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Pubertal male Syrian hamsters (Mesocricetus auratus) treated with anabolic/androgenic steroids (AASs) during adolescence (P27-P56) display a highly intense aggressive phenotype that shares many behavioral similarities with pathological aggression in youth. Anticonvulsant drugs like valproate that enhance the activity of the γ-aminobutyric acid (GABA) neural system in the brain have recently gained acceptance as a primary treatment for pathological aggression. This study examined whether valproate would selectively suppress adolescent AAS-induced aggressive behavior and whether GABA neural signaling through GABAA subtype receptors in the latero-anterior hypothalamus (LAH; an area of convergence for developmental and neuroplastic changes that underlie aggression in hamsters) modulate the aggression-suppressing effect of this anticonvulsant medication. Valproate (1.0-10.0 mg/kg, intraperitoneal) selectively suppressed the aggressive phenotype in a dose-dependent fashion, with the effective anti-aggressive effects beginning at 5 mg/kg, intraperitoneally. Microinfusion of the GABAA receptor antagonist bicuculline (7.0-700 ng) into the LAH reversed valproate's suppression of AAS-induced aggression in a dose-dependent fashion. At the 70 ng dose of bicuculline, animals expressed the highly aggressive baseline phenotype normally observed in AAS-treated animals. These studies provide preclinical evidence that the anticonvulsant valproate selectively suppresses adolescent, AAS-induced aggression and that this suppression is modulated, in part, by GABA neural signaling within the LAH., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Male Syrian hamsters (Mesocricetus auratus) administered anabolic/androgenic steroids during adolescent development display increased aggression and decreased anxious behavior during the adolescent exposure period. Upon withdrawal from anabolic/androgenic steroids, this neurobehavioral relationship shifts and hamsters exhibit decreased aggression and increased anxious behavior. This study investigated the hypothesis that alterations in anterior hypothalamic signaling through serotonin type-3 receptors modulate the behavioral shift between adolescent anabolic/androgenic steroid-induced aggressive and anxious behaviors during the withdrawal period. To test this, hamsters were administered anabolic/androgenic steroids during adolescence then withdrawn from drug exposure for 21 days and tested for aggressive and anxious behaviors following direct pharmacological manipulation of serotonin type-3 receptor signaling within the latero-anterior hypothalamus. Blockade of latero-anterior hypothalamic serotonin type-3 receptors both increased aggression and decreased anxious behavior in steroid-treated hamsters, effectively reversing the pattern of behavioral responding normally observed during anabolic/androgenic steroid withdrawal. These findings suggest that the state of serotonin neural signaling within the latero-anterior hypothalamus plays an important role in behavioral shifting between aggressive and anxious behaviors following adolescent exposure to anabolic/androgenic steroids., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Adolescent Syrian hamsters (Mesocricetus auratus) treated with anabolic/androgenic steroids display increased offensive aggression and decreased anxiety correlated with an increase in vasopressin afferent development, synthesis, and neural signaling within the anterior hypothalamus. Upon withdrawal from anabolic/androgenic steroids, this neurobehavioral relationship shifts as hamsters display decreased offensive aggression and increased anxiety correlated with a decrease in anterior hypothalamic vasopressin. This study investigated the hypothesis that alterations in anterior hypothalamic vasopressin neural signaling modulate behavioral shifting between adolescent anabolic/androgenic steroid-induced offensive aggression and anxiety. To test this, adolescent male hamsters were administered anabolic/androgenic steroids and tested for offensive aggression or anxiety following direct pharmacological manipulation of vasopressin V1A receptor signaling within the anterior hypothalamus. Blockade of anterior hypothalamic vasopressin V1A receptor signaling suppressed offensive aggression and enhanced general and social anxiety in hamsters administered anabolic/androgenic steroids during adolescence, effectively reversing the pattern of behavioral response pattern normally observed during the adolescent exposure period. Conversely, activation of anterior hypothalamic vasopressin V1A receptor signaling enhanced offensive aggression in hamsters exposed to anabolic/androgenic steroids during adolescence. Together, these findings suggest that the state of vasopressin neural development and signaling in the anterior hypothalamus plays an important role in behavioral shifting between aggression and anxiety following adolescent exposure to anabolic/androgenic steroids., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Syrian hamsters exposed to anabolic/androgenic steroids (AAS) during adolescence consistently show increased aggressive behavior across studies. Although the behavioral and anatomical profiles of AAS-induced alterations have been well characterized, there is a lack of data describing physiological changes that accompany these alterations. For instance, behavioral pharmacology and neuroanatomical studies show that AAS-induced changes in the vasopressin (AVP) neural system within the latero-anterior hypothalamus (LAH) interact with the serotonin (5HT) and dopamine (DA) systems to modulate aggression. To characterize the electrophysiological profile of the AAS aggression circuit, we recorded LAH neurons in adolescent male hamsters in vivo and microiontophoretically applied agonists and antagonists of aggressive behavior. The interspike interval (ISI) of neurons from AAS-treated animals correlated positively with aggressive behaviors, and adolescent AAS exposure altered parameters of activity in regular firing neurons while also changing the proportion of neuron types (i.e., bursting, regular, irregular). AAS-treated animals had more responsive neurons that were excited by AVP application, while cells from control animals showed the opposite effect and were predominantly inhibited by AVP. Both DA D2 antagonists and 5HT increased the firing frequency of AVP-responsive cells from AAS animals and dual application of AVP and D2 antagonists doubled the excitatory effect of AVP or D2 antagonist administration alone. These data suggest that multiple DA circuits in the LAH modulate AAS-induced aggressive responding. More broadly, these data show that multiple neurochemical interactions at the neurophysiological level are altered by adolescent AAS exposure., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Previously, we have shown that anabolic androgenic steroid (AAS) exposure throughout adolescence stimulates offensive aggression while also reducing anxious behaviors during the exposure period. Interestingly, AAS exposure through development correlates with alterations to the serotonin system in regions known to contain 5HT3 receptors that influence the control of both aggression and anxiety. Despite these effects, little is known about whether these separate developmental AAS-induced behavioral alterations occur as a function of a common neuroanatomical locus. To begin to address this question, we localized 5HT3 receptors in regions that have been implicated in aggression and anxiety. To examine the impact these receptors may have on AAS alterations to behavior, we microinjected the 5HT3 agonist mCPBG directly into a region know for its influence over aggressive behavior, the lateral division of the anterior hypothalamus, and recorded alterations to anxious behaviors using the elevated plus maze. AAS exposure primarily reduced the presence of 5HT3 receptors in aggression/anxiety regions. Accordingly, mCPBG blocked the anxiolytic effects of adolescent AAS exposure. These data suggest that the 5HT3 receptor plays a critical role in the circuit modulating developmental AAS-induced changes to both aggressive and anxious behaviors, and further implicates the lateral division of the anterior hypothalamus as an important center for the negative behavioral effects of developmental AAS-exposure., (Copyright © 2015. Published by Elsevier Inc.)

