Thesis (M.S.)--Villanova University, 2009. / Psychology Dept. Includes bibliographical references.

Thesis (Ph. D.)--University of Texas at Austin, 1998. / Vita. Includes bibliographical references (leaves 179-229). Available also in a digital version from Dissertation Abstracts.

Thesis (Ph. D.)--Washington State University, August 2007. / Includes bibliographical references.

Thesis (Ph.D.)--Baylor University, 2006. / Includes bibliographic references (p. 163-189).

Proefschrift Universiteit van Amsterdam. / Hfst. 4 ontbreekt i.v.m. embargo. Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Dopamine has an important role in normal cognition and reward processing, both of which are impaired in disorders involving dopamine dysfunction such as addiction, schizophrenia, and Parkinson's disease. However, our understanding of the interplay between different aspects of the dopamine system and reward-guided behavior in humans is limited. Food is an important type of reward that is critical for survival and impacts the decisions we make every day. Here, we characterize the relationship between two food-reward related phenotypes and dopamine synthesis capacity (related to tonic dopamine) as well as dopamine D1 and D2 receptor availability in healthy humans. First, we examined the link between dopamine synthesis and receptor availability and body mass regulation in 117 individuals with body mass index (BMI) values ranging from normal to obese. We found that current BMI was related to a pattern of increased dopamine synthesis in the hypothalamus, a region important for homeostatic control of appetite, but decreased dopamine D₂ receptor availability in the midbrain, where D₂ autoreceptors regulate dopamine release throughout the brain. This suggests that increased BMI is related to a dopamine imbalance between homeostatic drivers of appetite and reward system regulatory control mechanisms that could result in an overactive, unregulated intake of food. Building on this finding, we studied the link between dopamine synthesis capacity and receptor availability and an important food-reward related behavior, foraging. Fifty-seven healthy volunteers completed a computer-based foraging task where we measured their threshold for leaving one group of rewards to search for another in four different reward environments varying from a low to high rate of reward receipt. We found that two particular patterns of dopamine synthesis and receptor availability in the anterior cingulate cortex and basal ganglia were linked to the amount that individuals changed their threshold based on the reward rate of the environment. Finally, since the prefrontal cortex is known to be important for reward-guided behavior, we implemented two methodological advancements aimed to address limitations that make it difficult to measure cortical dopamine in humans with PET imaging. The first method involves partial volume correction and surface-based smoothing in order to increase the signal to noise in the cortex. The second method is a data-driven PET data parcellation and automated reference region selection algorithm to optimize the voxels included in the reference region. In conclusion, we have characterized the dopaminergic contribution of two different foodreward guided phenotypes and have developed two techniques that will aid future research on the role of cortical dopamine. Understanding the neural mechanisms underlying these rewardguided behaviors helps us to not only understand normal behavior, but also serves as a reference for comparison when studying related pathological states.

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Neural communication is imperative for physical and mental health. Dysfunction in either ionic signaling or chemical neurotransmission can cause debilitating disorders. Thus, study of neurotransmission is critical not only to answer important fundamental questions regarding learning, decision making, and behavior but also to gain information that can provide insight into the neurochemistry of neurological disorders and lead to improved treatments. The work presented herein describes the development of techniques and instrumentation to enable advancements in neuroscientific inquiry. The effect of different temporal patterns and durations of simulation of the prefrontal cortex on dopamine release in the nucleus accumbens was examined and revealed a complex interaction that can help improve deep brain stimulation therapies. A measurement platform that combines electrophysiological and electrochemical techniques is described. The instrumentation is capable of concurrent monitoring of neural activity and dopamine release in vivo and in freely moving rodents. Analysis techniques to allow absolute quantification of tonic dopamine concentrations in vivo are detailed and the temporal resolution of the technique was vastly improved from ten minutes to forty seconds. An instrument that can simultaneously probe both dopamine and serotonin dynamics in either of their two temporal modes of signaling (tonic and phasic) using either fast-scan cyclic voltammetry or fast-scan controlled-adsorption voltammetry at two individually addressable microelectrodes is described. Together these new tools represent a significant step forward in the field of neuroanalytical chemistry by enable multiple brain regions, signaling modes (ionic flux in addition to both tonic and phasic neurotransmission), neurochemicals, and to be measured together.

Despite substantial progress in the area of depression research, the current treatments for Major Depressive Disorder (MDD) remain suboptimal. Therefore, various medications are often used as augmenting agents in pharmacotherapy of treatment-resistant MDD. Despite the relative clinical success, little is known about the precise mechanisms of their antidepressant action. The present work was focused on describing the effects of three drugs with distinctive pharmacological properties (pramipexole, aripiprazole, and quetiapine) on function of the monoaminergic systems involved in the pathophysiology and treatment of MDD. Reciprocal interactions between the monoamines serotonin, norepinephrine, and dopamine systems allow the drugs targeting one neuronal entity to modify the function of the other two chemospecific entities. Electrophysiological experiments were carried out in anaesthetized rats after 2 and 14 days of drug administration to determine their immediate and the clinically-relevant long-term effects upon monoaminergic systems. Pramipexole is a selective D2-like agonist with no affinity for any other types of receptors. It is currently approved for use in Parkinson’s disorder and the restless leg syndrome. Long-term pramipexole administration resulted in a net increase in function of both dopamine and serotonin systems. Aripiprazole is a unique antipsychotic medication. Unlike all other representatives of this pharmacological class that antagonize D2 receptor, this drug acts as a partial agonist at this site. Chronic administration of aripiprazole elevated the discharge rate of the serotonin neurons, presumably increasing the overall serotonergic neurotransmission. Like aripiprazole, quetiapine is one of three atypical antypsicotic drugs approved for use in MDD. Prolonged administration of quetiapine led to a significant increase in both noradrenergic and serotonergic neurotransmission. Importantly, the clinically counter-productive decrease in the spontaneous firing of catecholaminergic neurons, induced by SSRIs, was overturned by the concomitant administration of both aripiprazole and quetiapine. The increase in serotonergic neurotransmission was a consistent finding between all three drugs studied herein. In every case this enhancement was attained in a distinctive manner. Understanding of the precise mechanisms leading to the amplification/normalization of function of monoamines enables potential construction of optimal treatment strategies thereby allowing clinicians greater pharmacological flexibility in the management of depressive symptoms.