Aggression and violence pose a significant public health concern to society. Aggression is a highly conserved behavior that shares common biological correlates across species. While aggression developed as an evolutionary adaptation to competition, its untimely and uncontrolled expression is maladaptive and presents itself in a number of neuropsychiatric disorders. A mechanistic hypothesis for pathological aggression links aberrant behavior with heightened dopamine function. However, while dopamine hyper-activity is a neural correlate of aggression, the developmental aspects and circuit level contributions of dopaminergic signaling have not been elucidated. In this dissertation, I aim to address these questions regarding the specifics of dopamine function in a murine model of aggressive behavior. In chapter I, I provide a review of the literature that describes the current state of research on aggression. I describe the background elements that lay the foundation for experimental questions and original data presented in later chapters. I introduce, in detail, published studies that describe the clinical manifestation and epidemiological spread, the dominant categories, the anatomy and physiology, and the pharmacology of aggression, with a particular emphasis on the dopaminergic system. Finally, I describe instances of genetic and environmental risk factors impacting aggression, concluding with studies revealing an important role for interactions among genetics, environmental factors, and age in the development of aggression. In chapter II, I investigate the developmental origins of aggression by examining sensitive periods during which perturbations to the dopaminergic system impact adult aggressive behavior. Previous work in our laboratory has concluded that periadolescent (postnatal days 22-41) elevation in dopamine, via transient dopamine transporter blockade, leads to increased adult aggression and heightened response to amphetamine. I expanded on these findings by temporally refining the opening and closing of this window of sensitivity, specifically to postnatal days 32 to 41, during which increases in dopaminergic tone increase adult aggression and behavioral sensitivity to psychostimulants. The potentiated response to amphetamine indicated to us a state of altered dopaminergic physiology. We next validated this hypothesis and found increased firing rate (in vitro), and increased bursting and population activity (in vivo) at baseline. These data indicate that elevated periadolescent dopamine impacts maturation of the dopamine system, leading to a hyper-active dopaminergic and aggressive predisposition. In conclusion, this chapter introduces a developmental component to the hyper-dopaminergic model of aggression. In chapter III, I report a series of experiments exploring the direct and causal involvement of dopamine in driving aggression. While dopamine hyper-activity is a neural correlate of aggression, the precise brain circuits involved have not been elucidated. Using optogenetics, I established a causal role for the ventral tegmental area (a key source of dopamine) in aggression modulation. I further advanced this finding by demonstrating that the modulatory role of dopamine, is population- and projection-specific. I found that activity of ventral tegmental area, but not substantia nigra, dopamine neurons promotes aggression. Furthermore, controlled stimulation of ventral tegmental area dopaminergic terminals in the lateral septum, but not the nucleus accumbens, mediates increased aggression. I selectively traced connectivity between the lateral septum and the ventral tegmental area using a Cre-driven, population-specific viral vector. I used this virus to show that anatomically distinct clusters of ventral tegmental area dopamine cells send projections to the lateral septum and the nucleus accumbens, thereby dissociating the two target sites both behaviorally and anatomically. Furthermore, I found that while local dopamine release in the lateral septum increases aggression, it has no bearing on reward behaviors thus indicating a stronger association with impulsive, and not motivated, aggression. In conclusion, this chapter offers causal evidence for dopamine’s role in modulating impulsive aggression by identifying a distinct pathway from the ventral tegmental area to the lateral septum that controls aggression. In the work described in chapter IV, my aim was to determine the mechanism underlying ventral tegmental area to lateral septum dopamine-mediated aggression. I first characterized the expression of dopamine receptors in the lateral septum and found that D2 receptors heavily colocalize with the dominant population of neurons in the lateral septum, i.e. GABAergic cells. Moreover, the D2 receptors are perfectly aligned with incoming dopamine afferents. Next we investigated, in acute brain slices, how D2 signaling affects lateral septum function. We revealed that activating D2 receptors hyperpolarizes D2-expressing lateral septum neurons. This effect was abolished with bath application of the D2 receptor antagonist, sulpiride. We validated the functional involvement of post-synaptic D2 signaling in a behavioral test, and found that the aggression induced by direct terminal release of dopamine at the lateral septum is reversed by acutely blocking local D2 receptor signaling. In conclusion, this chapter demonstrates that the ventral tegmental area to lateral septum dopamine pathway, via D2-mediated inhibition of GABAergic lateral septum neurons, is necessary to drive ventral tegmental area-triggered aggression. In chapter V, I engage in a general discussion addressing how the findings from each chapter can be linked to provide a more comprehensive outlook on environmental and genetic risk factors that can modulate ventral tegmental area-triggered aggression. I discuss possible pre- and post-synaptic mechanisms that could impact the functionality of the identified dopaminergic ventral tegmental area to lateral septum pathway. Moreover, in distinguishing this specific dopamine circuit and lateral septum D2 signaling as an underlying correlate of violent pathology, this dissertation aims to evoke deeper understanding of the mechanism of current antipsychotics used to manage aggression. I end this dissertation by proposing new empirical questions, techniques and lines of research that could further develop my findings as well strengthen the links between dominant models of aggression that exist in the field today.

Thesis (Ph. D.)--University of Texas at Austin, 2001. / Vita. Includes bibliographical references (leaves 105-133). Available also in a digital version from Dissertation Abstracts.

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Thesis (Ph. D.)--Northeastern University, 2008. / Title from title page (viewed March 3, 2009). Graduate School of Arts and Sciences, Dept. of Psychology. Includes bibliographical references (p. 148-156).

Thesis (Ph.D.) - University of St Andrews, April 2008.

