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.     

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.     

Pharmacological manipulations of brain catecholamines and the aggressive behavior induced by marihuana in REM-sleep-deprived rats

A marihuana extract, apomorphine, and amphetamine provoked in rats previously deprived of REM sleep for 96 hr an upright position with the animals pawing each other as in fighting. Nondeprived rats injected with the drugs did not show this aggressive behavior. The marihuana-treated animals also bit vigorously a rod introduced into the cage, a fact not observed with the apomorphine-treated rats. These data suggest that the marihuana aggressiveness could at least partially be mediated through the brain catecholamines. Haloperidol, chlorpromazine, α-methyl-p-tyrosine, and reserpine decreased the marihuana aggressiveness of the deprived rats. Increase of dopamine concentration by previous treatment with Dopa potentiated aggressiveness. Blockade of norepinephrine synthesis by FLA-63 was ineffective in reducing marihuana aggressiveness in the REM-sleep-deprived rats. Actually, in these animals aggressiveness appreared even without the marihuana injection. Phenoxybenzamine partially blocked marihuana aggressiveness but also severely depressed the rats. However, 20 mg/kg alone succeeded in provoking aggressiveness in the deprived rats. It is suggested that in rats with neural excitability heightened by previous REM-sleep deprivation dopamine facilitates aggressive behavior, an effect inhibited by porepinephrine. This hypothesis would imply that marihuana induces aggressiveness in REM-sleep-deprived rats by inhibiting, through an as yet unknown mechanism, the central norepinephrine system.     

Role of 5HT1A receptors in a variety of kinds of aggressive behavior in wild rats and counterparts selected for low defensiveness towards man

The 5HT_1A receptor agonist ipsapirone (10 mg/kg) suppressed shock-induced aggression in wild and domesticated rats but did not affect predatory aggression in either group of animals. Ipsapirone decreased neophobia and inhibited defensive reactions by wild rats towards man in the glove test. [³H]8-OH-DPAT binding, which labels 5HT_1A receptors, was significantly increased in the hypothalamus of domesticated rats in comparison with wild counterparts, while 5HT_1A density was unchanged in the frontal cortex in domesticated animals. In essence, the aggressive reactions contributing to the defensive behavior complex in wild rats appear to be regulated through 5HT_1A receptors. © 1992 Wiley-Liss, Inc.     

Hormonal state affects recovery from frontal cortex lesions in adult female rats

Pseudopregnant and normal cycling female Sprague-Dawley rats were trained on a delayed-spatial alternation task. After acquisition training, the subjects received frontal cortex lesions and were subsequently tested for retention. The pseudopregnant animals with lesions were less impaired than their normal cycling counterparts. Learning and retention testing were not affected by hormonal status in the noninjured controls. Histological examination showed that the normal cycling rats with frontal cortex lesions possessed enlarged ventricles, indicating the presence of edema in this surgical group. However, brain tissue of pseudopregnant subjects given the same lesion and sham operates of both hormonal states did not display this characteristic of edema. We speculate that the behavioral and anatomical impairment observed in the normal cycling females with brain injury is due to higher levels of vasopressin, a potent vasoconstrictor synchronized with brain injury in our manipulation.     

The decline of aggressiveness in male mice during group caging as determined by punishment delivered by the cage mates

Group-housed rodents are generally less aggressive than isolated counterparts. The present study examined the role of defeat by cage mates as a reason for this decline in aggressiveness. In Experiment I, highly aggressive isolated male mice were introduced into aggressive or nonaggressive resident groups. The intruder's level of aggressiveness directed toward a group-housed standard opponent declined more rapidly after daily exposure to the aggressive than to the nonaggressive groups. Intruders in the aggressive groups received more attacks from their cage mates, and delivered fewer attacks to them than did the intruders in the nonaggressive groups. In Experiment II, the intruders lived for seven days in small wire net cages in the middle of the group cages. Their level of aggressiveness toward standard opponents decreased little during the preexposure but after being put freely into the groups, their aggressiveness declined to a minimal level within a day. Experiment III showed that when the wire net protection in the middle of the cage was installed after the group caging experience, the aggressiveness of the intruders did not return to the isolation level as effectively as it did in isolation. This is explained by the aggression-inhibiting content that the cues from the cage mates have acquired during group caging. The decline of aggressiveness in male mice during group caging is determined by punishment delivered by the cage mates.     