Anabolic/androgenic steroid (AAS) use remains high in both teens and adults in the U.S. and worldwide despite studies showing that AAS use is associated with a higher incidence of aggression and anxiety. Recently we showed that chronic exposure to AAS through adolescence increases aggression and decreases anxious behaviors, while during AAS-withdrawal aggression is lowered to species-normative levels and anxiety increases. AAS exposure is known to differentially alter behaviors and their underlying neural substrates between adults and adolescents and thus the current study investigated whether exposure to AAS during adulthood affects the relationship between aggression and anxiety in a manner similar to that previously observed in adolescents. Male hamsters were administered a moderate dose of AAS (5.0mg/kg/day×30days) during adolescence (P27-56) or young adulthood (P65-P94) and then tested for aggression and anxiety during AAS exposure (i.e., on P57 or P95) and during AAS withdrawal (i.e., 30days later on P77 or P115). Adolescent exposure to AAS increased aggressive responding during the AAS exposure period and anxiety-like responding during AAS withdrawal. Neither behavior was similarly influenced by adult exposure to AAS. Adult AAS exposure produced no difference in aggressive responding during AAS exposure (P95) or AAS withdrawal (P115); however, while AAS exposure during adulthood produced no difference in anxiety-like responding during AAS exposure, adult hamsters administered AAS were less anxious than vehicle control animals following AAS withdrawal. Together these data suggest that the aggression and anxiety provoking influence of AAS are likely a developmental phenomenon and that adult exposure to AAS may be anxiolytic over the long term., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Male Syrian hamsters (Mesocricetus auratus) treated with anabolic/androgenic steroids (AAS) during adolescence (P27-P56) display highly escalated and mature forms of offensive aggression correlated with increased γ-aminobutyric acid (GABA) afferent development as well as decreased GABAA receptors in the lateroanterior hypothalamus (LAH) - an area of convergence for developmental and neuroplastic changes that underlie offensive aggressive behaviors in hamsters. This study investigated whether microinfusion of a GABAA receptor agonist (muscimol; 0.01-1.0 pmol/l) or antagonist (bicuculline; 0.04-4.0 pmol/l) directly into the LAH modulate adolescent AAS-induced offensive aggression. Activation of LAH GABAA receptors enhanced adolescent AAS-induced offensive aggression, beginning at the 0.1 pmol/l dose, when compared with AAS-treated animals injected with saline into the LAH. Importantly, GABAA receptor agonism within the LAH significantly increased the frequency of belly/rear attacks, while simultaneously decreasing the frequency of frontal attacks. These data identify a neuroanatomical locus where GABAA receptor activation functions to enhance aggression in adolescent AAS-treated animals, while also promoting the display of mature forms of aggression and suppressing juvenile play behaviors.

Aggression control has been investigated across species and is centrally mediated within various brain regions by several neural systems that interact at different levels. The debate over the degree to which any one system or region affects aggressive responding, or any behavior for that matter, in some senses is arbitrary considering the plastic and adaptive properties of the central nervous system. Nevertheless, from the reductionist point of view, the compartmentalization of evolutionarily maladaptive behaviors to specific regions and systems of the brain is necessary for the advancement of clinical treatments (e.g., pharmaceutical) and novel therapeutic methods (e.g., deep brain stimulation). The general purpose of this chapter is to examine the confluence of two such systems, and how their functional interaction affects aggressive behavior. Specifically, the influence of the serotonin (5HT) and arginine vasopressin (AVP) neural systems on the control of aggressive behavior will be examined individually and together to provide a context by which the understanding of aggression modulation can be expanded from seemingly parallel neuromodulatory mechanisms, to a single and highly interactive system of aggression control.

In the U.S. and worldwide anabolic/androgenic steroid use remains high in the adolescent population. This is concerning given that anabolic/androgenic steroid use is associated with a higher incidence of aggressive behavior during exposure and anxiety during withdrawal. This study uses pubertal Syrian hamsters (Mesocricetus auratus) to investigate the hypothesis that an inverse behavioral relationship exists between anabolic/androgenic steroid-induced aggression and anxiety across adolescent exposure and withdrawal. In the first experiment, we examined aggression and anxiety during adolescent anabolic/androgenic steroid exposure and withdrawal. Adolescent anabolic/androgenic steroid administration produced significant increases in aggression and decreases in anxiety during the exposure period followed by significant decreases in aggression and increases in anxiety during anabolic/androgenic steroid withdrawal. In a second experiment, anabolic/androgenic steroid exposed animals were separated into groups based on their aggressive response during the exposure period and then tested for anxiety during exposure and then for both aggression and anxiety during withdrawal. Data were analyzed using a within-subjects repeated measures predictive analysis. Linear regression analysis revealed that the difference in aggressive responding between the anabolic/androgenic steroid exposure and withdrawal periods was a significant predictor of differences in anxiety for both days of testing. Moreover, the combined data suggest that the decrease in aggressive behavior from exposure to withdrawal predicts an increase in anxiety-like responding within these same animals during this time span. Together these findings indicate that early anabolic/androgenic steroid exposure has potent aggression- and anxiety-eliciting effects and that these behavioral changes occur alongside a predictive relationship that exists between these two behaviors over time., (© 2013.)

Winning an aggressive encounter enhances the probability of winning future contests. This phenomenon, known as the winner effect, has been well studied across vertebrate species. While numerous animal models have been developed to study the winner effect in the laboratory setting, large variation in experimental design, choice of species, and housing conditions have resulted in conflicting reports on the behavioral outcomes. The Syrian hamster (Mesocricetus auratus) presents as a novel species with face validity to study the effects of repeated fighting on subsequent agonistic encounters. After a 14-day training period, "trained fighter" hamsters displayed elevated fighting behaviors characterized by more intense and severe displays of aggression along with increased displays of dominant postures compared to naïve residents with no prior social experience. To determine whether these phenotypic changes in fighting behavior reflect alterations in neurochemistry, brains of aggressive and naïve hamsters were examined for changes in dopaminergic innervation in key regions known to control social and motivational behavior. Interestingly, changes in tyrosine hydroxylase, the rate limiting enzyme for dopamine production, were observed in brain regions within the social decision-making network. These increases in aggression observed after repeated winning may reflect a learned behavior resulting from increases in neurotransmitter activity which serve to reinforce the behavior. The data implicate the presence of a winner effect in hamsters and provide evidence for a neural mechanism underlying the changes in aggressive behavior after repeated agonistic encounters., (© 2013 Wiley Periodicals, Inc.)

From the U.S. to Europe and Australia anabolic steroid abuse remains high in the adolescent population. This is concerning given that anabolic steroid use is associated with a higher incidence of pathological anxiety that often appears during withdrawal from use. This study uses pubertal Syrian hamsters (Mesocricetus auratus) to investigate the hypothesis that adolescent anabolic/androgenic steroid (AAS) exposure predisposes hamsters to heightened levels of anxiety during AAS withdrawal that is modulated by serotonin (5HT) neural signaling. In the first two sets of experiments, adolescent AAS-treated hamsters were tested for anxiety 21 days after the cessation of AAS administration (i.e., during AAS withdrawal) using the elevated plus maze (EPM), dark/light (DL), and seed finding (SF) tests and then examined for differences in 5HT afferent innervation to select areas of the brain important for anxiety. In the EPM and DL tests, adolescent AAS exposure leads to significant increases in anxiety-like response during AAS withdrawal. AAS-treated hamsters showed long-term reductions in 5HT innervation within several areas of the hamster brain implicated in anxiety, most notably the anterior hypothalamus and the central and medial amygdala. However, no differences in 5HT were found in other anxiety areas, e.g., frontal cortex and lateral septum. In the last experiment, adolescent AAS-treated hamsters were scored for anxiety on the 21st day of AAS withdrawal following the systemic administration of saline or one of three doses of fluoxetine, a selective serotonin reuptake inhibitor. Saline-treated hamsters showed high levels of AAS withdrawal-induced anxiety, while treatment with fluoxetine reduced AAS withdrawal-induced anxiety. These findings indicate that early AAS exposure has potent anxiogenic effects during AAS withdrawal that are modulated, in part, by 5HT signaling., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Fluoxetine is the only selective serotonin reuptake inhibitor registered for the treatment of major depressive disorder in pediatric populations, despite reports that it is disproportionately associated with an array of adverse side effects that include agitation, hostility, and overt acts of pathological aggression and violence in youth. This study examined the effects of repeated adolescent fluoxetine administration on offensive aggression and the development of the serotonin (5HT) and vasopressin (AVP) neural systems modulating this behavior using pubertal Syrian hamsters (Mesocricetus auratus) as an adolescent-animal model. Adolescent hamsters administered fluoxetine were tested for offensive aggression using the resident/intruder test, sacrificed the following day, and, using immunohistochemistry, examined for 5HT and AVP afferent innervation/development to areas of the brain implicated in aggression control. Repeated exposure to a low dose (0.3 mg/kg/day) of fluoxetine during adolescence increased nearly all measures of offensive aggression (i.e., upright offensive attacks, lateral attacks, flank/rump bites, pursuits, flank marks), whereas measures of social interest (i.e., olfactory investigation, contact time), comfort (i.e., grooming), and locomotion (i.e., contact time, cage climbing) remained constant. Fluoxetine exposure also increased 5HT and AVP afferent development to brain areas implicated in aggressive behavior, most notably the latero-anterior hypothalamus (LAH)-an area of convergence for developmental and neuroplastic changes correlated with offensive aggression in hamsters. These data indicate that repeated administration of clinically relevant doses of fluoxetine during adolescent development directly stimulates aggressive behavior and alters LAH 5HT and AVP development, yet only alterations in AVP afferent development within the LAH correlate with the fluoxetine-induced aggressive behavioral phenotype., (PsycINFO Database Record (c) 2012 APA, all rights reserved.)