Thesis (Ph. D.)--University of Chicago, Committee on Neurobiology, August 1999. / Includes bibliographical references. Also available on the Internet.

No description available.

The present experiments investigated the effects of different antidepressant treatments on dopamine (DA) transmission by employing in vivo microdialysis in the nucleus accumbens (NAC) and the striatum of freely moving rats. The treatments were: a) the tricyclic antidepressant desipramine (DMI), b) the novel antidepressant drug bupropion, and c) electrically induced seizures (ECS). The following results were obtained: 1) Neither acute (5 mg/kg), nor chronic (5 mg/kg, b.i.d. X 21) DMI influenced basal interstitial concentrations of DA in the NAC or the striatum. Chronic DMI did not influence apomorphine (25 μg/kg, s.c.)-induced decreases in extracellular DA in the NAC. In contrast, d-amphetamine (1.5 mg/kg, s.c.)-induced increases in extracellular DA were significantly enhanced in the NAC (not in striatum) of the chronic DMI group. d-Amphetamine-induced hypermotility was also enhanced in the chronic DMI group. 2) Bupropion (10, 25 and 100 mg/kg, i.p.) increased extracellular striatal DA concentrations in a dose-, time-, and action potential-dependent manner. Bupropion produced similar responses in the NAC. The in vivo neurochemical effects of bupropion were compared with the effects of other DA uptake inhibitors such as d-amphetamine, GBR 12909, cocaine, nomifensine, methylphenidate, and benztropine by direct administration of the drugs to the striatum via the perfusion fluid in increasing concentrations (1 to 1000 μM). The rank order of potency of these drugs as determined by the increases in extracellular DA produced by 10 or 100 μM (following correction for dialysis efficiency of the test compounds in vitro) was: GBR 12909> benztropine> amphetamine= nomifensine= methylphenidate> cocaine> bupropion. Simultaneous in vivo microdialysis in the NAC and striatum was employed to investigate the effects of chronic (10 mg/kg, b.i.d. X 21) bupropion treatment on bupropion (25 mg/kg, i.p.)-induced increases in extracellular DA concentrations. The effect of the challenge bupropion injection was significantly enhanced in the NAC (not in striatum) of the chronic bupropion group. Bupropion-induced hyperlocomotion was also enhanced in the chronic bupropion group. 3) Following a single ECS (150 V, 0.75 sec) interstitial concentrations of DA in the NAC and striatum increased sharply to 130% and 300%, respectively. The ECS-induced DA increase in the striatum was Ca⁺⁺-sensitive, partially TTX-independent, and was not influenced by barbiturate-induced anaesthesia. Seizure activity induced by flurothyl did not influence dialysate DA concentrations from the striatum, but increased dialysate DA from the NAC to 150%. These results suggest that the ECS-induced DA release in the striatum (not in the NAC) is related to the passage of current and not to the seizure activity. A course of ECS (8 treatments, one every second day) did not influence basal extracellular DA concentrations in the striatum or the NAC, while it significantly increased the DA metabolites in the striatum. Chronic ECS did not influence apomorphine (25 μg/kg, s.c.)-induced decreases in extracellular DA in the NAC. d-Amphetamine (1.5 mg/kg s.c.)-induced increases in extracellular DA were significantly enhanced in the NAC of the chronic ECS group. d-Amphetamine-induced hypermotility was also enhanced in the chronic ECS group. These results provide in vivo neurochemical confirmation that chronically administered DMI or ECS do not produce DA autoreceptor subsensitivity. They also demonstrate that chronic DMI- or chronic ECS-induced increases in the locomotor stimulant effects of d-amphetamine are accompanied by a potentiation of its effects on interstitial DA concentrations in the NAC. Moreover, these results demonstrate that chronic bupropion-induced behavioral sensitization is accompanied by a selective potentiation of its effects on interstitial DA concentrations in the NAC. Taken together, the present data provide direct neurochemical evidence that these antidepressant treatments can increase the functional output of the meso-accumbens dopaminergic system. / Medicine, Faculty of / Graduate

The present study ln male Wistar rats was designed to rate and analyze six specific cocaine-induced behaviors. These behavioral parameters have been defined by others as either dopaminergic (sniffing, grooming, and locomotor activity) or serotonergic (repetitive head movements, rearing, and Straub tail) in origin. Results were analyzed by analysis of variance in two ways : (i) as grouped dopaminergic or serotonergic scores, and (ii) as the net behavioral index (dopaminergic scores minus the serotonergic scores). The purpose of approaching the data in this way was to attempt to define the behavioral interactions of the two neurotransmitters. One conclusion that developed from this study was the indication that dopaminergic behaviors peak at lower doses of cocaine than do serotonergic behaviors. This relationship held true for all the individual parameters in addition to the dopaminergic and serotonergic totals. A dopaminergic blocker, haloperidol, significantly attenuated all responses elicited by cocaine. When the net behavioral index was analyzed, it was found that the response of the median dose of cocaine was significantly altered from a net dopaminergic score towards a net serotonergic score. In this sense, haloperidol was shown to have the capacity to attenuate dopaminergic-associated parameters to a greater extent than the serotonergic-associated parameters. Cyproheptadine, an antiserotonergic agent, did not significantly affect the net behavioral index; however, this compound did significantly increase the dopaminergic parameter of grooming at the high doses of cocaine and cyproheptadine. Also at this dose combination , gnawing was elicited -- a dopaminergic response seen under no other experimental conditions. Due to the antiserotonergic agent causing an increase in the dopaminergic parameters of grooming and gnawing, it is proposed that the serotonergic influence on these two dopaminergic behaviors is of an inhibitory type.