Grooming expresses harderian gland materials in the blind mole rat

The blind mole rat (Spalax ehrenbergi) is a highly aggressive and solitary rodent that shows the most striking physiological and behavioral adaptations to underground life. The eyes are not detectable externally; they are atrophied and covered by a thick layer of skin. A considerable part of the orbit is occupied by a very large Harderian gland. The current study demonstrates that during autogrooming the mole rat expresses Harderian gland materials from the conjunctival sac to the external nares and spreads them onto the fur. In contrast to other rodents, the mole rat's grooming behavior is usually confined to the front part of the body and does not progress after the head wipes to ventrolateral torso licking. Moreover, in highly aggressive encounters grooming sometimes ceases after the second phase-the nose wipe bouts. The unique first phase of the mole rat's grooming consists of highly rapid strokes over the skinny border of the head, which we assume help to squeeze Harderian materials from the gland. Unlike other rodents, in which grooming occupies a considerable part of their waking time, mole rats, cage individually, rarely perform autogrooming behavior. Grooming in mole rats has been found to be highly correlated with aggressive encounters, and submissive animals exhibit significantly more grooming than their dominant opponents. It is speculated that the Harderian gland discharge may serve as an appeasing substance when mole rats meet to reduce the extreme aggressiveness typical of these subterranean rodents. © 1995 Wiley-Liss, Inc.     

The effects of unilateral destruction of fimbria-fornix and supracallosal pathways in the rat

Rats with unilateral lesions of either the supracallosal regions (including the dorsal cingulate cortex) and the fimbria-fornix either on the same (S) or the opposite (O) sides of the brain were studied in a 16-hole open field without pharmacologic intervention and, subsequently, after 0.1 and after 1.0 mg/kg scopolamine HBr. Their performances were compared with those of unoperated control animals subjected to the same testing regime. Certain of their behaviors were compared with those of a larger number of animals with bilateral hippocampal destruction (and their control groups) from prior studies. Unilateral lesions of fimbria-fornix and supracallosal afferents to the hippocampal formation produced a decrease in hole poking activity relative to control animals. A further decrease in hole-poking behavior, coupled with increased locomotion, was observed in rats with fimbria-fornix and cingulate cortex lesions on opposite sides of the brain (group O). The smaller dose of scopolamine accentuated these effects. Indeed, the behavior of group O after scopolamine treatment was similar to animals with large bilateral hippocampal lesions. The large dose of scopolamine induced stereotyped rearing or hole poking in the brain-damaged animals but not in the control group. These findings suggest that both the fimbria-fornix and the supracallosal pathway is necessary for normal hippocampal function and that the behavioral deficit is greater when these structures are damaged on the opposite sides of the brain.     

Functional activity in the brain of socially deprivated rats produced by an active avoidance test after razobazam (Hoe 175) treatment: a 2-deoxyglucose study

The 2-deoxyglucose (2-DG) autoradiographic method was used to map metabolic activity in the brain of socially deprivated rats during an active avoidance test. The method investigated the effects of razobazam during this learning test. The animals were socially deprivated for 5 weeks. On the first experimental day the animals were trained to avoid a footshock by jumping onto a platform. During training and testing, the total number of avoidance responses was scored. On the second day during one 2-DG session of 40 min, razobazam increased the avoidance score by 18% as compared to controls. Autoradiographs were analyzed using a two-dimensional densitometric method. The analysis of the brain structures showed a 22% reduction of optical density in the nucleus habenularis lateralis, a 25% increase in the caudal part of the nucleus accumbens, and a 13% increase in the frontal cortex in rats treated with razobazam, but no change in the amygdala. These results provide a preliminary concept to explain how the new compound razobazam produced a better learning performance in socially deprivated rats.     

