Anabolic steroids alter the physiological activity of aggression circuits in the lateral anterior hypothalamus.

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.

Anterior hypothalamic vasopressin modulates the aggression-stimulating effects of adolescent cocaine exposure in Syrian hamsters.

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.

Mutant and native human beta-amyloid precursor proteins in transgenic mouse brain.

Human beta-amyloid precursor protein (beta APP) has been targeted to transgenic neurons using synapsin I promoter-based chimeric transgenes. Native human beta APP was introduced as well as beta APP containing mutations genetically linked to familial Alzheimer's disease (AD) and to hereditary cerebral hemorrhage with amyloidosis-Dutch type. In mouse brain, human beta APP RNA was up to 60% as abundant as total endogenous beta APP RNA. Human beta APP gene expression was most abundant in the CA subfields of the hippocampus and in the piriform cortex. Correct processing of human beta APP at the beta-secretase cleavage site was demonstrated in transgenic mouse brains. Despite a 40% increase in total beta APP immunoreactivity in lines expressing mutant human beta APP, no evidence of amyloid deposition was found in brains of mice up to 14 months in age. Higher levels of mutant human beta APP, increased age, or other factors may be necessary to elicit beta-amyloid-related neuropathologies in the rodent brain.

Temporal onset of synapsin I gene expression coincides with neuronal differentiation during the development of the nervous system.

Synapsin I is the best characterized member of a family of nerve terminal-specific phosphoproteins implicated in the regulation of neurotransmitter release. During development, the expression of synapsin I correlates temporally and topographically with synapse formation, and recent physiological studies (Lu et al. [1992] Neuron 8:521-529.) have suggested that synapsin I may participate in the functional maturation of synapses. To better understand the temporal relationship between synapsin I gene expression and particular cellular events during neuronal development, we have used in situ hybridization histochemistry to localize synapsin I mRNA throughout the rat central and peripheral nervous systems during embryonic and postnatal development. From the earliest embryonic time points assayed (E12), the expression of the synapsin I gene was detectable in both the central and peripheral nervous systems. While, in general, levels of synapsin I mRNAs were high in utero, synapsin I cDNA probes revealed specific patterns of hybridization in different regions of the embryonic nervous system. To determine precisely the temporal onset of expression of the synapsin I gene during neuronal development, we examined in detail the appearance of synapsin I mRNA during the well characterized postnatal development of granule cells of the rat cerebellum and hippocampus. In both regions, the onset of synapsin I gene expression correlated with the period of stem cell commitment to terminal differentiation. Finally, our data demonstrate that, in a second phase, synapsin I gene expression increases to a maximum for a given neuronal population during a particular phase of differentiation, i.e., synaptogenesis.

Expression of the p150Glued component of the dynactin complex in developing and adult rat brain.

p150Glued is a component of the dynactin (Glued) complex that has been shown in vitro to be a required activator of cytoplasmic dynein-mediated transport of vesicles along microtubules and, thus, may be an essential component of retrograde axonal transport. In vivo, a dominant mutation in the Drosophila homologue of p150Glued induces aberrant neuronal development when heterozygous and is lethal when homozygous. In order to characterize the role of the dynactin complex in the development and function of vertebrate neurons, the distribution of the p150Glued message was examined via in situ hybridization to serial sections of adult rat brain and to a developmental series of sections. In the adult rat brain, the most intense hybridization observed with the p150Glued probe was in the pyramidal cells of the hippocampus proper, the dentate granule neurons, the cingulate and piriform cortices, the ventromedial hypothalamus, and the granular cell layer of the cerebellum. White-matter fiber tracts and the neuropil were generally devoid of signal. The data indicate that the mRNA encoding p150Glued is highly enriched in the cell bodies of neurons within the central nervous system. In developing rat, p150Glued is expressed at very high levels in neural tissue from the earliest time points assayed. Particularly intense hybridization was observed in the multiple layers of the retina, which is consistent with the phenotype of the Drosophila mutation. Therefore, the distributions observed via in situ hybridization are consistent with an essential role for p150Glued in retrograde axonal transport.