Treatment with anabolic-androgenic steroids (AAS) throughout adolescence facilitates offensive aggression in Syrian hamsters. In the anterior hypothalamus (AH), the dopaminergic neural system undergoes alterations after repeated exposure to AAS, producing elevated aggression. Previously, systemic administration of selective dopamine receptor antagonists has been shown to reduce aggression in various species and animal models. However, these reductions in aggression occur with concomitant alterations in general arousal and mobility. Therefore, to control for these systemic effects, the current studies utilized microinjection techniques to determine the effects of local antagonism of D2 and D5 receptors in the AH on adolescent AAS-induced aggression. Male Syrian hamsters were treated with AAS throughout adolescence and tested for aggression after local infusion of the D2 antagonist eticlopride, or the D5 antagonist SCH-23390, into the AH. Treatment with eticlopride showed dose-dependent suppression of aggressive behavior in the absence of changes in mobility. Conversely, while injection of SCH-23390 suppressed aggressive behavior, these reductions were met with alterations in social interest and locomotor behavior. To elucidate a plausible mechanism for the observed D5 receptor mediation of AAS-induced aggression, brains of AAS and sesame oil-treated animals were processed for double-label immunofluorescence of GAD₆₇ (a marker for GABA production) and D5 receptors in the lateral subdivision of the AH (LAH). Results indicate a sparse distribution of GAD₆₇ neurons colocalized with D5 receptors in the LAH. Together, these results indicate that D5 receptors in the LAH modulate non-GABAergic pathways that indirectly influence aggression control, while D2 receptors have a direct influence on AAS-induced aggression., ((PsycINFO Database Record (c) 2010 APA, all rights reserved).)

In the Syrian hamster, treatment with anabolic/androgenic steroids (AAS) throughout adolescence increases dopamine and D2 receptor expression in the anterior hypothalamus (AH), a brain region implicated in the control of aggression. D2 receptor antagonists have reduced aggression in various species and animal models. However, these studies used systemic administration of drugs and reported concomitant changes in mobility. These data complicate the question of whether pharmacology targeting D2 receptors is specific to aggression or whether these drugs exert their antiaggressive effects through nonspecific mechanisms. To resolve this discrepancy, the current studies investigate whether administration of the D2 receptor antagonist eticlopride (0.01-10.0 microg in a final volume of 0.5 microl) into the AH modulates AAS-induced aggression. Antagonism of AH D2 receptors effectively suppressed AAS-induced aggression beginning at the 0.1 microg dose, with higher doses producing a floor effect, when compared with AAS-treated animals injected with saline into the AH. Importantly, these reductions in aggressive responding occurred in the absence of changes in locomotor behavior. Our findings identify a neuroanatomical locus where D2 receptor antagonism suppresses adolescent AAS-induced aggression in the absence of alterations to general mobility.

Considerable public attention has been focused on the issue of youth violence, particularly that associated with drug use. It is documented that anabolic steroid use by teenagers is associated with a higher incidence of aggressive behavior and serious violence, yet little is known about how these drugs produce the aggressive phenotype. Here we discuss work from our laboratory on the relationship between the development and activity of select neurotransmitter systems in the anterior hypothalamus and anabolic steroid-induced offensive aggression using pubertal male Syrian hamsters (Mesocricetus auratus) as an adolescent animal model, with the express goal of synthesizing these data into an cogent neural model of the developmental adaptations that may underlie anabolic steroid-induced aggressive behavior. Notably, alterations in each of the neural systems identified as important components of the anabolic steroid-induced aggressive response occurred in a sub-division of the anterior hypothalamic brain region we identified as the hamster equivalent of the latero-anterior hypothalamus, indicating that this sub-region of the hypothalamus is an important site of convergence for anabolic steroid-induced neural adaptations that precipitate offensive aggression. Based on these findings we present in this review a neural model to explain the neurochemical regulation of anabolic steroid-induced offensive aggression showing the hypothetical interaction between the arginine vasopressin, serotonin, dopamine, gamma-aminobutyric acid, and glutamate neural systems in the anterior hypothalamic brain region., (Copyright 2009 Elsevier Inc. All rights reserved.)

Adolescent exposure to anabolic-androgenic steroids (AAS) produces alterations to various neurochemical systems resulting in an elevated aggressive response. Both the GABAergic and dopaminergic neural systems are implicated in aggression control and are altered in the presence of AAS. The present studies provide a detailed report of the interaction between D2 receptors and GABAergic neurons in the lateral subdivision of the anterior hypothalamus (LAH), a brain region at the center of aggression control. Male Syrian hamsters were administered AAS throughout adolescence and their brains were processed for double-label immunofluorescence of GAD67 and D2 receptors. Results indicate an increase in the number of D2-ir and GAD67-ir cells in the LAH of AAS-treated animals. Although there were several cells in the LAH colocalized with both GAD67 and D2 receptors, there were no significant increases in the number of double-labeled GAD67/D2-ir neurons. Together, the data suggest the possibility of multiple GABAergic systems in the LAH allowing for differential inhibition of various neural systems. Given these changes in the number of GABAergic cells, it is likely that adolescent AAS exposure also alters the expression of GABAA receptors in brain areas innervated by the LAH. Thus, hamster brains were processed for immunohistochemistry and quantified for changes in GABAA-ir. Interestingly, adolescent exposure to AAS produced a significant decrease in the number of GABAA-ir elements in the LAH of aggressive hamsters. Taken together, results from the current studies provide a putative mechanism whereby dopamine stimulates aggression through removal of GABA inhibition in the LAH of AAS-treated animals.

Rationale: The role of serotonin (5-HT) on aggression has been extensively studied; nonetheless, the role of this neurotransmitter in aggression is still inconclusive., Objectives: The current meta-analytical review investigated the role of increased 5-HT neurotransmission in aggression., Methods: Preclinical studies using serotonin reuptake inhibitors, 5-hydroxytryptophan, L-tryptophan, or serotonin (5-HT) to increase 5-HT levels were included in this meta-analysis. An overall effect of serotonin on aggression was calculated, and the role of several moderator variables was analyzed., Results: A total of 218 effect sizes revealed that increased 5-HT had an overall significant inhibitory effect on aggression (r = 0.3). The results showed that increased 5-HT had the strongest inhibitory effect on aggression when (1) a specific strain or species (e.g., Long Evans) was used; (2) aggression was offensive or predatory and/or induced by administration of 5,7-dihydroxytryptamine or p-chlorophenylalanine; (3) zimelidine, sertraline, L-tryptophan, citalopram, or 5-HT were used to increase 5-HT; (4) treatment was acute; (5) long chronic treatment durations were used; and (6) time between last injection and behavior testing was within 8 h before or after peak plasma concentration of drug. In contrast, the results revealed that increased-5-HT-facilitated aggression could be predicted when (1) Wistar rats, (2) social isolation or stress to induce aggression, and/or (3) animals treated for less than 3 weeks were used., Conclusions: Although 5-HT has an overall inhibitory effect on aggression, the animal's genetic background, drug, treatment time, aggression inducing paradigm, and aggression type are critical variables that influence and modify this effect.

