Interaction of nitric oxide and serotonin in aggressive behavior

Nitric oxide (NO) modulates many behavioral and neuroendocrine responses. Genetic or pharmacological inhibition of the synthetic enzyme that produces NO in neurons evokes elevated and sustained aggression in male mice. Recently, the excessive aggressive and impulsive traits of neuronal NO synthase knockout (nNOS-/-) mice were shown to be caused by reductions in serotonin (5-HT) turnover and deficient 5-HT1A and 5-HT1B receptor function in brain regions regulating emotion. The consistently high levels of aggression observed in nNOS-/- mice could be reversed by 5-HT precursors and by treatment with specific 5-HT1A and 5-HT1B receptor agonists. The expression of the aggressive phenotype of nNOS-/- knockout mice requires isolated housing prior to testing. The effects of social factors such as housing condition and maternal care can affect 5-HT and aggression, but the interaction among extrinsic factors, 5-HT, NO, and aggression remains unspecified. Taken together, NO appears to play an important role in normal brain 5-HT function and may have significant implications for the treatment of psychiatric disorders characterized by aggressive and impulsive behaviors.     

Increased aggression and lack of maternal behavior in Dio3‐deficient mice are associated with abnormalities in oxytocin and vasopressin systems

Thyroid hormones regulate many aspects of brain development and function, and alterations in the levels of thyroid hormone action lead to abnormal anxiety‐ and depression‐like behaviors. A complement of factors in the brain function independently of circulating levels of hormone to strictly controlled local thyroid hormone signaling. A critical factor is the type 3 deiodinase (DIO3), which is located in neurons and protects the brain from excessive thyroid hormone. Here, we examined whether a local increase in brain thyroid hormone action secondary to DIO3 deficiency is of consequence for social behaviors. Although we did not observe alterations in sociability, Dio3?/? mice of both sexes exhibited a significant increase in aggression‐related behaviors and mild deficits in olfactory function. In addition, 85% of Dio3?/? dams manifested no pup‐retrieval behavior and increased aggression toward the newborns. The abnormal social behaviors of Dio3?/? mice were associated with sexually dimorphic alterations in the physiology of oxytocin (OXT) and arginine vasopressin (AVP), 2 neuropeptides with important roles in determining social interactions. These alterations included low adult serum levels of OXT and AVP, and an abnormal expression of Oxt, Avp and their receptors in the neonatal and adult hypothalamus. Our results demonstrate that DIO3 is essential for normal aggression and maternal behaviors, and indicate that abnormal local regulation of thyroid hormone action in the brain may contribute to the social deficits associated with neurodevelopmental disorders.     

Maternal and offspring methylenetetrahydrofolate‐reductase genotypes interact in a mouse model to induce autism spectrum disorder‐like behavior

Individuals with autism constitute a variable population whose members are spread along the autism spectrum. Subpopulations within that spectrum exhibit other conditions, such as anxiety, intellectual disabilities, hyperactivity and epilepsy, with different severities and co‐occurrences. Among the genes associated with the increased risk for autism is the methylenetetrahydrofolate‐reductase (MTHFR) 677C>T polymorphism, which impairs one‐carbon (C1) metabolic pathway efficiency. The frequency of the MTHFR677TT homozygote is markedly higher among autism patients and their mothers than in the general population. Here, we report on the Mthfr heterozygous knockout (KO) mouse as a rodent model of autism that shows the contributions of maternal and offspring genotypes to the development of autistic‐like behaviors. Maternal Mthfr‐deficiency was associated with developmental delays in morphogenic features and sensory‐motor reflexes in offspring. In the adult male mouse, behaviors representing core autism symptoms, such as repetitive behavior and restricted interest, were affected by maternal genotype while social behaviors were affected by both maternal and offspring genotypes. In females and males, behaviors associated with autism such as memory impairment, social aggression and anxiety were affected by both the maternal and offspring Mthfr genotypes, with sex‐dependent differences. Mthfr‐deficient male mice with observable impacts on behavior presented a particular laminar disturbance in parvalbumin interneuron density and innervation in superficial and deep layers of the cingulate cortex. This mouse model of autism will help to elucidate the molecular mechanisms that predispose a significant subgroup of autistic patients to abnormal development and to distinguish between the in‐utero and autonomous factors involved in autism.     

