Valproate selectively suppresses adolescent anabolic/androgenic steroid-induced aggressive behavior: implications for a role of hypothalamic γ-aminobutyric acid neural signaling.

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.

Contemporary Pharmacotherapeutics and the Management of Aggressive Behavior in an Adolescent Animal Model of Maladaptive Aggression.

Objective: Antipsychotic and anticonvulsant medications are increasingly being used as pharmacotherapeutic treatments for maladaptive aggression in youth, yet no information is available regarding whether these drugs exhibit aggression- specific suppression in preclinical studies employing adolescent animal models of maladaptive aggression. This study examined whether the commonly used antipsychotics medications haloperidol and risperidone and the anticonvulsant medication valproate exert selective aggression-suppressing effects using a validated adolescent animal model of maladaptive aggression.

Methods: Twenty-seven-day old Syrian hamsters () were administered testosterone for 30 consecutive days during the first 4 weeks of adolescent development.

Serotonin type-3 receptors differentially modulate anxiety and aggression during withdrawal from adolescent anabolic steroid exposure.

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.

Vasopressin differentially modulates aggression and anxiety in adolescent hamsters administered anabolic steroids.

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.

Aggression and anxiety in adolescent AAS-treated hamsters: A role for 5HT3 receptors.

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.

Dopamine D2 receptors act upstream of AVP in the latero-anterior hypothalamus to modulate adolescent anabolic/androgenic steroid-induced aggression in Syrian hamsters.

In pubertal male Syrian hamsters, exposure to anabolic/androgenic steroids (AAS) during adolescence facilitates a high level of offensive aggression modulated by the enhanced development and activity of the vasopressin (AVP) and dopamine (DA) neural systems within the latero-anterior hypothalamus (LAH), that is, a brain region implicated in the control of aggression. The present studies provide a detailed report of the pharmacologic interactions between AVP and DA D2 receptor signaling within the LAH in the control of adolescent AAS-induced offensive aggression. Male Syrian hamsters were treated with AAS throughout adolescence and tested for aggression after local infusion of the DA D2 receptor antagonist eticlopride (ETIC) alone, or in combination with AVP in the LAH in an effort to determine the influence of DA D2 receptors relative to AVP-receptor mediated aggression mechanisms.

Anabolic/androgenic steroid administration during adolescence and adulthood differentially modulates aggression and anxiety.

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.

γ-Aminobutyric acid neural signaling in the lateroanterior hypothalamus modulates aggressive behavior in adolescent anabolic/androgenic steroid-treated hamsters.

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.

Adolescent anabolic/androgenic steroids: Aggression and anxiety during exposure predict behavioral responding during withdrawal in Syrian hamsters (Mesocricetus auratus).

In the U.S. and worldwide anabolic/androgenic steroid use remains high in the adolescent population.

Prior fighting experience increases aggression in Syrian hamsters: implications for a role of dopamine in the winner effect.

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.

Preclinical investigations into the relationship between adolescent SSRI exposure and aggressive behavior: response to commentary by Rubin and Walkup (2012).

A Commentary published in the October 2012 issue of Behavioral Neuroscience entitled "SSRIs, Adolescents, and Aggression: Tempering Human Implications Regarding SSRI-Induced Aggression in Hamsters: Comment on Ricci and Melloni (2012)", presents an interpretation of findings from our report published in the same issue of Behavioral Neuroscience entitled "Repeated Fluoxetine Administration During Adolescence Stimulates Aggressive Behavior and Alters Serotonin and Vasopressin Neural Development in Hamsters". The commentary was informative, especially in its review of the prescribing demographics for SSRIs in youth and its review of human and animal aggression subtypes, and in several instances offered alternative explanations and interpretations of evidence cited in our report, particularly regarding putative relationships between human and animal models of aggression. In our response, we reply to comments made by the authors regarding the animal model of choice for our studies, the methodologies employed and the greater implication(s) of our published study as well as offer a disparate view of the evidence cited by the authors in their commentary as they pertain to the relevance of the models of aggression used in our study.

Serotonin modulates anxiety-like behaviors during withdrawal from adolescent anabolic-androgenic steroid exposure in Syrian hamsters.

From the U.S. to Europe and Australia anabolic steroid abuse remains high in the adolescent population.

Repeated fluoxetine administration during adolescence stimulates aggressive behavior and alters serotonin and vasopressin neural development in hamsters.

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.

Glutamate and the aggression neural circuit in adolescent anabolic steroid-treated Syrian hamsters (Mesocricetus auratus).

Adolescent exposure to anabolic androgenic steroids (AAS) alters the development and activity of the glutamate neural system in the latero-anterior hypothalamus (LAH) in hamsters (Mesocricetus auratus); that is, an important neural component of the adolescent AAS-induced aggressive response. In this article, we used retrograde tracing to investigate glutamate-specific alterations in the connections between the LAH and several other nuclei implicated in adolescent AAS-induced aggression. Briefly, hamsters were treated with AAS or sesame-oil control during adolescence and then microinjected with retrograde tracer into the medial amygdala (MeA), lateral septum (LS), or bed nucleus of the stria terminalis (BNST).

Developmental and withdrawal effects of adolescent AAS exposure on the glutamatergic system in hamsters.

In the Syrian hamster (Mesocricetus auratus) glutamate activity has been implicated in the modulation of adolescent anabolic-androgenic steroid (AAS)-induced aggression. The current study investigated the time course of adolescent AAS-induced neurodevelopmental and withdrawal effects on the glutamatergic system and examined whether these changes paralleled those of adolescent AAS-induced aggression. Glutamate activity in brain areas comprising the aggression circuit in hamsters and aggression levels were examined following 1, 2, 3, and 4 weeks of AAS treatment or 1, 2, 3, and 4 weeks following the cessation of AAS exposure.

Immunohistochemical characterization of 5-HT(3A) receptors in the Syrian hamster forebrain.

The Syrian hamster (Mesocricetus auratus) has been extensively used as an animal model to investigate neuronal networks underlying various behaviors where 5-HT(3A) receptors have been found to play a critical role. To date, however, there is no comprehensive description of the distribution of 5-HT(3A) receptors in the Syrian hamster brain. The current study examined the localization of 5-HT(3A) receptors across the neuraxis of the Syrian hamster forebrain using immunohistochemistry.

Adolescent exposure to anabolic/androgenic steroids and the neurobiology of offensive aggression: a hypothalamic neural model based on findings in pubertal Syrian hamsters.

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.

The effect of increased serotonergic neurotransmission on aggression: a critical meta-analytical review of preclinical studies.

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.

Interactions between the dopaminergic and GABAergic neural systems in the lateral anterior hypothalamus of aggressive AAS-treated hamsters.

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.

Adolescent anabolic-androgenic steroid exposure alters lateral anterior hypothalamic serotonin-2A receptors in aggressive male hamsters.

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.

Paliperidone suppresses the development of the aggressive phenotype in a developmentally sensitive animal model of escalated 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.

Alterations in the anterior hypothalamic dopamine system in aggressive adolescent AAS-treated hamsters.

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).

Adolescent anabolic androgenic steroids reorganize the glutamatergic neural circuitry in the hypothalamus.

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.

Repeated risperidone administration during puberty prevents the generation of the aggressive phenotype in a developmentally immature animal model of escalated aggression.

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.

Alterations in anterior hypothalamic vasopressin, but not serotonin, correlate with the temporal onset of aggressive behavior during adolescent anabolic-androgenic steroid exposure in hamsters (Mesocricetus auratus).

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.