Chronic anabolic-androgenic steroid (AAS) treatment during adolescence facilitates offensive aggression in male Syrian hamsters (Mesocricetus auratus). Serotonin (5-HT) modulates aggressive behavior and has been shown to be altered after chronic treatment with AAS. Furthermore, 5-HT type 2 receptors have been implicated in the control of aggression. For example, treatment with 5-HT(2A) receptor antagonists suppress the generation of the offensive aggressive phenotype. However, it is unclear whether these receptors are sensitive to adolescent AAS exposure. The current study assessed whether treatment with AAS throughout adolescence influenced the immunohistochemical localization of 5-HT(2A) in areas of the hamster brain implicated in the control of aggression. Hamsters were administered AAS (5.0 mg/kg) each day throughout adolescence, scored for offensive aggression, and then examined for differences in 5-HT(2A)-immunoreactivity (5-HT(2A)-ir). When compared with non-aggressive oil-treated controls, aggressive AAS-treated hamsters showed significant increases in 5-HT(2A)-ir fibers in the lateral portion of the anterior hypothalamus (LAH). Further analysis revealed that AAS treatment also produced a significant increase in the number of cells expressing 5-HT(2A)-ir in the LAH. Together, these results support a role for altered 5-HT(2A) expression and further implicate the LAH as a central brain region important in the control of adolescent AAS-induced offensive aggression.

Rationale: Atypical antipsychotics are commonly prescribed to clinically referred youngsters for treatment of heightened aggressive behavior associated with various psychiatric disorders. Previously, we demonstrated risperidone's anti-aggressive effects using a well-validated animal model of offensive aggression. Paliperidone, the main active metabolite of risperidone, is a potent serotonin-2A and dopamine-2 receptor antagonist with slightly different pharmacodynamic properties compared to risperidone. Given that much of risperidone's therapeutic efficacy is due to its active metabolite, paliperidone may effectively suppress aggression with fewer adverse side effects., Objectives: Investigate whether paliperidone administration would reduce heightened aggressive behavior induced by low-dose cocaine exposure in a developmentally sensitive model of offensive aggression., Materials and Methods: Male Syrian hamsters (n = 12/group) were administered an acute dose of paliperidone (0.05, 0.1, 0.2, and 0.3 mg/kg) and then tested for aggressive behavior using the resident-intruder paradigm. To investigate the effects of chronic paliperidone administration, a separate set of animals (n = 12/group) was exposed to repeated paliperidone administration (0.1 mg kg(-1) day(-1)) during different developmental periods and varying lengths of time (1-4 weeks)., Results: Experiment 1 results revealed a dose-dependent decrease in bite and attack behaviors with an effective dose observed at 0.1 mg/kg. In Experiment 2, the maximal reduction in aggressive behavior in response to chronic paliperidone treatment was observed in animals treated during the third week of adolescence, and this reduction occurred without concomitant alterations in non-aggressive behaviors., Conclusions: These results support the specific aggression-suppressing properties of paliperidone and the potential use of this compound in the treatment of maladaptive aggression in clinical settings.

Anabolic androgenic steroid (AAS) treatment throughout adolescence facilitates offensive aggression in male Syrian hamsters (Mesocricetus auratus). The present study was conducted to investigate the role of the dopaminergic system in the modulation of AAS-induced aggressive behavior. Hamsters were administered AAS during adolescence, scored for offensive aggression using the resident-intruder paradigm, and then examined for alterations in DA immunoreactivity in brain regions implicated in the aggressive phenotype, including the anterior hypothalamus (AH), the bed nucleus of the stria terminalis (BNST), the medial and central amygdala (MeA and CeA), the lateral septum (LS) and the ventrolateral hypothalamus (VLH). When compared with non-aggressive sesame-oil-treated controls, aggressive AAS-treated animals showed increased tyrosine hydroxylase immunoreactivity in anterior hypothalamic subnuclei, namely the nucleus circularis (NC) and medial supraoptic nucleus (mSON). In addition, AAS-treated animals showed altered D(2) receptor expression in the AH and the VLH, as measured by D(2)-immunoreactivity. Together these results suggest that alterations in DA synthesis and function together with modifications in D(2) receptor expression in the AH may underlie neuroplastic events which facilitate AAS-induced aggression.

Chronic treatment with anabolic-androgenic steroids (AAS) during adolescence alters the activity of various neurotransmitter systems in male Syrian hamsters (Mesocricetus auratus). The present study was conducted to determine whether glutamatergic cells in the lateral anterior hypothalamus (LAH), a sub-region of the anterior hypothalamus, have lasting activation following adolescent AAS exposure, and to examine AAS-induced alterations in the connections between the LAH and the ventrolateral hypothalamus (VLH) governed by glutamate. Hamsters were administered AAS during adolescence and then examined for changes in FOS (protein product of the immediate early gene c-fos) and phosphate activated glutaminase (PAG; the rate-limiting enzyme in the synthesis of glutamate) immunoreactivity (FOS/PAG-IR) using double-label immunohistochemistry. In a second experiment, a retrograde tracing study was conducted using a red fluorescent tracer microinjected into the VLH. Then brains were processes for PAG immunofluorescence and examined for AAS-induced changes in the number of PAG positive cells containing the tracer (PAG/Tracer) in the LAH. When compared to oil-treated controls, AAS-treated hamsters showed significant increases in PAG-IR and FOS/PAG-IR in the LAH, decreases in afferent innervation from the LAH to the VLH and decreases in the total number of glutamate cells in the LAH projecting to the VLH. Together with previous research from our lab showing increased AAS-induced expression of PAG in the AH and increased glutamate receptor expression in the VLH, the current results suggest that adolescent AAS exposure leads to alterations in the function and expression of the glutamatergic system as well as changes in hypothalamic neural connections. In addition, the current results further strengthen the notion that a specific nucleus in the AH, the LAH is a critical hypothalamic sub-region particularly sensitive to AAS-induced neurodevelopmental effects.

Risperidone has been shown to be clinically effective for the treatment of aggressive behavior in children, yet until recently no information was available regarding whether risperidone exhibits aggression-specific suppression in preclinical studies employing validated developmentally immature animal models of escalated aggression. Recently, using a pharmacologic animal model of escalated offensive aggression, we reported that acute risperidone treatment selectively and dose-dependently reduces the expression of the adult aggressive phenotype, with a significant reduction in aggressive responses observed at 0.1 mg/kg, i.e., a dose within the range administered to children and adolescents in the clinical setting. This study examined whether repeated exposure to risperidone during puberty would prevent the generation of the highly escalated aggressive phenotype in this animal model. To test this hypothesis, the aggression-eliciting stimulus (i.e., cocaine hydrochloride, 0.5 mg/kg/dayx28 days) was co-administered with an aggression-suppressing dose of risperidone (i.e., 0.1 mg/kg/day) during different time frames of puberty and for varied lengths of time (i.e., 1-4 weeks), and then animals were scored for targeted measures of offensive aggression during late puberty. Risperidone administration prevented the generation of the adult aggressive phenotype, with a complete blockade of matured offensive responses (i.e., lateral attacks and flank/rump bites) seen only after prolonged periods of exposure to risperidone (i.e., 3-4 weeks). The selective prevention of these aggressive responses, while leaving other measures of aggression intact (e.g., upright offensive postures), suggest that risperidone is acting in a highly discriminatory anti-aggressive fashion, targeting neurobehavioral elements important for the mature aggressive response pattern.

In hamsters (Mesocricetus auratus), anabolic-androgenic steroid (AAS) exposure during adolescence facilitates offensive aggression that is correlated with the enhanced development of the arginine vasopressin (AVP) neural system and reduced development of the serotonin (5-HT) neural system in the anterior hypothalamus (AH). This study examined the temporal onset of these effects by measuring aggression and AH AVP and 5-HT during progressively shorter periods of AAS exposure during adolescent development. The authors tested adolescent hamsters that received AAS for 3, 7, 14, or 28 days for offensive aggression and then examined the hamsters for AVP/5-HT afferent innervation to the AH using immunohistochemistry. While reductions in AH 5-HT afferent innervation were detectable by 7 days of AAS exposure, no concomitant increases in offensive aggression were observed compared to oil-treated littermates. In contrast, by Day 14 of AAS treatment, AH AVP and offensive aggression were significantly higher than oil-treated controls. These data indicate that relatively short-term adolescent AAS exposure alters aggression and AH 5-HT and AVP development, yet only alterations in AH AVP development correlate with temporal onset of the aggressive behavioral phenotype during adolescent AAS exposure., ((PsycINFO Database Record (c) 2007 APA, all rights reserved).)