Synapsin I gene expression in the adult rat brain with comparative analysis of mRNA and protein in the hippocampus.

Synapsin I is the best characterized member of a family of neuron-specific phosphoproteins thought to be involved in the regulation of neurotransmitter release. In this report, we present the first extensive in situ hybridization study detailing the regional and cellular distribution of synapsin I mRNA in the adult rat brain. Both the regional distribution and relative levels of synapsin I mRNA established by in situ hybridization were confirmed by RNA blot analysis. Our data demonstrate the widespread yet regionally variable expression of synapsin I mRNA throughout the adult rat brain. The greatest abundance of synapsin I mRNA was found in the pyramidal neurons of the CA3 and CA4 fields of the hippocampus, and in the mitral and internal granular cell layers of the olfactory bulb. Other areas abundant in synapsin I mRNA were the layer II neurons of the piriform cortex and layer II and V neurons of the entorhinal cortex, the granule cell neurons of the dentate gyrus, the pyramidal neurons of hippocampal fields CA1 and CA2, and the cells of the parasubiculum. In general, the pattern of expression of synapsin I mRNA paralleled those encoding other synaptic terminal-specific proteins, such as synaptophysin, VAMP-2, and SNAP-25, with noteworthy exceptions. To determine specifically how synapsin I mRNA levels are related to levels of synapsin I protein, we examined in detail the local distribution patterns of both synapsin I mRNA and protein in the rat hippocampus. These data revealed differential levels of expression of synapsin I mRNA and protein within defined synaptic circuits of the rat hippocampus.

Dynamics of synapsin I gene expression during the establishment and restoration of functional synapses in the rat hippocampus.

Synapse development and injury-induced reorganization have been extensively characterized morphologically, yet relatively little is known about the underlying molecular and biochemical events. To examine molecular mechanisms of synaptic development and rearrangement, we looked at the developmental pattern of expression of the neuron-specific gene synapsin I in granule cell neurons of the dentate gyrus and their accompanying mossy fibers during the main period of synaptogenic differentiation in the rat hippocampus. We found a significant difference between the temporal expression of synapsin I messenger RNA in dentate granule somata and the appearance of protein in their mossy fiber terminals during the postnatal development of these neurons. Next, to investigate the regulation of neuron-specific gene expression during the restoration of synaptic contacts in the central nervous system, we examined the expression of the synapsin I gene following lesions of hippocampal circuitry. These studies show marked changes in the pattern and intensity of synapsin I immunoreactivity in the dendritic fields of dentate granule cell neurons following perforant pathway transection. In contrast, changes in synapsin I messenger RNA expression in target neurons, and in those neurons responsible for the reinnervation of this region of the hippocampus, were not found to accompany new synapse formation. On a molecular level, both developmental and lesion data suggest that the expression of the synapsin I gene is tightly regulated in the central nervous system, and that considerable changes in synapsin I protein may occur in neurons without concomitant changes in the levels of its messenger RNA. Finally, our results suggest that the appearance of detectable levels of synapsin I protein in in developing and sprouting synapses coincides with the acquisition of function by those central synapses.

Dde-I restriction endonuclease fragmentation: a novel method of generating cDNA probes for in situ hybridization in brain.

We present a novel procedure for detection of low- and high-abundance messenger RNAs in the brain by in situ hybridization histochemistry, by using fragmented double-stranded cDNA as molecular probes. The procedure involves digesting the cDNA of interest with the restriction endonuclease from Desulfocibrio desulfuricans (Dde I digestion), followed by random primed labeling, which generates a family of high specific activity cDNA fragments. This procedure is a rapid, straightforward, and reproducible method of obtaining sensitive probes for in situ hybridization and is generally applicable to the analysis of the expression of a large number of genes. Here we report the use of this procedure to prepare probes for the detection of synapsin I, p150Glued, neurotensin, c-fos, and c-jun mRNAs in brain, using both isotopic and non-isotopic labeling methods. Because this procedure does not require complex recombinant DNA manipulations or oligonucleotide design, it should prove useful to the non-molecular biologist examining the expression of genes in the central nervous system.