Activity‐regulated cytoskeleton‐associated protein (Arc/Arg3.1) regulates anxiety‐ and novelty‐related behaviors

The activity‐regulated cytoskeleton‐associated protein (Arc, also known as Arg3.1) regulates glutamatergic synapse plasticity and has been linked to neuropsychiatric illness; however, its role in behaviors associated with mood and anxiety disorders remains unclear. We find that stress upregulates Arc expression in the adult mouse nucleus accumbens (NAc)—a brain region implicated in mood and anxiety behaviors. Global Arc knockout mice have altered AMPAR‐subunit surface levels in the adult NAc, and the Arc‐deficient mice show reductions in anxiety‐like behavior, deficits in social novelty preference, and antidepressive‐like behavior. Viral‐mediated expression of Arc in the adult NAc of male, global Arc KO mice restores normal levels of anxiety‐like behavior in the elevated plus maze (EPM). Consistent with this finding, viral‐mediated reduction of Arc in the adult NAc reduces anxiety‐like behavior in male, but not female, mice in the EPM. NAc‐specific reduction of Arc also produced significant deficits in both object and social novelty preference tasks. Together our findings indicate that Arc is essential for regulating normal mood‐ and anxiety‐related behaviors and novelty discrimination, and that Arc's function within the adult NAc contributes to these behavioral effects.     

Severe deficits in 5‐HT2A‐mediated neurotransmission in BDNF conditional mutant mice

BDNF is thought to provide critical trophic support for serotonin neurons. In order to determine postnatal effects of BDNF on the serotonin system, we examined a line of conditional mutant mice that have normal brain content of BDNF during prenatal development but later depletion of this neurotrophin in the postnatal period. These mice show a behavioral phenotype that suggests serotonin dysregulation. However, as shown here, the presynaptic serotonin system in the adult conditional mutant mice appeared surprisingly normal from histological, biochemical, and electrophysiological perspectives. By contrast, a dramatic and unexpected postsynaptic 5‐HT_2A deficit in the mutant mice was found. Electrophysiologically, serotonin neurons appeared near normal except, most notably, for an almost complete absence of expected 5‐HT_2A‐mediated glutamate and GABA postsynaptic potentials normally displayed by these neurons. Further analysis showed that BDNF mutants had much reduced 5‐HT_2A receptor protein in dorsal raphe nucleus and a similar deficit in prefrontal cortex, a region that normally shows a high level of 5‐HT_2A receptor expression. Recordings in prefrontal slice showed a marked deficit in 5‐HT_2A‐mediated excitatory postsynaptic currents, similar to that seen in the dorsal raphe. These findings suggest that postnatal levels of BDNF play a relatively limited role in maintaining presynaptic aspects of the serotonin system and a much greater role in maintaining postsynaptic 5‐HT_2A and possibly other receptors than previously suspected. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006     

Paternal aggression in a biparental mouse: parallels with maternal aggression

Environmental and social factors have important effects on aggressive behaviors. We examined the effect of reproductive experience on aggression in a biparental species of mouse, Peromyscus californicus. Estrogens are important in mediating aggressive behavior so we also examined estrogen receptor expression and c-fos for insights into possible mechanisms of regulation. Parental males were significantly more aggressive than virgin males, but no significant differences in estrogen receptor alpha or beta expression were detected. Patterns of c-fos following aggression tests suggested possible parallels with maternal aggression. Parental males had more c-fos positive cells in the medial amygdala, and medial preoptic area relative to virgin males. The medial preoptic area is generally considered to be relatively less important for male-male aggression in rodents, but is known to have increased activity in the context of maternal aggression. We also demonstrated through habituation-dishabituation tests that parental males show exaggerated investigation responses to chemical cues from a male intruder, suggesting that heightened sensory responses may contribute to increased parental aggression. These data suggest that, in biparental species, reproductive experience leads to the onset of paternal aggression that may be analogous to maternal aggression.     

Impaired reproductive behavior by lack of GluR-B containing AMPA receptors but not of NMDA receptors in hypothalamic and septal neurons

The roles of ionotropic glutamate receptors in mammalian reproduction are unknown. We therefore generated mice lacking a major subtype of (S)-alpha-amino-3-hydroxy-5-methyl-isoxazolepropionic acid (AMPA) receptors or all N-methyl-d-aspartate (NMDA) receptors in GnRH neurons and other mainly limbic system neurons, primarily in hypothalamic and septal areas. Male mice without NMDA receptors in these neurons were not impaired in breeding and exhibited similar GnRH secretion as control littermates. However, male mice lacking GluR-B containing AMPA receptors in these neurons were poor breeders and severely impaired in reproductive behaviors such as aggression and mounting. Testis and sperm morphology, testis weight, and serum testosterone levels, as well as GnRH secretion, were unchanged. Contact with female cage bedding failed to elicit male sexual behavior in these mice, unlike in control male littermates. Their female counterparts had unchanged ovarian morphology, had bred successfully, and had normal litter sizes but exhibited pronounced impairments in maternal behaviors such as pup retrieval and maternal aggression. Our results suggest that NMDA receptors and GluR-B containing AMPA receptors are not essential for fertility, but that GluR-B containing AMPA receptors are essential for male and female reproduction-related behaviors, perhaps by mediating responses to pheromones or odorants.     