Short-term effects of postnatal manipulation on central beta-adrenoceptor transmission

Neonatal handling is known to induce long-lasting changes in behavioral and neuroendocrine responses to stress. Since the central noradrenergic system participates in the adaptive responses to stressful conditions we have analyzed the effects of postnatal handling on beta-adrenoceptor binding sites and isoprenaline- and forskolin-stimulated cyclic AMP accumulation in cerebral cortex, hippocampus and cerebellum of rats at 1 and 3 months of age. Handled animals showed reduced emotional reactivity and lower ACTH and corticosterone secretion after stress. Binding studies using [(3) H]CGP12-177 revealed increased beta-adrenoceptor binding sites in handled rats in cerebellum and cerebral cortex with no changes in hippocampus, and decreased affinity in all cerebral regions. Handling reduced basal levels of cyclic AMP in hippocampus and cerebellum but not in cerebral cortex. The concentration-response curves of cyclic AMP to isoprenaline were displaced to the right in cerebellum of handled rats without differences in Emax; however, Emax was significantly reduced in cerebral cortex and hippocampus. Direct stimulation of the catalytic subunit of adenylyl cyclase by forskolin reduced the efficiency in hippocampus and cerebellum, but not in cerebral cortex of handled animals. It is concluded that neonatal handling reduces the binding properties of beta-adrenoceptor and its primary biochemical responses in the young rat brain, which may account for the reduced responsiveness to stress attained in the handled rats, and may explain the persistence of the effect. The present study emphasizes the role of the central noradrenergic system in modulating the behavioral and neurendocrine responses to neonatal handling.     

Suppression of VMH-lesion-induced reactivity and aggressiveness in the rat by stimulation of lateral septum, but not medial septum or cingulate cortex

Animals made vicious with bilateral ventromedial hypothalamic lesions had bipolar electrodes implanted unilaterally in the lateral septum, medial septum, or cingulate cortex. Four days later, the animals' reactivity and aggressiveness were evaluated 5 min before, during, and 5 min after stimulation at 20 micronA (60 Hz, sine wave). Lateral septal stimulation suppressed reactivity and aggressiveness by almost 80% compared with pre- and poststimulation levels. Stimulation of neither the cingulate cortex nor the medial septum produced a change reliably different from that seen in unstimulated control animals. Further tests with stimulation of the lateral septum at the 20-micronA level showed that neither rewarding self-stimulation nor disruption of ongoing water drinking was produced. These results are congruent with evidence from lesion studies that the lateral septum normally acts to suppress reactivity and aggressiveness in the rat; they do not support previous suggestions that the medial septum is involved in the modulation of these behaviors.     

Fragile X mental retardation protein levels increase following complex environment exposure in rat brain regions undergoing active synaptogenesis

Fragile X mental retardation protein (FMRP), which is absent in fragile X syndrome, is synthesized in vitro in response to neurotransmitter activation. Humans and mice lacking FMRP exhibit abnormal dendritic spine development, suggesting that this protein plays an important role in synaptic plasticity. Previously, our laboratory demonstrated increased FMRP immunoreactivity in visual cortex of rats exposed to complex environments (EC) and in motor cortex of rats trained on motor-skill tasks compared with animals reared individually in standard laboratory housing (IC). Here, we use immunohistochemistry to extend those findings by investigating FMRP levels in visual cortex and hippocampal dentate gyrus of animals exposed to EC or IC. Rats exposed to EC for 20 days exhibited increased FMRP immunoreactivity in visual cortex compared with animals housed in standard laboratory caging. In the dentate gyrus, animals exposed to EC for 20 days had higher FMRP levels than animals exposed to EC for 5 or 10 days. In light of possible antibody crossreactivity with closely related proteins FXR1P and FXR2P, FMRP immunoreactivity in the posterior-dorsal one-third of cerebral cortex was also examined by Western blotting following 20 days of EC exposure. FMRP levels were greater in EC animals, whereas levels of FXR1P and FXR2P were unaffected by experience. These results provide further evidence for behaviorally induced alteration of FMRP expression in contrast to its homologues, extend previous findings suggesting regulation of its expression by synaptic activity, and support the theories associating FMRP expression with alteration of synaptic structure both in development and later in the life-cycle.     

Place and response learning of rats in a Morris water maze: differential effects of fimbria fornix and medial prefrontal cortex lesions

The question examined in this study is concerned with a possible functional dissociation between the hippocampal formation and the prefrontal cortex in spatial navigation. Wistar rats with hippocampal damage (inflicted by a bilateral lesion of the fimbria fornix), rats with damage to the medial prefrontal cortex, and control-operated rats were examined for their performance in either one of two different spatial tasks in a Morris water maze, a place learning task (requiring a locale system), or a response learning task (requiring a taxon system). Performance of the classical place learning (allocentric) task was found to be impaired in rats with lesions of the fimbria fornix, but not in rats with damage of the medial prefrontal cortex, while the opposite effect was found in the response learning (egocentric) task. These findings are indicative of a double functional dissociation of these two brain regions with respect to the two different forms of spatial navigation. When the place learning task was modified by relocating the platform, the impairment in animals with fimbria fornix lesions was even more pronounced than before, while the performance of animals with medial prefrontal cortex lesions was similar to that of their controls. When the task was again modified by changing the hidden platform for a clearly visible one (visual cue task), the animals with fimbria fornix lesions had, at least initially, shorter latencies than their controls. By contrast, in the animals with medial prefrontal cortex damage this change led to a slight increase in escape latency.     