Background: Risperidone has been shown to be clinically effective for the treatment of aggressive behavior in children, yet no information is available regarding whether risperidone exhibits aggression-specific suppression in preclinical studies that use validated developmentally immature animal models of escalated aggression. Previously, we have shown that exposure to low doses of the psychostimulant cocaine-hydrochloride (.5 mg/kg intraperitoneally) during the majority of pubertal development (postnatal days [P]27-57) generates animals that exhibit a high level of offensive aggression. This study examined whether risperidone exerts selective aggression-suppressing effects by using this pharmacologic animal model of highly escalated offensive aggression., Methods: Experimental hamsters were tested for offensive aggression after the acute administration of risperidone (.05-1.0 mg/kg, intraperitoneally)., Results: Risperidone dose-dependently reduced the highly aggressive phenotype, with a significant reduction observed at .1-.2 mg/kg for most aggressive responses measured. Experimental animals treated with higher doses of risperidone (.3-1.0 mg/kg) showed significant reductions in aggression and social interest toward intruders, indicating more general behavioral inhibition., Conclusions: These studies provide evidence that risperidone exerts specific aggression-suppressing effects in a developmentally immature animal model of escalated aggression.

Male Syrian hamsters (Mesocricetus auratus) treated with moderately high doses (5.0mg/kg/day) of anabolic/androgenic steroids (AAS) during adolescence (P27-P56) display highly escalated offensive aggression. The current study examined whether adolescent AAS-exposure influenced the immunohistochemical localization of phosphate-activated glutaminase (PAG), the rate-limiting enzyme in the synthesis of glutamate, a fast-acting neurotransmitter implicated in the modulation of aggression in various species and models of aggression, as well as glutamate receptor 1 subunit (GluR1). Hamsters were administered AAS during adolescence, scored for offensive aggression using the resident-intruder paradigm, and then examined for changes in PAG and GluR1 immunoreactivity in areas of the brain implicated in aggression control. When compared with sesame oil-treated control animals, aggressive AAS-treated hamsters displayed a significant increase in the number of PAG- and area density of GluR1-containing neurons in several notable aggression regions, although the differential pattern of expression did not appear to overlap across brain regions. Together, these results suggest that altered glutamate synthesis and GluR1 receptor expression in specific aggression areas may be involved in adolescent AAS-induced offensive aggression.

Repeated exposure to anabolic/androgenic steroids (AAS) during adolescence stimulates high levels of offensive aggression in Syrian hamsters. The current study investigated whether adolescent AAS exposure activated neurons in areas of hamster forebrain implicated in aggressive behavior by examining the expression of FOS, i.e., the protein product of the immediate early gene c-fos shown to be a reliably sensitive marker of neuronal activation. Adolescent AAS-treated hamsters and sesame oil-treated littermates were scored for offensive aggression and then sacrificed 1 day later and examined for the number of FOS immunoreactive (FOS-ir) cells in regions of the hamster forebrain important for aggression control. When compared with non-aggressive, oil-treated controls, aggressive AAS-treated hamsters showed persistent increases in the number of FOS-ir cells in select aggression regions, namely the anterior hypothalamus and lateral septum. However, no differences in FOS-ir cells were found in other areas implicated in aggression such as the ventrolateral hypothalamus, bed nucleus of the stria terminals, central and/or medial amygdala or in non-aggression areas, such as the samatosensory cortex and the suprachiasmatic nucleus. These results suggest that adolescent AAS exposure may constitutively activate neurons in select forebrain areas critical for the regulation of aggression in hamsters. A model for how persistent activation of neurons in one of these brain regions (i.e., the anterior hypothalamus) may facilitate the development of the aggressive phenotype in adolescent-AAS exposed animals is presented.

In hamsters (Mesocricetus auratus), anabolic-androgenic steroid (AAS) exposure during adolescence facilitates offensive aggression that is modulated, in part, by serotonin (5-HT) signaling and development and by signaling and expression of 5-HT1B receptors. To examine whether these effects are persistent or reversible, the authors administered AAS to hamsters, then examined them for aggression at 1, 4, 11, 18, or 25 days following cessation of AAS treatment. Then, 1 day later, hamsters were killed by transcardial perfusion and examined for 5-HT afferents to and 5-HT1B receptor-containing neuronal puncta and somata in areas of the brain altered by AAS, namely, the anterior hypothalamus, ventrolateral hypothalamus, and medial amygdala. Although aggression resulting from AAS exposure returned to control, nonaggressive levels by 18 days following cessation of AAS treatment, alterations in 5-HT afferent innervation and 5-HT1B receptor localization were observed throughout the extended time period examined. These data suggest that adolescent AAS exposure may have long-term, irreversible effects on 5-HT neural systems and that return to nonaggressive behavioral phenotypes following adolescent AAS exposure may not be a function of plasticity in central 5-HT systems., (2006 APA, all rights reserved)

Repeated high dose (5.0 mg/kg) anabolic/androgenic steroid exposure during adolescence stimulates offensive aggression in male Syrian hamsters. These studies examined whether anabolic/androgenic steroid-induced aggression was regulated by the activity and expression of serotonin (5HT) type-1A receptors. In a first experiment, adolescent male hamsters were treated with a mixture of anabolic/androgenic steroids and then scored for offensive aggression in the absence or presence of the selective 5HT1A receptor agonist R(+)-8-OH-DPAT (0.1-0.6 mg/kg). Adolescent anabolic/androgenic steroid-treated hamsters displayed high levels of offensive aggression that could be reversed by enhancing the activity of 5HT1A receptors. The agonist R(+)-8-OH-DPAT dose-dependently reduced the steroid-induced aggressive response, with significant reductions in aggression observed at 0.1-0.3 mg/kg. In a second set of experiments, adolescent hamsters were administered anabolic/androgenic steroids or vehicle and then examined for 5HT1A receptor localization and expression in regions of the brain important for aggression control. Hamsters treated with anabolic/androgenic steroids showed significant decreases in 5HT1A receptor-immunoreactive staining and protein levels in the anterior hypothalamus (i.e., a brain region central to the control of offensive aggression in hamsters) with no concomitant decrease in the number of 5HT1A receptor-expressing neurons. Together, these data support a role for site-specific down-regulation of 5HT1A receptor activity in adolescent anabolic/androgenic steroid-induced aggression.

Agonistic interactions are present throughout the animal kingdom as well as in humans. In this report, we present a model system to study neurological correlates of dominant-subordinate relationships. Zebrafish, Danio rerio, has been used as a model system for developmental biology for decades. We propose here that it is also an excellent model for studying social behavior. Adult male zebrafish were separated for 5 days and then pairs were formed and allowed to interact for 5 days. Under these conditions, aggression is prevalent and dominant-subordinate relationships are quickly established. Dominant behavior is characterized by a repeated pattern of chasing and biting, whereas subordinates engage in retreats. By day 5, the dominant-subordinate relationship was firmly established and there were differences in behavior over time. Chases, bites and retreats were all less frequent on day 5 of the social interaction than on day 1. Arginine vasotocin is the teleostean homologue of arginine vasopressin, a neuropeptide whose expression has been linked to aggression and social position in mammals. Immunohistochemistry indicated differences in vasotocin staining between dominant and subordinate individuals. Dominant individuals express vasotocin in one to three pairs of large cells in the magnocellular preoptic area whereas subordinate individuals express vasotocin in 7-11 pairs of small cells in the parvocellular preoptic area. These results suggest that the vasotocinergic system may play a role in shaping dominant-subordinate relationships and agonistic behavior in this model organism.