Deficiency of sterol regulatory element‐binding protein‐1c induces schizophrenia‐like behavior in mice

Schizophrenia is a hereditary disease that approximately 1% of the worldwide population develops. Many studies have investigated possible underlying genes related to schizophrenia. Recently, clinical studies suggested sterol regulatory element‐binding protein (SREBP) as a susceptibility gene in patients with schizophrenia. SREBP controls cellular lipid homeostasis by three isoforms: SREBP‐1a, SREBP‐1c and SREBP‐2. This study used SREBP‐1c knockout (KO) mice to examine whether a deficiency in SREBP‐1c would affect their emotional and psychiatric behaviors. Altered mRNA expression in genes downstream from SREBP‐1c was confirmed in the brains of SREBP‐1c KO mice. Schizophrenia‐like behavior, including hyperactivity during the dark phase, depressive‐like behavior, aggressive behavior and deficits in social interaction and prepulse inhibition, was observed in SREBP‐1c KO mice. Furthermore, increased volume of the lateral ventricle was detected in SREBP‐1c KO mice. The mRNA levels of several γ‐aminobutyric acid (GABA)‐receptor subtypes and/or glutamic acid decarboxylase 65/67 decreased in the hippocampus and medial prefrontal cortex of SREBP‐1c KO mice. Thus, SREBP‐1c deficiency may contribute to enlargement of the lateral ventricle and development of schizophrenia‐like behaviors and be associated with altered GABAergic transmission.     

Maternal nurturing is dependent on her innate anxiety: the behavioral roles of brain oxytocin and vasopressin

The maternal brain undergoes remarkable physiological and behavioral changes in the peripartum period to meet the demands of the offspring. Here, the brain neuropeptides oxytocin and vasopressin, together with prolactin, play important roles. These neuropeptides are critically involved in the regulation of maternal behavior. Furthermore, reduced anxiety in lactation is another adaptation of the maternal brain. Therefore, a link between maternal behavior and maternal anxiety has been repeatedly postulated. This is supported by our studies in rats bred for high (HAB) and low (LAB) anxiety-related behavior. While female HAB rats become less anxious in lactation, their anxiety level is still four times higher compared with LAB dams. Interestingly, HAB dams display an intense and protective mothering style including increased arched back nursing and pup retrieval whereas LAB dams display only low levels of maternal care. The amount of maternal care directed towards the pups correlates with the mother's innate anxiety. In addition to differences in maternal care, HAB dams are also more protective as they show heightened aggression against a virgin intruder compared with the less aggressive LAB dams. The level of maternal aggression correlates with both their innate anxiety level as well as with the release of oxytocin and vasopressin in hypothalamic and limbic brain areas. Importantly, manipulations of the brain oxytocin and vasopressin systems alter maternal behavior and — depending on the brain region — can also alter the dam's anxiety. Thus, the mother's innate anxiety determines her maternal performance and oxytocin and vasopressin are involved in both parameters.     

Brain vasopressin signaling modulates aspects of maternal behavior in lactating rats

The brain vasopressin system mediates various social behaviors as has been studied mostly in males. Only recently, advances in social neuroscience revealed that central vasopressin signaling via its V1a and V1b receptors also facilitates female social behavior, including maternal behavior. In this review, we show how maternal care, maternal motivation and maternal aggression of lactating rat mothers are modulated in a V1 receptor subtype‐ and brain region‐specific manner. Measuring local release pattern of vasopressin via intracerebral microdialysis in the behaving rat mother as well as using pharmacological approaches to activate or block vasopressin receptors with subsequent behavioral observation provide detailed insight into the functional role of the vasopressin system in maternal behavior. In this context, the complementary rat animal model of high (HAB) and low anxiety‐related behavior (LAB) is particularly helpful due to the genetically determined high activity of the vasopressin gene in HAB rats, which also underlies their high levels of maternal behavior. Furthermore, first studies in humans indicate that the vasopressin system in general and the V1a receptor in more particular might mediate mothering.     

