Adolescent anabolic-androgenic steroids and the neurobiology of aggression: The role of the glutamatergic system

The first aim of this dissertation examined whether repeated adolescent anabolic androgenic steroid (AAS) exposure altered glutamate expression in the center of aggression control, the AH. Immunohistochemical results showed that in the AH of aggressive AAS-treated animals there was a significant increase in the number of cells expressing phosphate activated glutaminase (i.e., PAG the rate limiting enzyme for glutamate synthesis), vesicular glutamate transporter 2 (VGLUT2 an immunohistochemical marker for identification of glutamate cells) and PAG cells containing FOS (i.e., a marker of neuronal activation) (Carrillo et al., 2009 Carrillo et al., 2010a). Notably, close anatomical examination showed that changes in PAG, VGLUT2 and PAG/FOS were mainly localized to the ventrolateral portion of the AH (LAH). These findings supported a facilitatory role of glutamate in AAS-induced aggression and identified the LAH as a key subregion of the AH where AAS-induced changes in glutamate activity primarily occur.Given that glutamate is the predominant excitatory neurotransmitter in the hypothalamus, that it modulates the majority of hypothalamic excitatory post-synaptic potentials and that AAS treatment induces increased activity of this neural system within the center of aggression control (i.e., the LAH), the next aim of this research determined whether in the LAH glutamate functioned as the aggression output system to other brain areas implicated in aggression control. This study used retrograde tracing to investigate glutamate specific alterations in the connections between the LAH and BNST, LS, MeA and VLH in AAS-treated animals. Specifically, animals were microinjected with retrograde tracer into the BNST (BNST group), LS (LS group), MeA (MeA group) or VLH (VLH group). Brains were then processed for VGLUT2 (i.e., BNST, LS and MeA) or PAG (i.e., VLH) immunofluorescence and examined for AAS-induced changes in (1) VGLUT2 or PAG, (2) cells with retrograde tracer and (3) VGLUT2 or PAG cells containing tracer within the LAH. Results showed that repeated adolescent AAS exposure produced significant increases in glutamate activity (i.e.,VGLUT2 or PAG) in all brain regions examined compared to sesame oil (SO)-treated controls. While no changes in the total number of cells with tracer were detected in the LAH of animals from the LS and MeA group, significant increases in the BNST group and decreases in the VLH group were observed. Moreover, when compared with SO-treated controls, animals from the BNST group showed a significant increase in the number of VGLUT2 immunopositive cells containing tracer within the LAH, while animals from the VLH and MeA group showed a significant reduction in the number of PAG and VGLUT2 cells containing tracer in the LAH. Lastly, no changes were detected in the number of VGLUT2 immunopositive cells with tracer within the LAH of AAS-treated animals in the LS group compared to vehicle-treated controls. Together these results indicate that glutamate likely functions as the aggression output system from the LAH and that adolescent AAS treatment significantly alters the neural circuitry modulating aggression.This study examined whether in AAS-treated animals increased glutamate-specific connectivity between the LAH and BNST is dependent on the AVPergic system. In this investigate aggression levels in AAS-treated animals were measured following simultaneous administration of manning compound (i.e., an AVP V1a antagonist 0.9mM) or saline into the LAH and AMPA (i.e., an AMPA receptor agonist 0.01nm, 0.1nmol or 0.3nmol) or saline into the BNST. The results from this study replicated previous findings showing that blockade of LAH-AVP using an AVP V1a receptor antagonist significantly reduces aggressive behavior.In summary, the research from this dissertation provides compelling evidence supporting a key role of the glutamatergic system in the modulation of AAS-induced aggression, specifically having a facilitatory role in the expression of offensive aggression. In addition, short-term AAS exposure and long-term AAS withdrawal studies showed that AAS treatment produced alterations in glutamate activity in various brain areas implicated in aggression control however, only alterations in LAH-glutamate paralleled the time course of AAS-induced changes in aggressive behavior. Further, retrograde tracing and behavior pharmacology results identified the BNST as a critical brain area where the stimulatory activity of the glutamatergic system is necessary for the elevated aggression levels observed in AAS-treated animals. Lastly, the current research showed that synergistic stimulatory actions of AVP and glutamate are necessary for the expression of aggression in AAS-treated animals. (Abstract shortened by UMI.)...