Richard H. Melloni - US grants

DESCRIPTION: (Applicant's Abstract) The abuse of androgenic-anabolic steroids (AAS) has increased dramatically amongst the adolescent population and represents a serious drug problem in the United States. The most consistently cited behavioral sequelae of AAS abuse is increased aggressive behavior. The arginine vasopressin (AVP) neural system has been strongly implicated in the regulation of aggressive behavior. It is hypothesized that abuse of anabolic steroids during the adolescent period of neural development results in increased aggressive behavior correlated with developmental changes in the AVP neural system. These changes may be a function of alterations in the expression of AVP and/or the expression and activity of specific AVP receptors. Alternatively, these developmental changes may be due to modifications in the synaptic connectivity of the AVP neural system. Studies outlined in this proposal will utilize an animal model to examine the behavioral and neurobiological effects of high dose AAS exposure during a period that is physiologically similar to adolescence in humans. The first set of experiments will determine whether exposure to AAS during adolescent development facilitates aggressive behavior in golden hamsters using the resident/intruder paradigm of offensive aggression. The next set of experiments will determine whether AAS exposure during adolescence alters the molecular biology and neurochemistry of the AVP neural system. These studies will employ the use of cDNA fragments, antibodies, and selective receptor ligands to visualize and quantitate the activity of the genes encoding AVP and the AVP V1A subtype receptor. The last set of experiments will determine whether exposure to AAS during adolescent development alters the synaptic connections of the AVP neural system. Changes in synaptic connectivity will be visualized and quantitated by wide-field digital microscopy and immunoelectron microscopy. The data obtained from these studies should provide valuable information regarding the increased risk of aggressive and violent behavior in those individuals who abuse AAS during early life, and the neurobiological sequelae of prolonged high dose use of AAS. This knowledge is important in helping us to identify developmental periods that are particularly vulnerable to environmental insult, and to document the neurobiological changes that may predispose individuals to behave in a self-destructive or violent manner later in life.

DESCRIPTION (provided by applicant): 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.

During the past 40 years research in aggression has identified the main neurotransmitters and brain areas involved in the modulation of aggressive behavior. However, how key brain areas and neurotransmitters interact to modulate aggression is unknown. In the lateral anterior hypothalamus (i.e., LAH; the center of control of aggression that receives and integrates aggression inputs from other brain areas involved in aggression control and sends output projections back), vasopressin is a neuropeptide that facilitates aggression. Moreover, in this brain area glutamate (i.e., a predominant excitatory amino acid in the hypothalamus) has been previously hypothesized to be the aggression output system to other aggression brain areas. The current project will focus on understanding how interactions between vasopressin and glutamate in the LAH modulate the aggressive behavior. Specifically, male Syrian hamsters (Mesocricetus auratus) exposed to moderate doses of anabolic androgenic steroids will be used to investigate whether increased hypothalamic vasopressin stimulates the activity of glutamate cells and underlies the escalated aggressive behavior observed in these animals. This project will primarily use behavior pharmacology to investigate how changes in aggressive behavior map to changes in brain activity.

The findings from this project will not only provide new knowledge that will further our understanding on the neurobiology of aggression but it will also make a contribution to other research areas investigating how brain mechanisms regulate behavior. Moreover, this project will promote the development as an early neuroscientist of a female PhD student and training in laboratory of various undergraduate students from underrepresented groups.