NPY‐Y1 coexpressed with NPY‐Y5 receptors modulate anxiety but not mild social stress response in mice

The Y1 and Y5 receptors for neuropeptide Y have overlapping functions in regulating anxiety. We previously demonstrated that conditional removal of the Y1 receptor in the Y5 receptor expressing neurons in juvenile Npy1r^Y5R?/? mice leads to higher anxiety but no changes in hypothalamus‐pituitary‐adrenocortical axis activity, under basal conditions or after acute restraint stress. In the present study, we used the same conditional system to analyze the specific contribution of limbic neurons coexpressing Y1 and Y5 receptors on the emotional and neuroendocrine responses to social chronic stress, using different housing conditions (isolation vs. group‐housing) as a model. We demonstrated that control Npy1r^2lox male mice housed in groups show increased anxiety and hypothalamus‐pituitary‐adrenocortical axis activity compared with Npy1r^2lox mice isolated for six weeks immediately after weaning. Conversely, Npy1r^Y5R?/? conditional mutants display an anxious‐like behavior but no changes in hypothalamus‐pituitary‐adrenocortical axis activity as compared with their control littermates, independently of housing conditions. These results suggest that group housing constitutes a mild social stress for our B6129S mouse strain and they confirm that the conditional inactivation of Y1 receptors specifically in Y5 receptor containing neurons increases stress‐related anxiety without affecting endocrine stress responses.     

Changes in the Expression of Monoaminergic Genes under the Influence of Repeated Experience of Agonistic Interactions: From Behavior to Gene

The role of genetic and environmental factors as well as brain neurochemistry in regulating aggressive and submissive behaviors in animals are considered. We present a review of data on changes in brain monoaminergic activity (synthesis, catabolism, receptors) and on the expression of monoaminergic genes under repeated daily agonistic confrontations in male mice. A repeated experience of aggression was shown to result in the total activation of the dopaminergic systems and the inhibition of the serotonergic one. This was accompanied by a decrease in the mRNA level of the cathecol-O-methyltransferase gene in the midbrain and an increase of the mRNA level of the dopamine transporter and tyrosine hydroxylase genes in the ventral tegmental area of aggressive male mice. Repeated experience of social defeats produced dynamic changes in the serotonergic system of some brain areas and an increase of the mRNA level of the serotonin transporter and monoamine oxidase A genes in the midbrain raphe nuclei. Theoretical and methodological possibilities of the proposed ethological approach for studying molecular mechanisms of agonistic behavior are discussed in the context of the fundamental problem of investigating the ways of regulation from behavior to gene.     

Vomeronasal phenotype and behavioral alterations in G alpha i2 mutant mice

Several social and reproductive behaviors are under the influence of the vomeronasal (VN) organ; VN neurons detect odorous molecules emitted by individuals of the same species. There are two types of VN neurons, and these differ in their expression of chemosensory receptors and G protein subunits. The significance of this dichotomy is largely unknown. VN neurons express high levels of either G alpha i2 or G alpha o. A mouse line carrying a targeted disruption of the G alpha i2 gene offered the opportunity for studying the effects of a lack of receptor signaling through the heterotrimeric Gi2 protein in one VN cell type. As a consequence of this deficiency, the number of VN neurons that normally express G alpha i2 is decreased by half. These residual neurons are defective in eliciting a response in their target neurons in the accessory olfactory bulb. Moreover, G alpha i2 mutant mice show alterations in behaviors for which an intact VN organ is known to be important. Display of maternal aggressive behavior is severely blunted, and male mice show significantly less aggression toward an intruder. However, male mice show unaltered sexual-partner preference. This suggests that the two types of VN neurons may have separate functions in mediating behavioral changes in response to chemosensory information.     