Dominance-subordinance in cohabiting pairs of adult rats: Effects on Aggressive behavior

Following an initial intruder aggression test, 10 pairs of adult male rats matched on aggressiveness were formed. The first 20 min of paired cohabitation were used to determine dominance and subordinance between pau members. Residents judged to be dominant from this observation session gained significantly more weight during cohabitation and exhibited significantly more aggression on the second aggression test than their subordinate counterparts. Significant correlations among various measures of aggression were found, but open field performance did not correlate, with the measures of aggression nor did changes in open field scores reflect changes in aggression.     

Effects of BIM-22015, an analog of ACTH4-10, on functional recovery after frontal cortex injury.

Male rats, 90-100 days old, with frontal cortex lesions were given either subcutaneous sterile water (SW) as a vehicle control or 1, 10, or 100 micrograms of BIM-22015 every other day for 20 days. Brain-injured subjects tested in the Morris water maze with either 10 micrograms BIM-22015 or SW took significantly more trials than sham-operated rats to locate a submerged platform eight consecutive times within 60 s. The animals given 1 or 100 micrograms BIM-22015 took significantly fewer trials to reach criterion than brain-injured animals in the other drug treatment groups. On a percentage of savings, measured 8 days after reaching criterion, the brain-injured subjects given 1, 10, or 100 micrograms BIM-22015 did not differ from sham-operated rats. In contrast, the brain-injured animals given SW took longer to find the submerged platform than they did during the initial training. To assess long-term effects of the ACTH analog treatment, rats were trained on a delayed spatial alternation task 30 days after receiving the last injection. On this task, brain-injured rats treated with the 10-micrograms dose performed significantly better than those given sterile water. Acetylcholinesterase (AChE)-labeled neurons counted in the nucleus basalis magnocellularis indicated that rats with frontal cortex damage given the 10-micrograms treatment did not differ from the sham controls and had significantly more AChE-positive neurons than injured counterparts treated with SW or 100 micrograms.     

Fetal brain tissue transplants reduce visual deficits in adult rats with bilateral lesions of the occipital cortex

Fetal brain tissue from the occipital or the frontal cortex was implanted into the damaged occipital cortex of adult rats. The animals receiving grafts of embryonic frontal cortex showed partial restoration of brightness discrimination while recipients given homologous implants of occipital cortex were as impaired as those animals with lesions alone. Neither frontal nor occipital grafts aided in the performance of a pattern discrimination problem; both groups of brain-damaged animals were unable to learn the task. Nonetheless, both groups of animals had viable and enlarged grafts with similar neuronal and glial profiles.     

The relationship of structural ischemic brain damage to neurobehavioural deficit: the effect of postischemic MK-801

