Context: Dopamine has been implicated as an important neurotransmitter involved in regulating appetite and food intake by modulating the reinforcement of food via the meso-limbic circuitry of the brain. Several genes have been linked with the regulation of dopamine. Monoamine oxidase A (MAOA) modulates the metabolism of serotonin and dopamine, both of which are neurotransmitters involved in the regulation of appetite and food intake. The gene coding for MAOA contains a 30-bp tandem repeat (uVNTR) polymorphism in its promoter region that has been previously identified to be associated with energy balance behaviors and body mass index (BMI). The gene coding for dopamine receptor D4 (DRD4) contains a 16 amino acid (48-bp) repeat polymorphism that has been linked with food consumption and BMI. Lastly, the dopamine transporter gene (SLC6A3: Solute carrier family 6 – neurotransmitter transporter, dopamine – member 3) codes for a dopamine transporter protein (DAT) that mediates the active reuptake of dopamine from the synapse. The transport gene contains a 40-base variable number tandem repeat (VNTR) at the 3’ untranslated region (3’-UTR) that has been previously identified to be associated with variable levels of postsynaptic dopamines. Objective: Our goals were to investigate the population effects of the aforementioned functional polymorphisms on various types of food consumption (soda, fast food, snack, and ready to eat foods) and physical activity (exercise and TV watching), and to further explore gender differences and interaction effects with negative stressors. Methods: The analyses were conducted with data on genotypes and self-reported behavioral characteristics among 951 Chinese adolescents 11-15 years old living in Wuhan, China. Results: Males with the high-activity allele of MAOA had lower odds of increased soda intake (adjusted OR=0.63; 95% CI: 0.41-0.98, p=0.03) than those with low activity allele. Experience of negative stressors significantly strengthened the protective genetic effect on increasing odds of engaging in vigorous activity (adjusted OR for interaction=1.89 with 95% CI of 1.89-2.52, pvalue for interaction=0.04). Additionally, combined males and females with DRD4 variant had greater odds of engaging in vigorous exercise (adjusted OR=1.39; 95% CI: 1.01-1.86, p=0.03) and of increased soda intake (adjusted OR=1.33; 95% CI: 1.01-1.76, p=0.04) than those with the wild-type allele. Among females, wild-type carriers (no 2R or 7R allele) when exposed to negative stressors were significantly more likely to engage in vigorous exercise (adjusted OR=0.14, 95% CI: 0.047-0.43, p=0.000586). Lastly, combined males and females with the DAT variant had increased odds of watching TV (adjusted OR=1.59; 95% CI: 0.61-1.77) and decreased odds of consuming fast foods (adjusted OR=0.60; 95% CI: 0.38-0.95, p=0.030654) than those with DAT wild-type. Experience of negative stressors significantly weakened the protective genetic effect on the odds for fast food consumption (adjusted OR=0.30; 95% CI: 0.13-0.66, p=0.002639). Conclusions: Our findings confirm the genetic effects of the dopamine regulating genes polymorphisms on food consumption and physical activity, and provide new insights about interactions with negative stressors.

The work described in this dissertation aims to understand how postural instability (PI), a troubling symptom of advanced Parkinson's disease (PD) in humans, develops from the degeneration of nigrostriatal dopamine neurons characteristic of PD. The studies herein (1) outline the development of clinically relevant methods for evaluating PI in experimental rodents, (2) indicate that PI may not result directly from disruption of dopamine systems but may instead arise from non-dopaminergic changes that occur subsequent to dopamine depletion, and (3) search for specific evidence of plasticity or degeneration outside of the damaged nigrostriatal dopamine system that may be linked to the development of PI. It is hoped that this work will help lay the foundation for the development of novel prophylactic treatments aimed at preventing the progression of PD to advanced stages where treatment-resistant symptoms such as PI appear. / text

Dopamine signaling in the prefrontal cortex is thought to play a role in ethanol abuse. However, little is known about how ethanol affects dopamine signaling in the region. There are a few rodent studies regarding the matter, but both the pharmacological effects of ethanol and the effects of self-administered ethanol on extracellular dopamine in the medial prefrontal cortex remain unclear. The goal of the studies conducted for this dissertation is to clarify these relationships. To accomplish this, we monitored both dialysate dopamine and ethanol concentrations in the medial prefrontal cortex of Long Evans rats while an experimenter administered or a rat operantly self-administered ethanol. In naïve rats, dopamine dose-dependently increased after the intravenous infusions of a 10% ethanol solution, while no changes were noted after saline infusions. In rats trained to orally self-administer drinking solutions, dopamine transiently increased at the initiation of consumption in both ethanol-plus-sucrose- and sucrose-solution-consuming rats. Dopamine concentrations remained significantly elevated for the entire 21-minute drinking period in the ethanol-plus-sucrose-consuming group and for the first seven minutes of the drink period in the sucrose-consuming group. Additionally, in the ethanol-plus-sucrose-consuming group, dialysate ethanol concentrations were lowest at the initiation of drinking and then slowly increased, peaking 35 minutes after drinking commenced. Taken together, these data suggest that the mesocortical dopamine system is responsive to acute, intravenous and repeatedly, orally, self-administered ethanol. It appears that direct pharmacological effects of ethanol were responsible for the dopamine increase after acute, ethanol administration. Furthermore, while is it possible that the direct pharmacological effects of ethanol also bolstered the dopamine response seen after ethanol self-administration, we cannot firmly conclude by what mechanism ethanol elicited the differences. Overall, our clarifying and novel results support a role for the mesocortical dopamine system in ethanol abuse, which deserves continued investigation. In addition to completing the two aforementioned data studies, we also published the methods we use to monitor dialysate ethanol concentrations, in a specific brain region, during ethanol self-administration in a video-methods journal. The methods are presented in both a detailed written protocol, as well as a video demonstrating how to perform the procedures. / text