Hippocampal SPARC regulates depression‐related behavior

SPARC (secreted protein acidic and rich in cysteine) is a matricellular protein highly expressed during development, reorganization and tissue repair. In the central nervous system, glial cells express SPARC during development and in neurogenic regions of the adult brain. Astrocytes control the glutamate receptor levels in the developing hippocampus through SPARC secretion. To further characterize the role of SPARC in the brain, we analyzed the hippocampal‐dependent adult behavior of SPARC KO mice. We found that SPARC KO mice show increased levels of anxiety‐related behaviors and reduced levels of depression‐related behaviors. The antidepressant‐like phenotype could be rescued by adenoviral vector‐mediated expression of SPARC in the adult hippocampus, but anxiety‐related behavior persisted in these mice. To identify the cellular mechanisms underlying these behavioral alterations, we analyzed neuronal activity and neurogenesis in the dentate gyrus (DG). SPARC KO mice have increased levels of neuronal activity, evidenced as more neurons that express c‐Fos after a footshock. SPARC also affects cell proliferation in the subgranular zone of the DG, although it does not affect maturation and survival of new neurons. SPARC expression in the adult DG does not revert the proliferation phenotype in KO mice, but our results suggest a role of SPARC in limiting the survival of new neurons in the DG. This work suggests that SPARC could affect anxiety‐related behavior by modulating neuronal activity, and that depression‐related behavior is dependent upon the adult expression of SPARC, which affects adult brain function by mechanisms that need to be elucidated.     

Disruption of the vasopressin 1b receptor gene impairs the attack component of aggressive behavior in mice

Vasopressin affects behavior via its two brain receptors, the vasopressin 1a and vasopressin 1b receptors (Avpr1b). Recent work from our laboratory has shown that disruption of the Avpr1b gene reduces intermale aggression and reduces social motivation. Here, we further characterized the aggressive phenotype in Avpr1b -/- (knockout) mice. We tested maternal aggression and predatory behavior. We also analyzed the extent to which food deprivation and competition over food increases intermale aggression. We quantified defensive behavior in Avpr1b -/- mice and later tested offensive aggression in these same mice. Our results show that attack behavior toward a conspecific is consistently reduced in Avpr1b -/- mice. Predatory behavior is normal, suggesting that the deficit is not because of a global inability to detect and attack stimuli. Food deprivation, competition for food and previous experience increase aggression in both Avpr1b +/+ and -/- mice. However, in these circumstances, the level of aggression seen in knockout mice is still less than that observed in wild-type mice. Defensive avoidance behaviors, such as boxing and fleeing, are largely intact in knockout mice. Avpr1b -/- mice do not display as many 'retaliatory' attacks as the Avpr1b +/+ mice. Interestingly, when territorial aggression was measured following the defensive behavior testing, Avpr1b -/- mice typically show less initial aggressive behavior than wild-type mice, but do show a significant increase in aggression with repeated testing. These studies confirm that deficits in aggression in Avpr1b -/- mice are limited to aggressive behavior involving the attack of a conspecific. We hypothesize that Avpr1b plays an important role in the central processing that couples the detection and perception of social cues (which appears normal) with the appropriate behavioral response.     

Attenuated stress‐evoked anxiety,increased sucrose preference and delayed spatial learning in glucocorticoid‐induced receptor‐deficient mice

The glucocorticoid‐induced receptor (GIR) is a stress‐responsive gene that is abundantly expressed in forebrain limbic regions. Glucocorticoid‐induced receptor has been classified as a Neuropeptide Y‐like receptor, however, physiological attributes have not been investigated. In this study, mice lacking GIR (?/?) were screened in various paradigms related to stress, anxiety, activity, memory, fear and reward. GIR ?/? mice elicited behavioral insensitivity to the anxiogenic effects of restraint stress. However, hypothalamic pituitary adrenal axis response to stress was not impacted by GIR deficiency. Increased preference for sucrose was observed in GIR ?/? mice suggestive of modulation of reward‐associated behaviors by the receptor. A delayed acquisition of spatial learning was also observed in GIR ?/? mice. There were no effects of genotype on the modulation of anxiety‐like behavior, activity, fear‐conditioning and extinction. Our data extend previous studies on GIR regulation by glucocorticoids and provide novel evidence for a role of GIR in reward, learning and the behavioral outcomes of stress .     

