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. 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.

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. 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.

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. 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.

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. 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.

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. As previously shown, ETIC infusion into the LAH suppressed adolescent AAS-induced aggressive responding; however, the AAS-induced aggressive phenotype was rescued by the coinfusion of AVP into the LAH. These behavioral data indicate that interactions between AVP and DA neural systems within the LAH modulate the control of aggression following adolescent exposure to AAS and that DA D2 receptor signaling functions upstream of AVP in the LAH to control this behavioral response.

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. 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.

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; 0.01-1.0 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.

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. 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.

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. 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.

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. 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.

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. 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.

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). Brains were then processed for vesicular glutamate transporter 2 (VGLUT2) and examined for AAS-induced changes in the number VGLUT2 cells containing retrograde tracer (VGLUT2/tracer) within the LAH. It is interesting to note that while aggressive AAS-treated hamsters injected retrograde tracer into the MeA showed a significant reduction in the number of VGLUT2/tracer cells in the LAH, aggressive AAS-treated hamsters injected tracer into the BNST showed a significant increase in the number of VGLUT2/tracer cells in the LAH when compared with controls. Last, AAS hamsters injected with tracer into the LS had a comparable number of LAH-VGLUT2/tracer cells to controls. The current results indicate that glutamate likely functions as the major aggression output system from the LAH and that adolescent AAS treatment significantly alters the neural circuitry modulating aggression. Moreover, increases in the number of glutamate projections from the LAH to the BNST in AAS hamsters identify the BNST as an area particularly important for the regulation of AAS-induced aggression.

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. In these studies glutamate activity was examined using vesicular glutamate transporter 2 (VGLUT2). The onset of aggression was observed following 2 weeks exposure to AAS and continued to increase showing maximal aggression levels after 4 weeks of AAS treatment. This aggressive phenotype was detected after 2 weeks of withdrawal from AAS. The time-course of AAS-induced changes in latero-anterior hypothalamus (LAH)-VGLUT2 closely paralleled increases in aggression. Increases in LAH-VGLUT2 were first detected in animals exposed to AAS for 2 weeks and were maintained up to 3 weeks following the cessation of AAS treatment. AAS treatment also produced developmental and long-term alterations in VGLUT2 expression within other aggression areas. However, AAS-induced changes in glutamate activity within these regions did not coincide with changes in aggression. Together, these data indicate that adolescent AAS treatment leads to alterations in the glutamatergic system in brain areas implicated in aggression control, yet only alterations in LAH-glutamate parallel the time course of AAS-induced changes in the aggressive phenotype.

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. Overall, 5-HT(3A) receptors were widely and heterogeneously distributed across the neuraxis of the Syrian hamster brain. Notably, the most intense 5-HT(3A) immunolabeling patterns were observed in the cerebral cortex and amygdala. In addition, high variability in receptor density and expression patterns (i.e., perikarya, fibers and/or neuropilar puncta) was observed within the majority of brain areas examined, indicating that the role this receptor has in the modulation of a particular neural function differs depending on brain region. In some regions (i.e., nucleus accumbens) differences in the immunolabeling pattern between rostral, medial and caudal portions were also observed, suggesting functional heterogeneity of this receptor within a single brain region. Together, these results and the localization of this receptor to brain areas involved in the regulation of sexual behavior, aggression, circadian rhythm, drug abuse and anxiety implicate 5-HT(3A) receptors in the modulation of various behaviors and neural functions in the Syrian hamster. Further, these results underscore the importance of evaluating 5-HT(3A) receptors as a pharmacological target for the treatment of various psychopathological disorders.

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. 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.

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. 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.

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. 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.

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. 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.

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. 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.