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To understand how the brain functions and what disruptions underlie neurological diseases and disorders, analytical methods are needed that can succeed in the complexity of the native brain environment. To make a measurement in functioning, live tissue, these methods must be selective for specific analytes in a matrix that has over 1000 different chemical species, be able to measure chemical changes on multiple timescales (10-3 s to 104 s), have a high spatial resolution (μm), and be sensitive (pM to μM). The work described within, details the development and application of a voltammetric method, fast-scan controlled adsorption voltammetry (FSCAV) that is capable of monitoring baseline levels of serotonin and dopamine, as well as monitoring changes on multiple time scales with high sensitivity and selectivity. Because FSCAV is performed using a carbon-fiber microelectrode, the same sensor can be used for fast-scan cyclic voltammetry to monitor rapid (phasic) changes of dopamine and serotonin in the extracellular space. Thus a single-sensor strategy for measuring tonic and phasic concentrations of these important neurotransmitters is developed and used to elucidate important insight into the differences of serotonin and dopamine regulation. Additionally it is revealed that dopamine exhibits a coaction between tonic and phasic signaling where serotonin does not. Using this approach, a method for evaluating pain processing in a preclinical model is developed, which reveals an important relationship between chronic pain and dopamine signaling. Furthermore, a mathematical model to describe mass-transport limited adsorption is developed and used to determine the diffusion coefficient of both dopamine and serotonin in situ. The work described within details an important advancement in neuroanalytical methodology that will provide new insights both short-term and long-term for studying fundamental chemical mechanisms of neurotransmission.

The placebo effect represents a fascinating example of how cognition can influence the physiology of the brain and body. The expectation of therapeutic benefit elicited by a placebo given in the guise of active medication has been proposed to be a form of reward expectation, and is associated with activation of brain reward circuitry. Prominent placebo effects occur in Parkinson’s disease (PD), where the expectation of symptom improvement stimulates dopamine release in the striatum. In the work described in this dissertation, positron emission tomography with [¹¹C] raclopride was used to investigate the relationship between the strength of expectation of benefit and the degree of dopamine release in PD, and how this relationship corresponds to current models of dopamine function in reward. Chapter 3 describes a pilot study conducted in patients who had undergone subthalamic nucleus deep-brain stimulation (STN-DBS) in which we examined how awareness of stimulator status (ON or OFF) affected synaptic dopamine levels compared to when subjects were blind. No difference was detected between conditions; however, it proved to be difficult to maintain blinding due to the profound effects of STN-DBS. Chapter 4 describes the development of the methodology for the analysis of high-resolution PET data, in which we utilized the combined efforts of neuroscience and imaging physics to optimize the analysis of [¹¹C] raclopride PET data. In Chapter 5, I describe the use of verbal instructions to manipulate patients’ expectations in order to investigate how the likelihood of receiving levodopa influenced dopamine release when the patients were in fact given placebo. Placebo-induced dopamine release was differentially modulated by expectation in the dorsal and ventral striatum: dopamine release in the putamen was related monotonically to expected reward value, whereas dopamine released in the ventral striatum reflected the uncertainty of benefit or the salience of the expectation. The placebo effect in PD therefore involves at least two related but separate mechanisms: the expectation of benefit itself, which is scaled to reflect the value of the drug to the patient and is mediated by nigrostriatal dopamine, and the uncertainty or salience of benefit that is mediated by mesolimbic dopamine.

The activity of neurons in the prefrontal cortex (PFC) may underlie working memory processes in the brain. Both the performance of working memory tasks and the activity of PFC neurons are modulated by dopamine. The goal of the present thesis was to gain insight into the neural basis of working memory by studying the PFC, and the DA system in the PFC, from both a behavioral and cellular perspective. The functional contribution of the PFC to working memory processes in the rat was assessed in Chapter 2 of the present thesis using memory-based foraging tasks on an 8-arm radial maze. The results of these studies indicated that lidocaine-induced inactivations of the PFC selectively disrupted the ability to use mnemonic information to guide foraging, but not the ability to acquire or retain such information. The ability to use mnemonic information to guide foraging was also disrupted by microinjection of a D1 but not D2 receptor antagonist into the PFC. Chapters 3-5 investigated how PFC neurons process synaptic inputs to their dendrites to produce spike output. The intrinsic membrane properties and synaptic responses at the soma and dendrites of deep layer PFC pyramidal neurons were recorded using sharp intracellular or whole-cell patch-clamp techniques in a brain-slice preparation. Different passive and active membrane properties of the soma and dendrites of PFC neurons were observed. The distal dendrites of PFC neurons responded most effectively to strong, highly coincident synaptic inputs. Ca²⁺currents near the soma both amplified the effects of these inputs and modulated the spike output pattern. Spike output at the soma was also controlled by the interplay of slowly-inactivating Na⁺ and K⁺ currents. Chapter 6 investigated the modulation of PFC neurons by DA. DA or a D1 but not D2 receptor agonist increased the evoked firing of PFC neurons via a D1- mediated modulation of slowly-inactivating Na⁺ and K⁺ currents. Concurrently, D1 receptor activation reduced burst firing in PFC neurons, due to a attenuation of Ca²⁺ currents. D1 receptor activation also increased both GABA[sub A] IPSPs and NMDA EPSPs. The final chapter of this thesis integrated these data into a cellular model of PFC function and its modulation by DA. It is proposed that DA may tune PFC neurons such that they respond selectively to strong synchronized inputs from other cortical areas. In the presence of DA, working memory processes mediated by the PFC may be influenced selectively by stimuli of behavioral significance.