Reproduction de : Thèse de doctorat : Physiologie, biologie cellulaire et moléculaire : Poitiers : 2008. / Contient des textes en anglais, extraits de diverses publications et revues, 2008. Titre provenant de l'écran-titre. Bibliogr.

Thesis (Ph. D.)--University of Texas at Austin, 2003. / Supervisor: Christine L. Duvauchelle. Vita. Includes bibliographical references. Available also from UMI Company.

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.