Chronic anabolic-androgenic steroid treatment during adolescence increases anterior hypothalamic vasopressin and aggression in intact hamsters.

The present study examines the hypothesis that exposure to anabolic-androgenic steroids (AAS) during adolescent development predisposes hamsters to heightened levels of aggressive behavior by influencing the anterior hypothalamic-arginine vasopressin (AH-AVP) neural system. To test this, adolescent male hamsters (Mesocricetus auratus) were treated with high doses of AAS, tested for offensive aggression in the absence or presence of AH-AVP receptor antagonists, and then examined for changes in AH-AVP expression and neural organization. AAS exposure during adolescence significantly increased aggression intensity (number of attacks and bites) and initiation (latency to the first bite). Yet, only increases in aggression intensity were inhibited by AH-AVP receptor antagonism. Adolescent AAS-treated hamsters showed significant increases in AH-AVP fiber density and peptide content. However, no alterations in AH-AVP neuronal organization or mRNA expression were found. Together, these data suggest that adolescent AAS exposure increase aggression intensity by altering AH-AVP expression and activity, providing direct evidence for a causal role of AH-AVP expression and function in early onset AAS-stimulated aggression.

Positive- and negative-acting promoter sequences regulate cell type-specific expression of the rat synapsin I gene.

The phosphoprotein synapsin I is expressed exclusively in neuronal cells. We are interested in elucidating the promoter sequences involved in cell type-specific expression of the synapsin I gene. The PC12 cell line expresses the 3.4 kb and 4.5 kb synapsin I mRNAs and is used to analyze cell type-specific gene expression. A series of deletion fragments of the rat synapsin I gene promoter were fused to the promoterless reporter gene encoding bacterial chloramphenicol acetyltransferase (CAT) for transfection analysis in PC12 cells and in HeLa cells, which do not express the gene. A -349 bp to +110 bp rat synapsin I promoter fragment contains a positive regulator, shown to be 33-times more active in PC12 cells than HeLa cells. Transfection of reporter plasmids containing up to 4.4 kb of rat synapsin I gene promoter sequences exhibit significantly reduced CAT activity in PC12 cells. The reduction in CAT expression was attributed to a negative regulator located between -349 bp and -1341 bp in the rat synapsin I promoter. Our results suggest that both positive and negative-acting sequence elements regulate cell type-specific expression of the rat synapsin I gene.

Behavioural and neuroendocrine adaptations to repeated stress during puberty in male golden hamsters.

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.

Adolescent anabolic steroid use and aggressive behavior in golden hamsters.

In the present study, the ability of high-dose androgens, namely AAS, administered during adolescence to facilitate aggressive behavior in experimental animals was examined. Data from these studies show clearly that exposure to high doses of multiple AAS during adolescent development can predispose animals to intense bouts of aggressive behavior during young adulthood. Specifically, young adult hamsters treated with high doses of AAS throughout adolescence were more likely to attack and bite intruders placed in their home cage than sesame oil (vehicle)-treated control animals. Further, AAS-treated animals displayed a higher intensity of attack during the test period, exhibiting greater than four times the number of attacks/bites of control animals. Given the recent reports of increased incidence of AAS abuse in the adolescent population and the documented stimulatory effects of AAS on aggressive behavior, the study of the behavioral and neurobiological effects of prolonged exposure to AAS during critical phases of development such as adolescence warrants further investigation.

Overt categorical aggression in referred children and adolescents.

OBJECTIVE: To investigate descriptive and predictive correlates of aggression in children and adolescents who exhibit a high frequency of daily physical assault after admission to a structured residential treatment program and to examine correlations between subcategories of overt categorical aggression (OCA) in the same population. METHOD: Fifty-one admissions to a residential treatment program were assessed for frequency of physical assault after admission; analyses were corrected for length of stay. Patients with a high frequency of daily assault were compared with patients with a low frequency of daily assault on variables assessing demographics, history, family, concurrent behavior, treatment, and outcome. RESULTS: A high prevalence of OCA was found in this sample. Variables assessing history and concurrent behavior were significantly associated and predictive of subjects exhibiting a high frequency of daily physical assault after admission. Physical assault was significantly correlated with verbal aggression, property destruction, and self-injurious behavior. CONCLUSIONS: These findings support the distinctiveness of OCA as a separate subtype of aggression encompassing four subcategories. Further research on treatment, outcome, and associated comorbidity of OCA is warranted.