CB1 receptor signaling regulates social anxiety and memory

The endocannabinoid (eCB) system regulates emotion, stress, memory and cognition through the cannabinoid type 1 (CB₁) receptor. To test the role of CB₁ signaling in social anxiety and memory, we utilized a genetic knockout (KO) and a pharmacological approach. Specifically, we assessed the effects of a constitutive KO of CB₁ receptors (CB₁KOs) and systemic administration of a CB₁ antagonist (AM251; 5 mg/kg) on social anxiety in a social investigation paradigm and social memory in a social discrimination test. Results showed that when compared with wild‐type (WT) and vehicle‐treated animals, CB₁KOs and WT animals that received an acute dose of AM251 displayed anxiety‐like behaviors toward a novel male conspecific. When compared with WT animals, KOs showed both active and passive defensive coping behaviors, i.e. elevated avoidance, freezing and risk‐assessment behaviors, all consistent with an anxiety‐like profile. Animals that received acute doses of AM251 also showed an anxiety‐like profile when compared with vehicle‐treated animals, yet did not show an active coping strategy, i.e. changes in risk‐assessment behaviors. In the social discrimination test, CB₁KOs and animals that received the CB₁ antagonist showed enhanced levels of social memory relative to their respective controls. These results clearly implicate CB₁ receptors in the regulation of social anxiety, memory and arousal. The elevated arousal/anxiety resulting from either total CB₁ deletion or an acute CB₁ blockade may promote enhanced social discrimination/memory. These findings may emphasize the role of the eCB system in anxiety and memory to affect social behavior .     

Persistent conditioned place preference to aggression experience in adult male sexually‐experienced CD‐1 mice

We recently developed a conditioned place preference (CPP) procedure, commonly used to study rewarding drug effects, to demonstrate that dominant sexually‐experienced CD‐1 male mice form CPP to contexts previously associated with defeating subordinate male C57BL/6J mice. Here we further characterized conditioned and unconditioned aggression behavior in CD‐1 mice. In Exp. 1 we used CD‐1 mice that displayed a variable spectrum of unconditioned aggressive behavior toward younger subordinate C57BL/6J intruder mice. We then trained the CD‐1 mice in the CPP procedure where one context was intruder‐paired, while a different context was not. We then tested for aggression CPP 1 day after training. In Exp. 2, we tested CD‐1 mice for aggression CPP 1 day and 18 days after training. In Exp. 3–4, we trained the CD‐1 mice to lever‐press for palatable food and tested them for footshock punishment‐induced suppression of food‐reinforced responding. In Exp. 5, we characterized unconditioned aggression in hybrid CD‐1 × C57BL/6J D1‐Cre or D2‐Cre F1 generation crosses. Persistent aggression CPP was observed in CD‐1 mice that either immediately attacked C57BL/6J mice during all screening sessions or mice that gradually developed aggressive behavior during the screening phase. In contrast, CD‐1 mice that did not attack the C57BL/6J mice during screening did not develop CPP to contexts previously paired with C57BL/6J mice. The aggressive phenotype did not predict resistance to punishment‐induced suppression of food‐reinforced responding. CD‐1 × D1‐Cre or D2‐Cre F1 transgenic mice showed strong unconditioned aggression. Our study demonstrates that aggression experience causes persistent CPP and introduces transgenic mice for circuit studies of aggression.     

Changes in the expression of monoaminergic genes under the influence of repeated experience of agonistic interactions: from behavior to gene

The role of genetic and environmental factors as well as brain neurochemistry in regulating aggressive and submissive behaviors in animals are considered. We present a review of data on changes in brain monoaminergic activity (synthesis, catabolism, receptors) and on the expression of monoaminergetic genes under repeated daily agonistic confrontations in male mice. A repeated experience of aggression was shown to result in the total activation of the dopaminergic system and the inhibition of the serotonergic one. This was accompanied by a decrease in the mRNA level of the catechol-O-methyltransferase gene in the midbrain and an increase of the mRNA level of the dopamine transporter and tyrosine hydroxylase genes in the ventral tegmental area of aggressive male mice. Repeated experience of social defeats produced dynamic changes in the serotonergic system of some brain areas and an increase of the mRNA level of the serotonin transporter and monoamine oxidase A genes in the midbrain raphe nuclei. Theoretical and methodological possibilities of the proposed ethological approach for studying molecular mechanisms of agonistic behavior are discussed in the context of the fundamental problem of investigating the ways of regulation from behavior to gene.     

Effect of the D1-receptor antagonist SCH-23390 on the individual and aggressive behavior in male mice with various aggression experience

It has been shown that dopaminergic systems are involved in mechanisms of aggressive behavior. Effects of SCH 23390 (dopamine Di receptors antagonist. 0-1 mg/kg, i/p, 30 min) on aggressive and individual behaviors were studied in male C57BL/6J mice with different experience of aggression. SCH 23390 reduced aggressive attacks in animals without preliminary experience of aggression. However total time of hostile behavior (sum of the total time of attacks, aggressive grooming and diggings) didn't changed. No significant effects on behaviors were found in mice with long (20 days) repeated experience of aggression. It was supposed that long aggressive experience produces pharmacological desensitization of Di receptors as a result of enhanced dopaminergic activity shown earlier in aggressive animals.