Richard H. Melloni
Marcelo Febo, John Coley, Cliff Summers
Date of Award
Doctor of Philosophy
Department or Academic Unit
College of Science, Department of Psychology
neurosciences, behavioral sciences
Hypothalamus, Aggressiveness in adolescence, Anabolic steroids
Adolescence is a developmental period where neurobiological mechanisms regulating complex behaviors, such as aggression, are particularly sensitive to circulating androgens. For example, an increased incidence of aggressive behavior correlates with elevated levels of endogenous testosterone in mid-to-late adolescent males (Dabbs et al. 1987; Dabbs et al. 1991; Mattsson et al. 1980; Scerbo and Kolko 1994) but not in prepubertal males (Constantino et al. 1993; Schaal et al. 1996; Susman et al. 1987), suggesting a link between circulating androgens and the development of the aggressive phenotype. This link between testosterone and aggression is particularly concerning for adolescent populations who abuse synthetic testosterone and its derivatives, collectively termed anabolic androgenic steroids (AAS), for their performance enhancing effects (NIDACapsules 2008). Abuse of AAS remains high in the adolescent population, with more than a half million 8th-10th graders in the U.S. reporting AAS use each year (NIDACapsules 2008). This is particularly concerning given the high incidence of psychological and physiological ramifications associated with taking AAS, including increased violence, rage, and aggression (Dukarm et al. 1996; Loeber and Hay 1997).
For over a decade, the Syrian hamster has been used as a valid animal model to investigate the neurobiological consequences of adolescent AAS exposure (Melloni et al. 1997a). These studies have revealed that AAS-treatment produces activational and organizational alterations in distinct neurochemical systems across key aggression loci of the brain (Melloni and Ricci 2010). Of particular interest are the neurochemical systems altered in the anterior hypothalamus (AH), a brain region essential to the control of aggressive behavior. For example, dopamine has been localized to the AH, though its sensitivity to adolescent AAS-exposure and ability to modulate aggression is not well understood.
To investigate the effects of AAS-exposure on the dopamine neural system, male Syrian hamsters were treated with AAS throughout adolescence and their brains were processed for immunohistochemistry of tyrosine hydroxylase (TH: the rate limiting enzyme for dopamine synthesis), as well as dopamine D2 and D5 receptors. Aggressive adolescent AAS-treated hamsters were found to have a significant increase in the number of dopaminergic cell bodies in two subnuclei of the AH, the nucleus circularis (NC) and medial supraoptic nucleus (mSON), i.e., the two principal nuclei responsible for innervating the lateral subdivision of the AH, referred to as the LAH. Increases in LAH TH correlate with aggression intensity in AAS-treated animals, demonstrating a direct link between AAS-induced aggression and hypothalamic dopamine production. Interestingly, both D2 and D5 receptors were localized to cell bodies within the LAH, suggesting that AAS-induced increases in dopamine results in increased activation to these local receptor pools, eliciting the elevated aggressive responses.
To investigate this hypothesis, aggressive AAS-treated hamsters were microinjected with a selective D2 or D5 antagonist into the LAH and measured for changes in aggressive responding. The selective D2 receptor antagonist eticlopride dose-dependently decreased aggression while leaving all other non-aggressive related behaviors intact. Conversely, only high doses of the D5 receptor antagonist SCH-23390 suppressed AAS-induced aggression and these reductions in aggressive responding were met with concomitant reductions in general arousal and motor activity. While these findings suggest that dopamine's action at D5 receptors in the LAH may regulate other hypothalamic-mediated behaviors non-specific to aggression, it is possible that their function in the control of aggression may still be important, albeit difficult to discern. Therefore it was necessary to investigate what neural systems express these D2 and D5 receptors in the LAH and how they may be altered by AAS-exposure throughout adolescent development.
Double-label immunofluorescence studies revealed that D2, but not D5, receptors are expressed on a subpopulation of GABAergic interneurons in the LAH, suggesting that AAS-induced alterations in dopamine synthesis increases aggression through inhibition of GABAergic neurons resulting in disinhibition of hypothalamic activity. The finding that only a subpopulation of GABA neurons in the LAH is modulated by dopamine led to the investigation of the serotonin neural system and how it modulates GABA through excitatory 5-HT2A receptors. Aggressive AAS-treated hamsters showed increased expression of 5-HT2A receptors in the LAH. These increases in receptor levels correlated with the elevated aggressive response produced by AAS-treatment. 5-HT2A receptors were found to colocalize with a subpopulation of GABAergic neurons indicative of multiple GABAergic pathways in the LAH. Together, serotonin and dopamine are postulated to differentially modulate multiple GABAergic populations in the LAH resulting in differential regulation of inhibitory and excitatory neural inputs. Perturbation of these neural systems as a result of AAS-use during adolescence results in increased hypothalamic activity and exaggerated aggressive responding. Given that pharmacology used to treat aggression in clinical youth target D2 and 5-HT2A receptors, findings from this dissertation elucidates a plausible brain locus where these drugs may work to directly modulate aggressive behaviors and provide a putative neural mechanism whereby adolescent AAS-abuse alters brain neurochemistry resulting in increased offensive aggression.
Jared J. Schwartzer
Schwartzer, Jared J., "Integrating the neural systems of the lateral anterior hypothalamus in adolescent AAS-induced offensive aggression" (2011). Psychology Dissertations. Paper 18. http://hdl.handle.net/2047/d20000980
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