In hamsters, adolescent anabolic-androgenic steroid (AAS) exposure facilitates offensive aggression, in part by altering the development and activity of anterior hypothalamic arginine vasopressin (AH-AVP). This study assessed whether these effects were lasting by examining aggression and AH-AVP during AAS withdrawal. Adolescent hamsters administered AAS were tested as adults for aggression at 1, 4, 11, 18, or 25 days of withdrawal, sacrificed the following day, and examined for AH-AVP afferent innervation using immunohistochemistry. Through Day 12 of withdrawal, aggression and AVP were significantly higher in AAS-treated hamsters than in controls. These differences were no longer observable by Day 19 of withdrawal, at which point the behavior and neurobiology of AAS-treated hamsters reverted to that observed in controls. These data indicate that adolescent AAS exposure has short-term, reversible effects on both aggression and AH-AVP, correlating AH-AVP with the aggressive/nonaggressive behavioral phenotype during AAS withdrawal.

Repeated high dose (5.0 mg/kg) anabolic-androgenic steroid (AAS) exposure during adolescence stimulates offensive aggression in male Syrian hamsters. These studies examined whether AAS-induced aggression was regulated by the activity of serotonin (5HT) type-1B receptors and correlated with altered 5HT1B expression. AAS-treated hamsters were tested for offensive aggression following the administration of the 5HT1B agonist anpirtoline (0.125-0.5 mg/kg). Anpirtoline dose-dependently reduced select components of the AAS-induced aggressive response, with significant reductions observed at 0.25 mg/kg. Aggressive, AAS-treated hamsters showed significant decreases in the area covered by 5HT1B-containing neuronal puncta and increases in the number of 5HT1B-containing neuronal somata in select brain regions implicated in aggression control. Together, these data support a role for site-specific alterations in 5HT1B signaling and expression in adolescent AAS-induced aggression.

Hamsters repeatedly exposed to cocaine throughout adolescence display highly escalated offensive aggression compared to saline-treated littermates. Recently, we have shown that serotonin neural signaling and development play an important role in adolescent cocaine-induced offensive aggression. This study examined whether the adolescent cocaine-induced aggressive response was modulated by serotonin type 1A (5HT1A) receptors. To test this, adolescent male Syrian hamsters were administered cocaine hydrochloride (0.5 mg/kg, i.p.) throughout adolescent development (P27-57) and then tested for offensive aggression after the administration of the 5HT(1A) receptor agonist R(+)-8-OH-DPAT (0.1, 0.3, 0.6, 1.0, 1.25 mg/kg, i.p.). R(+)-8-OH-DPAT dose-dependently reduced cocaine-induced offensive aggression, with a significant reduction observed at 0.3 mg/kg for most of the offensive responses measured. Animals treated with higher doses of R(+)-8-OH-DPAT (0.6-1.25 mg/kg) prior to testing showed significant reductions in all measures of offensive aggression and social interest towards intruders (i.e., contact time), indicating more general behavioral inhibition. Adolescent cocaine-treated animals did not differ in body weight from controls, suggesting that the increased aggression was not due to increased body mass. These data support a role for 5HT1A signaling in adolescent cocaine-induced aggression.

Hamsters repeatedly exposed to cocaine throughout adolescence display highly escalated offensive aggression compared to saline-treated littermates. The current study investigated whether adolescent cocaine exposure activated neurons in areas of hamster forebrain implicated in aggressive behavior by examining the expression of FOS, i.e., the protein product of the immediate early gene c-fos shown to be a reliably sensitive marker of neuronal activation. Adolescent cocaine-treated hamsters and saline-treated littermates were scored for offensive aggression and then sacrificed 1 day later and examined for the number of FOS immunoreactive (FOS-ir) cells in regions of the hamster forebrain important for aggression control. When compared with non-aggressive, saline-treated controls, aggressive cocaine-treated hamsters showed persistent increases in the number of FOS-ir cells in several aggression regions, including the anterior hypothalamus, nucleus circularis, lateral hypothalamus (i.e., the hypothalamic attack area), lateral septum, and medial and corticomedial amygdaloid nuclei. Conversely, aggressive cocaine-treated hamsters showed a significant decrease in FOS-ir cells in the medial supraoptic nucleus, bed nucleus of the stria terminalis, and central amygdala when compared with controls. However, no differences in FOS-ir cells were found in other areas implicated in aggression such as the paraventricular hypothalamic nucleus, or in a number of non-aggression areas. These results suggest that adolescent cocaine exposure may constitutively activate neurons in select forebrain areas critical for the regulation of aggression in hamsters. A model for how persistent activation of neurons in one of these brain regions (i.e., the hypothalamus) may facilitate the development of the aggressive phenotype in adolescent cocaine-exposed animals is presented.

Hamsters repeatedly exposed to cocaine during adolescence display high levels of offensive aggression compared to saline-treated littermates. The escalated offensive phenotype observed in adolescent cocaine-treated animals is modulated by serotonin (5-HT) signaling and can be suppressed by inhibiting 5-HT type 3 receptors, suggesting that these receptors might play an important role in the aggression-stimulating effects of adolescent cocaine exposure. The current study examined this hypothesis and extended earlier studies investigating the relationship between 5HT(3) receptor neural signaling and the offensive response patterns of aggressive, adolescent cocaine-treated animals compared to non-aggressive, saline-treated littermates. Adolescent cocaine-treated hamsters and saline-treated littermates were tested for offensive aggression after the administration of either the 5-HT(3) antagonist 3-tropanylindole-3-carboxylate methiodide (tropisetron) or the 5-HT(3) agonist 1-(m-chlorophenyl)-biguanide hydrochloride (mCPBG). Tropisetron significantly reduced the high levels of offensive responding observed in adolescent cocaine-treated animals, whereas treatment with the 5-HT(3) receptor agonist mCPBG failed to affect the escalated offensive response. Conversely, tropisetron failed to affect very low, baseline levels of aggressive responding seen in adolescent saline-treated animals, while 5-HT(3) receptor activation via mCPBG triggered highly escalated levels of offensive aggression in these animals. Together, these data support a stimulatory role for 5-HT(3) neural signaling in offensive aggression.

Repeated low-dose cocaine treatment (0.5 mg/kg/day) during adolescence induces offensive aggression in male Syrian hamsters (Mesocricetus auratus). This study examines the hypothesis that adolescent cocaine exposure predisposes hamsters to heightened levels of aggressive behavior by increasing the activity of the anterior hypothalamic-vasopressinergic neural system. In a first experiment, adolescent male hamsters were treated with low-dose cocaine and then scored for offensive aggression in the absence or presence of vasopressin receptor antagonists applied directly to the anterior hypothalamus. Adolescent cocaine-treated hamsters displayed highly escalated offensive aggression that could be reversed by blocking the activity of vasopressin receptors within the anterior hypothalamus. In a second set of experiments, adolescent hamsters were administered low-dose cocaine or vehicle, tested for offensive aggression, and then examined for differences in vasopressin innervation patterns and expression levels in the anterior hypothalamus, as well as the basal- and stimulated-release of vasopressin in this same brain region. Aggressive, adolescent cocaine-treated hamsters showed no differences in vasopressin afferent innervation and/or peptide levels in the anterior hypothalamus compared with non-aggressive, saline-treated littermates. Conversely, significant increases in stimulated, but not basal, vasopressin release were detected from the anterior hypothalamus of aggressive, cocaine-treated animals compared with non-aggressive, saline-treated controls. Together, these data suggest that adolescent cocaine exposure increases aggression by increasing stimulated release of vasopressin in the anterior hypothalamus, providing direct evidence for a causal role of anterior hypothalamic-vasopressin activity in adolescent cocaine-induced offensive aggression. A model for how alterations in anterior hypothalamic-vasopressin neural functioning may facilitate the development of the aggressive phenotype in adolescent-cocaine exposed animals is presented.