Global cerebral ischemia is well known to cause neuronal necrosis in selectively vulnerable sectors of the hippocampus. Since the hippocampus of the rat is involved in spatial navigation, learning, and memory, selective deficits in these abilities may arise from ischemic brain damage. Previous studies have shown (a) a detectable neurobehavioural deficit due to ischemic brain damage limited to half of the CA1 sector of the hippocampus and (b) a reduction of ischemic neuronal necrosis with the noncompetitive N-methyl-D-Aspartate (NMDA) antagonist MK-801. This study was designed to determine the relationship between the improvement in structural brain damage in postischemically treated rats and any improvement in neurobehavioural performance, using a learning-set water task. Seventeen male Wistar rats received 10.5 min of forebrain ischemia induced by carotid clamping and hypotension. Brain temperature was estimated with probes in the temporalis muscle. Ten of these animals received no therapy (controls), and seven animals received 5 mg/kg MK-801 iv, 20 min postischemia. Six additional rats underwent a sham operation. Postischemic hypothermia was prevented with heating lamps. Four controls and one MK-801 treated animal died. The survivors were then tested on a place learning-set task in a swimming pool paradigm, and quantitative histopathologic analysis of their entire brains was done. The learning-set task revealed defects in spatial navigation, reflected as increased errors and latency in the performance of the untreated control rats. The performance of the MK-801 treated group progressively approached that of sham-operated rats over the course of testing and was significantly better than controls. Importantly, no long-term detrimental effect of MK-801 on the learning-set task performance was seen. Quantitative neuropathology revealed significantly less damage in the MK-801 treated group in all major brain regions. In the hippocampus, MK-801 treated animals showed hippocampal damage limited to the vulnerable portion of the pyramidal cell band comprising 48.8% of the CA1 pyramidal cells, as opposed to 72.4% in untreated controls. Extra-hippocampal damage was evident only in untreated control animals. MK-801 totally prevented neuronal necrosis in both the cerebral cortex and striatum and also prevented infarction in the neocortex and thalamus. Three conclusions emerge from the study. First, postischemic MK-801 mitigates structural brain damage in several brain regions in the absence of concomitant hypothermia. Second, neurobehavioural performance appears to be improved by MK-801 when performance trends are examined, but is somewhat less sensitive than quantitated histopathology due to compounding interanimal variation in performance abilities.(ABSTRACT TRUNCATED AT 400 WORDS)     

Differences between two strains of mice,selectively bred for high and low aggressiveness,in the capacity of male odors to affect aggressive behavior

The connection between a genetic disposition for aggressive behavior and the odor signal system in male mice was studied. The males belonged to two strains of mice which have been developed by selective breeding for high- (TA) and low aggressiveness (TNA). Urine from the high aggressive strain (TA), when applied to castrates, stimulated the aggressiveness of NMRI males while TA-soiled bedding suppressed their aggressiveness. In response to male odors from the low aggressive strain (TNA), the NMRI males showed quite contrasting reactions. The results provide evidences of a correlation between the hereditarily determined disposition for aggressive behavior and the odor signal system in TA- and TNA males.     

Trait Aggressiveness and Aggressive Behavior in the Context of Provocation and Inhibition

Aggressive behavior often occurs despite salient cues within the immediate environment that indicate aversive consequences will likely follow. Prior research has shown high trait aggressiveness to be related to sensitivity to situational provocation; however, little research has examined whether it is also related to insensitivity to situational inhibitors. This study examines the relationship between trait aggressiveness and aggressive behavior in a provocative context with, and without, an unambiguous inhibitory stimulus. Prior to experiencing provocation and being afforded the opportunity to retaliate, participants who varied in trait aggressiveness were explicitly given (or not given) an instruction that aggressive behavior might lead to aversive consequences and, thus, one should not behave aggressively. Findings revealed that without the instruction, those higher in trait aggressiveness exhibited steeper increases in aggressive responding as provocation increased. In the group that received the instruction, trait aggressiveness was unrelated to aggressive responding at all levels of provocation.     

Brain Oxidative Damage Following Acute Immobilization and Mild Emotional Stress

We studied the role of free radicals on brain oxidative damage in rats after acute immobilization stress (restraint) and mild emotional stress (handling). To investigate brain oxidative damage, CuZn and Mn dependent superoxide dismutase (CuZn SOD, Mn SOD) activities, lipid peroxidation (TBARs), Na ⁺ K ⁺ ATPase activity, protein carbonyl (PrC), and reduced and oxidized glutathione (GSH, GSSG) levels were measured in the cerebral cortex (CTX), hippocampus (HIP), and striatum (ST) of the animals after the two different stress stimuli. Because stress produces abnormalities in the hypothalamic-pituitary-adrenal axis, the intensity of the two stress conditions were measured by plasmatic corticosteroid (COR) levels: particularly, COR levels doubled in handled rats and increased 15-fold in restrained animals. The SOD activities increased in CTX and decreased in HIP of the handled rats, while in ST a significant decrease in handled animals but an increase in restrained animals occurred. TBARs, GSH, and GSSG levels remained unchanged, while an index of glutathione redox decreased significantly in ST of handled animals and in CTX of restrained ones. Na ⁺ K ⁺ ATPase activity increased significantly in the HIP and ST of both groups of stressed rats. The stress induced a remarkable increase in PrC levels in all studied cerebral areas. These findings provide evidence to support the idea that stress produces oxidants but that the oxidative damage in stress differs in cerebral areas and could contribute to the degenerative mechanism of aging.