The dorsomedial shell of the nucleus accumbens facilitates cocaine-induced locomotor activity during the induction of behavioral sensitization.

The mesolimbic dopamine system has been intensely studied as the neural circuit mediating the locomotor response to psychostimulants and behavioral sensitization. In particular, the dopaminergic innervation of the nucleus accumbens has been implicated as a site responsible for the manifestations of behavioral sensitization. Previous studies have demonstrated an augmented release of dopamine in the nucleus accumbens upon a systemic injection of a psychostimulant. In addition, alterations in the dopaminergic innervation patterns in this brain region have been demonstrated in animals that received repeated injections of cocaine. Furthermore, lesions of projection sites that have terminations in the nucleus accumbens have demonstrated alterations in psychostimulant induced locomotion, both acutely, as well as in sensitization paradigms. Since dopamine in the nucleus accumbens is believed to regulate several excitatory amino acid inputs, the present study examined the effects of a localized electrolytic lesion in the dorsomedial shell of the nucleus accumbens in order to better understand the functional role this brain region has in behavioral sensitization. All animals received bi-daily injections of 15 mg/kg i.p. cocaine. Only those demonstrating behavioral sensitization after a subsequent challenge dose were included in the analysis. Following acute exposure to cocaine, lesioned animals did not show any difference in their locomotor response when compared with sham controls. However, after repeated exposure to cocaine, sensitized animals demonstrated a significant attenuation in locomotor behavior when compared with sensitized sham controls. This decrease in horizontal locomotion persisted 2 days into withdrawal, yet dissipated in the sensitized animals that were challenged 2 weeks following their last injection. The data presented here demonstrate that the dorsomedial shell of the nucleus accumbens plays an important role in the initial stages of behavioral sensitization to cocaine.

Combined pharmacotherapy in children and adolescents in a residential treatment center.

OBJECTIVE: To investigate characteristics of children and adolescents with a history of combined pharmacotherapy (CPT) and compare them with a group with no history of CPT. METHOD: Eighty-three consecutive admissions to a residential treatment center were divided into a CPT and a no-CPT group based on treatment history and compared by chart review. Prevalence of lifetime psychiatric medication use and CPT exposure were assessed. Demographic, diagnostic, treatment, behavioral, and medication variables were compared across the two groups. RESULTS: Medication use was present in the treatment history for 89.2% and a history of CPT was found for 60.3% of subjects. Admission to current placement from inpatient psychiatry, lifetime number of psychiatric placements, lifetime number of psychiatric diagnoses, and nonseizure neuropsychiatric comorbidity were significantly associated with CPT. Aggression and neuroleptic use were also significantly associated with CPT. Admission psychiatric diagnostic comorbidity was not associated with CPT. CONCLUSIONS: A high prevalence of psychiatric medication use and CPT was found in this population. Variables assessing illness severity, aggressive behavior, and nonseizure neuropsychiatric comorbidity may identify youths in psychiatric treatment settings with a high prevalence of past or current CPT exposure. Further research on the CPT of aggression is warranted.

Chronic low-dose cocaine treatment during adolescence facilitates aggression in hamsters.

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.

Anabolic-androgenic steroid exposure during adolescence and aggressive behavior in golden hamsters.