Repeated cocaine (0.5 mg/kg) exposure throughout adolescence stimulates offensive aggression in hamsters. These studies examined whether the cocaine-induced aggressive response was regulated by serotonin Type 3 (5-HT(3)) receptor activity and correlated with altered 5-HT(3) receptor expression. Cocaine-treated Syrian hamsters (Mesocricetus auratus) were tested for aggression after the administration of either the 5-HT(3) antagonist 3-tropanylindole-3-carboxylate methiodide (tropisetron; 0.01-1.20 mg/kg) or the 5-HT(3) agonist l-(m-chlorophenyl)-biguanide hydrochloride (mCPBG; 5.0-15.0 mg/kg), alone or in combination. Tropisetron alone dose dependently reduced cocaine-induced aggression, with a significant reduction at 0.3 mg/kg, whereas mCPBG was ineffective. mCPBG administered prior to tropisetron required a higher dose (1.2 mg/kg) of antagonist to block aggression, indicating a selective 5-HT(3) effect. Cocaine-treated hamsters showed altered 5-HT-sub-3 immunoreactivity in several brain areas implicated in aggression control. These data support a role for 5-HT(3) receptors in adolescent cocaine-induced aggression.

In adult animals, the consequences of stress are often severe and long lasting. Repeated subjugation in adult male golden hamsters inhibits aggression and increases submissive and avoidant behaviours. By contrast, subjugation during puberty enhances offensive aggression. The goals of this study were to characterize behavioural and neuroendocrine responses of naïve and repeatedly subjugated juveniles to social defeat and to assess potential recovery from social stress. From the onset of puberty on postnatal day 28 (P28) to mid puberty (P42), animals were either socially subjugated or placed in a clean and empty cage for 20 min daily. The subjugated and control groups were further divided into subgroups and sacrificed under basal conditions or after social defeat on P28, P35 (early puberty), P45 (mid puberty) and P70 (early adulthood). On P35 and P45, repeatedly subjugated juveniles showed a complete inhibition of olfactory investigation (i.e. risk assessment) towards aggressive adults. Repeatedly subjugated also animals had lower postdefeat cortisol levels than controls on P45. Interestingly, basal cortisol levels increased gradually during puberty but did not differ between treatment groups at any point. Repeated subjugation was also associated with increased tyrosine hydroxylase immunoreactivity (ir-TH) within the extended medial amygdala. After a 4-week recovery period, none of these variables differed between subjugated and control groups. In an additional experiment, subjugated adults also had increased ir-TH in the medial extended amygdala, suggesting that these neurones are particularly responsive to social stress. In conclusion, puberty may be a developmental period characterized by behavioural and neuroendocrine plasticity in stress responsiveness. Furthermore, peri-pubertal changes in stress hormones may explain why juvenile hamsters are more resilient to social stress than adults.

Investigating different types of aggression is important to facilitate a better understanding of excessive maladaptive aggression in referred youth. Using regression analysis, the authors investigated demographic, historical, diagnostic, and treatment correlates of proactive aggression and reactive aggression in a heterogeneous population (N = 323) of psychiatrically referred youths. Ratings of proactive and reactive aggression significantly correlated with more established measures of aggression. Results suggest the importance of hyperactive/impulsive behavior, disruptive behavior disorders, and self-reported hostility in youths with both reactive and proactive aggression. Substance use disorders, a family history of substance abuse, and family violence were specifically associated with proactive aggression. Younger age and a history of abuse were correlated with reactive aggression. Implications for clinical interventions and future research are discussed.

Our objective was to investigate the relationship between a lifetime history of traumatic stress, defined as physical and/or sexual abuse and aggression and psychosocial functioning in a sample of clinically referred and nonclinically referred children and adolescents. This is a retrospective case comparison study. Three groups of children were identified, assessed, matched for age, and partially matched for gender. Children clinically referred to residential treatment with a history of abuse (N = 29) were compared with children clinically referred to residential treatment without a history of abuse (N = 29), and a nonclinical group of children residing in the community (N = 29). Variables investigating specific types of aggression, IQ, and psychopathology were assessed across the three groups. Clinically referred children scored worse on all measures compared with nonclinical community children. Clinically referred abused children scored higher on measures of aggression and significantly higher on measures of reactive aggression and verbal aggression than clinically referred nonabused children. Clinically referred abused children had significantly lower verbal IQ scores than clinically referred nonabused children, but no difference in psychopathology. Results support the importance of assessing specific types of aggression in samples of traumatized youths. Verbal information processing may be especially vulnerable in abused children and adolescents and enhance vulnerability to aggressive responding.

Chronic anabolic-androgenic steroid (AAS) treatment during adolescence facilitates offensive aggression in male Syrian hamsters (Mesocricetus auratus). The current study assessed whether adolescent AAS exposure influenced the immunohistochemical localization of glutamic acid decarboxylase (GAD65), the rate-limiting enzyme in the synthesis of gamma-aminobutyric acid (GABA), in areas of hamster brain implicated in aggressive behavior. Hamsters were administered high dose AAS throughout adolescence, scored for offensive aggression, and then examined for differences in GAD65 puncta to regions of the hamster brain important for aggression. When compared with control animals, aggressive AAS-treated hamsters showed significant increases in the area covered by GAD65 immunoreactive puncta in several of these aggression regions, including the anterior hypothalamus, ventrolateral hypothalamus, and medial amygdala. Conversely, aggressive AAS-treated hamsters showed a significant decrease in GAD65-ir puncta in the lateral septum when compared with oil-treated controls. However, no differences in GAD65 puncta were found in other aggression areas, such as the bed nucleus of the stria terminalis and central amygdala. Together, these results support a role for altered GAD65 synthesis and function in adolescent AAS-facilitated offensive aggression.

The purpose of our investigation was to study gender differences in proactive and reactive aggression in a sample of 323 clinically referred children and adolescents (68 females and 255 males). Proactive aggression and reactive aggression were assessed using the Proactive/Reactive Aggression Scale. Demographic, historical, family, diagnostic, and treatment variables were entered into stepwise regression analyses to determine correlates of proactive and reactive aggression in males and females. Results reveal high rates of aggression in both males and females in the sample. Self reported drug use, expressed hostility, and experiences of maladaptive parenting were correlated with proactive aggression for both genders. Hyperactive/impulsive behaviors were correlated with male reactive aggression. An early age of traumatic stress and a low verbal IQ were correlated with female proactive aggression. Gender differences in correlates of proactive and reactive aggression may provide possible targets for research, prevention, and treatment efforts focused on reducing maladaptive aggression in clinically referred youth.

Chronic anabolic-androgenic steroid (AAS) treatment during adolescence facilitates offensive aggression in male Syrian hamsters (Mesocricetus auratus). The current study assessed whether adolescent AAS-facilitated offensive attack was modulated by serotonin (5-HT) and if AAS exposure during this developmental period influenced 5-HT innervation to areas of hamster brain implicated in aggressive behavior. In a first experiment, hamsters were administered high-dose AAS throughout adolescence, and then scored for offensive attack following the systemic administration of saline or fluoxetine, a selective 5-HT reuptake inhibitor. Saline-treated hamsters showed high levels of offensive attack, while treatment with fluoxetine attenuated the AAS-facilitated aggressive response. In a second experiment,were administered high-dose AAS or sesame oil throughout adolescence, tested for offensive attack and then examined for differences in 5-HT innervation to areas of the hamster brain important for aggression. Aggressive AAS-treated hamsters showed significant reductions in the number of 5-HT immunoreactive (5-HT-ir) varicosities and fibers in several of these areas, most notably the anterior hypothalamus (AH), ventrolateral hypothalamus (VLH) and medial amygdala (MeA). However, no differences in 5-HT afferent innervation were found in other aggression areas, such as the bed nucleus of the stria terminalis (BNST) and lateral septum (LS). Together, these results support a role for altered 5-HT innervation and function in adolescent AAS-facilitated offensive aggression.

