delivered by a conspecific, whether or not another rat was present behind a divider. Thus isolates' greater reactivity may be restricted to situations involving pain coupled with close proximity to and contact with another rat. A secondary finding was that there were no differences in defensive behaviors other than immobility. The appropriate generalization to be drawn from these studies is that early social deprivation facilitates the defensive response to a social threat that happens to be prepotent under the given experimental conditions.     

Reflexive fighting in the albino rat: Aggressive or defensive behavior?

Specific agonistic responses of albino rats were compared for dominant colony rats and intruders, and for rats in a “reflexive fighting” task. The “reflexive fighters” showed high levels of defensive responses such as boxing and freezing, and very low levels of aggressive behaviors such as piloerection, biting, and the lateral display. This pattern clearly suggests that the behaviors measured in the reflexive fighting task reflect conspecific defensive reactions, rather than “shockelicited aggression.” Moreover, striking responses seen in the reflexive fighting task also occur at a high rate when footshock is given to a solitary rat held in a boxing posture. Thus it appears that “reflexive fighting” primarily involves defensive rather than aggressive responses.     

The ventromedial hypothalamus and aggressive behaviour in rats

Male rats were given bilateral lesions in either the anterior or posterior ventromedial hypothalamus (VMH). The intermale aggressive behaviour of these animals within their own territory was observed before and after the surgical procedure and compared with the behaviour of sham-operated animals. The effects of anterior VMH lesions include an increased tendency to respond with frontal threatening upon approach of a conspecific male. This behaviour closely resembles the aggressive responses described in “shock-induced aggression” tests. Posterior VMH lesions facilitate territorial aggressive behaviour characterized by approaching the opponent followed by lateral threatening and fighting. It is suggested that 2 distinct neural substrates exist, which serve to inhibit defensive (anterior-VMH) and offensive (posterior-VMH) intermale aggression, respectively.     

Colony aggression in laboratory rats: A review and some recommendations

The behavioral response of established colonies of domesticated rats to the presence of an unfamiliar intruder of the same species represents one of the most effective procedures yet developed to study aggression in the laboratory. Here, the social, experiential, and environmental variables that influence attack severity are reviewed and several important methodological issues are discussed. Brief exposures of intruders to intact colonies may produce misleading results but long-term test sessions increase the likelihood that intruders will be either killed or severely injured. We describe a simple modification of the colony-intruder procedure whereby intruders can successfully defend themselves during long sessions and thus reduce serious injury. The modified procedure appears to conform more closely to what happens during aggressive encounters in free-living populations of wild rats.     

Effects of serotonin receptor agonists and antagonists on offensive aggression in mice

The effects of serotonin receptor agonists 5-methoxytryptamine and quipazine, and antagonist mianserin on resident-intruder offensive aggression were investigated. Both agonists reduced aggression. The fact that 5-methoxytryptamine preferentially binds to 5-HT-1 receptors strongly suggest that the decreased aggression with S-methoxytryptamine was related to stimulation of an inhibitory 5-HT-1 receptor. It is also suggested that the reduction in aggression with quipazine was related to quipazine's preferential binding to the 5-HT-1 receptor. The 5-HT-2 receptor antagonist mianserin reduced aggression suggesting that 5-HT-2 receptor blockade is inhibitory for aggression. Thus, two serotonin classes of receptors may be differentially involved in offensive aggression.     

A study of the spin-Hamiltonian parameters for Cr5+ at the rhombically-distorted tetrahedral P5+ site of Ca2PO4Cl crystal using a two-mechanism model

The complete high-order perturbation formulae of spin-Hamiltonian (SH) parameters (g factors g_i and hyperfine structure constants A_i , where i = x, y, z) containing contributions from both the crystal-field (CF) and charge-transfer (CT) mechanisms (the latter mechanism is neglected in the widely-used CF theory) are established for d¹ ions in rhombic tetrahedra. From these formulae, the SH parameters of Cr⁵⁺ ion at the rhombically-distorted tetrahedral P⁵⁺ site of Ca₂PO₄Cl crystal are calculated. The CF and CT energy levels used in the calculation are obtained from the optical spectra of the studied Ca₂PO₄Cl : Cr⁵⁺ crystal. The calculated results showed reasonable agreement with the experimental values. The signs of the hyperfine structure constants A_i and the relative importance of the CT mechanism to SH parameters are acquired from the calculations.