Anabolic androgenic steroid (AAS) abuse by adolescents represents a significant health care risk due to the potential for long-term negative physical and psychological sequelae, including increased aggressive behavior. The current experiments examined the effects of AAS use in young male adolescent hamsters (Mesocricetus auratus) and their consequences on aggressive behavior. It was hypothesized that AAS administration during adolescence predisposes hamsters to heightened levels of aggressive behavior (i.e., offensive aggression). To test this hypothesis adolescent male hamsters were administered high doses of synthetic AAS to mimic a 'heavy use' self-administration regimen used by athletes. Immediately following the exposure to AAS hamsters were tested for aggressive behavior using a resident-intruder model. Animals treated with high doses of AAS during their adolescent development showed heightened measures of offensive aggression i.e., decreased latency to bite and increased total number of attacks and bites) during the test period, while measures of total activity (total contact time) between the animals remained unchanged. AAS-treated males did not differ in body weight from controls, suggesting that the increased aggression was not due to increased body mass. The results of this study show that exposure to AAS during adolescence facilitates aggressive response patterns, but does not alter body weight.

Repeated cocaine treatment activates flank marking in adolescent female hamsters.

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.

Prevalence and patterns of psychotropic and anticonvulsant medication use in children and adolescents referred to residential treatment.

The prevalence and patterns of use of psychiatric and anticonvulsant medications were studied in 83 seriously emotionally disturbed children and adolescents at the time of their admission to a residential treatment facility. Youths (aged 5-19, mean = 13.6 years), consecutively admitted over 17 months, were assessed for the prevalence and patterns of use of psychotropic and anticonvulsant treatments. At admission, 76% of the youths were receiving psychiatric pharmacotherapy, 40% with more than one psychiatric agent, and 15% with a combination of psychotropic and anticonvulsant medications. Frequently prescribed medications were neuroleptics (35 % of the medicated youths), sedative-hypnotics (26 %), and anticonvulsants (15%). Psychostimulants (16%) and antidepressants (22%) were under-prescribed relative to their diagnostic indications. Over 50 different medication combinations were used. The neuroleptic + lithium combination was most common (25 % of the polypharmacological treatments). Neuroleptics were the most commonly prescribed medication and mostly used for nonpsychotic, nontic, and nonbipolar indications (55% of neuroleptic trials). Neuroleptics were used primarily for aggression regardless of diagnosis. Neuroleptics were used more in symptomatic treatments than in treatments for indicated diagnoses. The high prevalence of psychiatric and antiepileptic medication use in children and adolescents admitted to a residential treatment facility, and especially the pattern of their use, raises questions about prescribing practices for youths entering residential treatment and about pediatric psychopharmacotherapy in general.

Glutamate-vasopressin interactions and the neurobiology of anabolic steroid-induced offensive aggression.

In the latero-anterior hypothalamus (LAH) increased glutamate and vasopressin (AVP) activity facilitate anabolic androgenic steroid (AAS)-induced offensive aggression. In addition, adolescent AAS treatment increases the strength of glutamate-mediated connections between the LAH and the brain nucleus of stria terminalis (BNST). The current set of studies used male Syrian hamsters exposed to AAS during adolescence to examine whether increased glutamate-mediated stimulation of the BNST is dependent on LAH-AVP signaling and whether this neural pathway modulates adolescent AAS-induced offensive aggression. In the first set of AAS-treated animals offensive aggression was measured following blockade of glutamate activity within the BNST using NBQX. Then, in a second group of AAS-treated animals aggression levels were examined following simultaneous blockade of LAH-AVP activity using Manning compound and stimulation of BNST glutamate using AMPA. Lastly, the number of AVP fibers in apposition to glutamate cells was examined in AAS and control animals, using double-label immunofluorescence. The results showed that administration of NBQX into the BNST dose-dependently reduced aggressive behavior in AAS-treated animals. Further, the current results replicated previous findings showing that blockade of LAH-AVP significantly reduces aggressive behavior in AAS-treated animals. In these animals stimulation of BNST-AMPA receptors had a linear effect on aggression, where the smallest dose exacerbated the inhibitory effect of the V1a antagonist, the medium dose had no effect and the highest dose recuperated aggression to control levels. Finally when compared with control animals, AAS treatment produced a significant increase in the number of AVP fibers in apposition to LAH-glutamate cells. Overall, these results identify the BNST as a key brain region involved in aggression control and provide strong evidence suggesting that AVPergic-mediated stimulation of BNST-glutamate is a possible mechanism that facilitates aggression expression in adolescent AAS-treated animals.