Considerable public attention has been focused on the issue of youth violence, particularly that associated with drug use. It is well documented that anabolic steroid use is associated with a higher incidence of aggression and violence, yet little is known about how these drugs produce the aggressive phenotype. In previous studies, we showed that pubertal male Syrian hamsters (Mesocricetus auratus) exposed to moderate doses of commonly used anabolic steroids display a high level of offensive aggression that is modulated by the anterior hypothalamic (AH) arginine vasopressin (AVP) and serotonin (5HT) neural systems. Subsequently, we showed that developmental and neuroplastic changes in AH AVP alone correlated with the aggressive phenotype, suggesting that AH AVP activity was a stronger modulator of adolescent anabolic steroid-induced aggression than AH 5HT. In addition, we found that adolescent anabolic steroid exposure altered the AH dopamine (DA) and 3-amino-butyric acid (GABA) neural systems, suggesting that these signals may also play a role in anabolic steroid-induced aggression. Notably, alterations in the AVP, DA and GABA systems each occurred in the latero-anterior hypothalamic (LAH) sub-division of the AH, suggesting that this region may be an important site of convergence for anabolic steroid-induced neural adaptations that precipitate aggression. These findings are interesting given that current pharmacotherapeutic treatments for aggression in youth primarily influence DA and GABA signaling in brain, and that DA and GABA neurons have an anatomical and functional relationship with AH AVP neurons;opening the question of whether treatments for aggression in youth have their anti-aggressive properties as a result of downstream modulation of AH AVP. In this renewal we extend our study of the effects of adolescent anabolic steroid exposure on the AH neural circuit controlling aggression, with particular focus on AH neural systems influenced by the pharmacotherapeutic treatment of aggression in youth. We hypothesize that adolescent anabolic steroid exposure stimulates aggression by altering signaling between the LAH DA, GABA and AVP systems. To test this, we will ask three questions: (1) does adolescent anabolic steroid exposure affect the activity of select DA and GABA receptors in the LAH and does DA and GABA signaling through these receptors modulate LAH AVP release/activity and anabolic steroid-induced aggression;(2) do functional alterations between the LAH DA and GABA neural systems modulate LAH AVP release/activity and adolescent anabolic steroid-induced aggression;and (3) do current pharmacotherapeutic treatments for aggression in youth suppress adolescent anabolic steroid-induced aggression, and if so, do they act by modulating AVP release/activity at the level of the LAH.

Public Health Relevance

From the U.S. to Europe and Australia anabolic steroid abuse remains high in the adolescent population. This is concerning given that adolescent anabolic steroid use is associated with a higher incidence serious acts of aggressive and violent behavior. The focus of this renewal is to investigate the effects of adolescent anabolic steroid exposure on neural signaling between the hypothalamic DA/GABA and AVP neural systems and their role in anabolic steroid-induced aggressive behavior, with a focus on the influence of pharmacotherapeutic treatments for aggression in youth on the function of these neural systems. Completion of this research will provide new insight into the bio-behavioral processes driving anabolic steroid-induced aggression as well as provide translational information about the mechanism of action of select classes of pharmacotherapeutic agents that may prove useful for the treatment of youth predisposed to aggression due to early onset anabolic steroid use. When combined with data from other models of aggression, this knowledge will offer insight into the molecular mechanism(s) underlying aggression as well as provide translational information that may prove useful for the treatment of youth predisposed to this behavior across a spectrum.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA010547-13
Application #
8213612
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Pilotte, Nancy S
Project Start
1996-09-01
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
13
Fiscal Year
2012
Total Cost
$299,900
Indirect Cost
$99,900
Name
Northeastern University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Morrison, Thomas R; Ricci, Lesley A; Melloni Jr, Richard H (2014) ?-Aminobutyric acid neural signaling in the lateroanterior hypothalamus modulates aggressive behavior in adolescent anabolic/androgenic steroid-treated hamsters. Behav Pharmacol 25:673-83
Carrillo, Maria; Ricci, Lesley A; Melloni, Richard H (2011) Glutamate and the aggression neural circuit in adolescent anabolic steroid-treated Syrian hamsters (Mesocricetus auratus). Behav Neurosci 125:753-63
Carrillo, M; Ricci, L A; Melloni, R H (2011) Glutamate-vasopressin interactions and the neurobiology of anabolic steroid-induced offensive aggression. Neuroscience 185:85-96
Schwartzer, Jared J; Melloni Jr, Richard H (2010) Dopamine activity in the lateral anterior hypothalamus modulates AAS-induced aggression through D2 but not D5 receptors. Behav Neurosci 124:645-55
Carrillo, Maria; Ricci, Lesley A; Schwartzer, Jared J et al. (2010) Immunohistochemical characterization of 5-HT(3A) receptors in the Syrian hamster forebrain. Brain Res 1329:67-81
Schwartzer, Jared J; Melloni Jr, Richard H (2010) Anterior hypothalamic dopamine D2 receptors modulate adolescent anabolic/androgenic steroid-induced offensive aggression in the Syrian hamster. Behav Pharmacol 21:314-22
Schwartzer, Jared J; Ricci, Lesley A; Melloni Jr, Richard H (2009) Interactions between the dopaminergic and GABAergic neural systems in the lateral anterior hypothalamus of aggressive AAS-treated hamsters. Behav Brain Res 203:15-22
Carrillo, Maria; Ricci, Lesley A; Coppersmith, Glen A et al. (2009) The effect of increased serotonergic neurotransmission on aggression: a critical meta-analytical review of preclinical studies. Psychopharmacology (Berl) 205:349-68
Carrillo, Maria; Ricci, Lesley A; Melloni Jr, Richard H (2009) Adolescent anabolic androgenic steroids reorganize the glutamatergic neural circuitry in the hypothalamus. Brain Res 1249:118-27
Ricci, Lesley A; Schwartzer, Jared J; Melloni Jr, Richard H (2009) Alterations in the anterior hypothalamic dopamine system in aggressive adolescent AAS-treated hamsters. Horm Behav 55:348-55

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