Repeated anabolic-androgenic steroid treatment during adolescence increases hypothalamic vasopressin and facilitates offensive aggression in male Syrian hamsters (Mesocricetus auratus). The current study investigated whether anabolic-androgenic steroid exposure during this developmental period influenced vasopressin V(1A) receptor binding activity in the hypothalamus and several other brain areas implicated in aggressive behavior in hamsters. To test this, adolescent male hamsters were administered anabolic steroids or sesame oil throughout adolescence, tested for offensive aggression, and examined for differences in vasopressin V(1A) receptor binding using in situ autoradiography. When compared with control animals, aggressive, adolescent anabolic steroid-treated hamsters showed significant increases (20-200%) in the intensity of vasopressin V(1A) receptor labeling in several aggression areas, including the ventrolateral hypothalamus, bed nucleus of the stria terminalis, and lateral septum. However, no significant differences in vasopressin V(1A) receptor labeling were found in other brain regions implicated in aggressive responding, most notably the lateral zone from the medial preoptic area to anterior hypothalamus and the corticomedial amygdala. These data suggest that adolescent anabolic steroid exposure may facilitate offensive aggression by increasing vasopressin V(1A) receptor binding in several key areas of the hamster brain., (Copyright 2002 Elsevier Science (USA))

Studies have shown that the nucleus accumbens shell plays an integral role in the expression of psychostimulant-induced behavioural sensitization. Dopaminergic regulation of excitatory amino acid inputs in this region of the brain could be a key factor in the neural influence of this phenomenon. Alterations in the dopaminergic innervation patterns in the shell have been demonstrated in rats that received repeated cocaine injections. Furthermore, lesions of brain regions that send projections to the shell alter psychostimulant-induced locomotion, both acutely and in sensitization paradigms. A previous study from our laboratory demonstrated that lesions of the shell before repeated cocaine treatment decrease the locomotor response to cocaine during the induction phase of behavioural sensitization. To better understand the role of this brain region during the expression phase of behavioural sensitization, the present study examined the effects of two forms of cytotoxic lesions of the shell. Rats received a sensitization-inducing regimen of cocaine (bi-daily injections of 15 mg/kg i.p. for 5 consecutive days). Two days after the last injection, rats demonstrating behavioural sensitization received one of three bilateral microinjections into the shell: (i) 0.5 micro L 0.9% saline; (ii) 2.5 micro g/0.5 micro L ibotenic acid (which lesions the cell bodies at the injection site); or (iii), 0.5 ng/0.2 micro L of volkensin (a retrograde suicide transport lectin). Upon challenge with cocaine (15 mg/kg) 12 days after surgery, neither ibotenic acid- nor volkensin-lesioned rats showed any difference in their locomotor response compared with sham controls. These data indicate that bilateral shell lesions do not affect the long-term expression of behavioural sensitization in cocaine-sensitized rats.

The effects of chronic social stress on behavioral sensitization to cocaine were investigated in the Syrian hamster. Adolescent animals received either 15 mg/kg i.p. of cocaine or saline twice per day for 7 consecutive days. Two weeks following the last injection (young adulthood), they were given a challenge dose of 5 mg/kg i.p. of cocaine and scored for locomotion. Motor activity was significantly greater in cocaine-treated animals, demonstrating sensitization to this psychostimulant. Following the results of the first study, another group of adolescent animals was exposed to either a novel clean cage (control) or an aggressive resident male hamster (social stress) for 15 min following an injection of cocaine (20 mg/kg i.p. once daily) or saline for 7 consecutive days. The groups were as follows: Social Stress/Cocaine (SSC), No Social Stress/Cocaine (NSSC), Social Stress/Saline (SSS) and No Social Stress/Saline (NSSS). Two weeks following the last injection (Day 21), all animals were given a challenge dose of cocaine (5 mg/kg i.p.) and were rescored for locomotion. At that time, the suppressive effect of stress on locomotion was no longer detectable, as the expression of sensitization was observed in the NSSC but not in the SSC group. These results suggest that chronic social stress administered during adolescence does not cross-sensitize with cocaine in young adult hamsters.

Repeated low-dose cocaine treatment (0.5 mg/kg/day) during adolescence facilitates offensive aggression in male Syrian hamsters (Mesocricetus auratus). The current study assessed whether adolescent cocaine-facilitated offensive aggression was inhibited by increased serotonin activity and if cocaine exposure during this developmental period influenced serotonin development in the primary aggression areas of hamster brain. In a first experiment, hamsters were treated with low doses of cocaine throughout adolescence and then scored for offensive aggression following the systemic administration of vehicle or fluoxetine, a selective serotonin reuptake inhibitor. Vehicle-treated hamsters showed high levels of offensive aggression, while treatment with fluoxetine inhibited the cocaine-facilitated aggressive response. Only one out of ten fluoxetine-treated animals both attacked and bit intruders, compared to nine out of ten saline-treated animals. In a second experiment, hamsters were administered low doses of cocaine or saline throughout adolescence, tested for offensive aggression, and then examined for differences in serotonin afferent innervation to regions of the hamster brain implicated in aggressive responding. Aggressive cocaine-treated hamsters showed significant reductions (35-50%) in the number of serotonin immunoreactive varicosities and fibers in several aggression areas, including the anterior hypothalamus, lateral septum, medial amygdala, and bed nucleus of the stria terminalis. Together, these results support a role for serotonin innervation and function in adolescent cocaine-facilitated offensive aggression.

Objective: To determine by meta-analysis the effect size for stimulants on overt and covert aggression-related behaviors in children with attention-deficit/hyperactivity disorder (ADHD), separately from stimulant effects on the core symptoms of ADHD., Method: A review of the literature from 1970 to 2001 revealed 28 studies meeting inclusion/exclusion criteria for meta-analysis. These studies yielded 28 independent effects of overt aggression and 7 independent effects of covert aggression., Results: The overall weighted mean effect size was 0.84 for overt and 0.69 for covert aggression related behaviors in ADHD. Comorbid conduct disorder is associated with diminishing stimulant effect size for overt aggression., Conclusion: Stimulant effects for aggression-related behaviors in ADHD have effect sizes similar to those for the core symptoms of ADHD.

A single-sample, within-subject descriptive study was completed to ascertain individual subject characteristics associated with outcome for 87 youths discharged from a residential treatment facility. Two different methods of assessing outcome were also compared. Variables assessing a history of abuse and internalizing psychopathology at admission to residential care were associated with outcome. Low levels of staff agreement were found on the 2 outcome measures. Implications for acute residential care are discussed.

Cocaine abuse during adolescence represents a significant health risk due to the potential for both acute and long-term negative physical and psychological sequelae, including increased aggressive behavior. This study examined the effect of adolescent cocaine treatment on flank marking (i.e., a stereotypic motor behavior that is part of the response pattern of offensive aggression) in female and male Syrian hamsters (Mesocricetus auratus). Adolescent cocaine treatment activated flank marking in female hamsters when animals were measured upon return to their home cage immediately following drug treatment. Sex differences were observed in cocaine-induced flank marking, as males failed to flank mark when returned to the home cage. In females, the behavioral response was most marked on Day 11 of cocaine treatment in all doses tested. Yet, animals treated with low-dose cocaine (0.5 mg/kg/day) showed the most significant increase in flank marking on and from Day 11 forward as compared to medium- and high-dose cocaine-treated animals and controls. In addition, the response of cocaine-treated animals was vigorous and nearly immediate, as >75% of the flank marks scored were performed within the first 2 min of the behavioral test in >85% of animals examined. Measures of locomotion showed that cocaine had stimulatory effects on motor activity in adolescent female hamsters at all doses tested. Cocaine-treated animals did not differ in body weight gain from controls, suggesting no dramatic physiological effects of adolescent cocaine exposure on body growth at the doses tested.

Cocaine abuse during adolescence represents a significant health risk because of the potential for both acute and long-term negative physical and psychological sequelae, including increased aggressive behavior. This study examined the effects of chronic adolescent cocaine exposure on aggression in an animal model. It was hypothesized that chronic cocaine exposure during adolescence predisposes animals to heightened levels of aggressive behavior. To test this hypothesis, adolescent male golden hamsters (Mesocricetus auratus) were administered cocaine hydrochloride during their entire adolescent development (Postnatal Days 27-54) and then tested for offensive aggression using the resident-intruder model. Animals treated with low-dose cocaine during adolescence showed significantly elevated measures of offensive aggression (i.e., increased number of bites, attacks, and decreased latencies to bite), whereas measures of social communication, sexual motivation and motor activity remained constant. Cocaine-treated animals did not differ in body weight gain from controls, suggesting no dramatic physiological effects of adolescent cocaine exposure on body growth at the doses tested.