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Psychological stress increases dopamine release in the striatum and is thought toplay a role in susceptibility to psychotic illness. In schizophrenia, a prototypicalpsychotic illness, there is evidence of abnormal dopamine response to pharmacologicalchallenge or psychological stressors. Stress, like dopamine agonist drugs, can triggerrelapse in schizophrenic patients. It has been proposed that exaggerated responses tostress are key in the etiology of psychosis in vulnerable individuals. However, it is notknown whether differences in brain dopaminergic responsiveness precede psychosis ordevelop subsequent to illness onset. / Le stress psychologique augmente le niveau de dopamine dans le striatum, phenomene qui pourrait contribuer a la vulnerabilite aux maladies psychotiques. Dans la schizophrenie, une maladie psychotique prototypique, les etudes ont montre qu'il y a une liberation anormale de la dopamine en reponse aux drogues ou au stress psychologique. Le stress, comme les agonistes dopaminergiques, peut precipiter une rechute chez des patients schizophrenes. On avance Phypothese que les reponses excessives au stress sont primordiales dans l'etiologie de la psychose chez les individus vulnerables. Cependant, on ne sait pas si les anomalies de la reponse dopaminergique du cerveau precedent la psychose, ou se developpent apres le debut de la maladie.

Dopamine receptors are members of the G protein-coupled receptor superfamily and play important roles in neuronal transmission. A D1-D2 receptor heterooligomer generating a G-protein linked PLC-dependent intracellular calcium signal was previously identified. The discovery of this dopamine mediated calcium signal implicated a direct link between dopamine receptors and calcium generation, but its regulation remained to be elucidated. By measuring calcium signaling with Fluo-4 fluorescence or cameleon FRET, rapid desensitization of the calcium signal in heterologous cells and striatal neurons was demonstrated by pre-treatment with SKF 83959, which selectively activates D1-D2 receptor heteromers, or SKF 83822 which only activates D1 receptor homooligomers. Although SKF 83822 was unable to activate D1-D2 receptor heteromers, it still permitted desensitization of the calcium signal. This suggested that occupancy of the D1 receptor binding pocket by SKF 83822 resulted in conformational changes sufficient for desensitization without activation of the heteromer. BRET and co-immunoprecipitation studies indicated an agonist induced interaction between the D1-D2 receptor heteromer and GRK2. Increased expression of GRK2 led to a decrease in the calcium signal and decreased expression of GRK2 led to an increased calcium signal. Expression of the catalytically inactive and RGS mutated GRK2 constructs each led to a partial recovery of the GRK2-attenuated calcium signal. These results indicated that desensitization of the D1-D2 receptor heteromer mediated calcium signal can occur by agonist occupancy even without activation and is regulated by two distinct functions of GRK2. Immunocytochemistry and calcium assays demonstrated that recycling of internalized D1 and D2 receptors and resensitization of the desensitized calcium signal occurred after dopamine pre-treatment but not SKF 83959, suggesting that the trafficking and resensitization response associated with the D1-D2 receptor heteromer is differentially regulated by specific ligands. Overall, these results suggest that D1-D2 receptor heterooligomers are uniquely regulated from their constituent receptors which are not coupled to Gq.

Dopamine receptors are members of the G protein-coupled receptor superfamily and play important roles in neuronal transmission. A D1-D2 receptor heterooligomer generating a G-protein linked PLC-dependent intracellular calcium signal was previously identified. The discovery of this dopamine mediated calcium signal implicated a direct link between dopamine receptors and calcium generation, but its regulation remained to be elucidated. By measuring calcium signaling with Fluo-4 fluorescence or cameleon FRET, rapid desensitization of the calcium signal in heterologous cells and striatal neurons was demonstrated by pre-treatment with SKF 83959, which selectively activates D1-D2 receptor heteromers, or SKF 83822 which only activates D1 receptor homooligomers. Although SKF 83822 was unable to activate D1-D2 receptor heteromers, it still permitted desensitization of the calcium signal. This suggested that occupancy of the D1 receptor binding pocket by SKF 83822 resulted in conformational changes sufficient for desensitization without activation of the heteromer. BRET and co-immunoprecipitation studies indicated an agonist induced interaction between the D1-D2 receptor heteromer and GRK2. Increased expression of GRK2 led to a decrease in the calcium signal and decreased expression of GRK2 led to an increased calcium signal. Expression of the catalytically inactive and RGS mutated GRK2 constructs each led to a partial recovery of the GRK2-attenuated calcium signal. These results indicated that desensitization of the D1-D2 receptor heteromer mediated calcium signal can occur by agonist occupancy even without activation and is regulated by two distinct functions of GRK2. Immunocytochemistry and calcium assays demonstrated that recycling of internalized D1 and D2 receptors and resensitization of the desensitized calcium signal occurred after dopamine pre-treatment but not SKF 83959, suggesting that the trafficking and resensitization response associated with the D1-D2 receptor heteromer is differentially regulated by specific ligands. Overall, these results suggest that D1-D2 receptor heterooligomers are uniquely regulated from their constituent receptors which are not coupled to Gq.

Retinal image properties such as contrast and spatial frequency play important roles in the development of normal vision. For example, visual environments comprised solely of low contrast and/or low spatial frequencies induce myopia. The visual image is processed by the retina and it then locally controls eye growth. In terms of the retinal neurotransmitters that link visual stimuli to eye growth, there is strong evidence to suggest involvement of the retinal dopamine (DA) system. For example, effectively increasing retinal DA levels by using DA agonists can suppress the development of form-deprivation myopia (FDM). However, whether visual feedback controls eye growth by modulating retinal DA release, and/or some other factors, is still being elucidated. This thesis is chiefly concerned with the relationship between the dopaminergic system and retinal image properties in eye growth control. More specifically, whether the amount of retinal DA release reduces as the complexity of the image degrades was determined. For example, we investigated whether the level of retinal DA release decreased as image contrast decreased. In addition, the effects of spatial frequency, spatial energy distribution slope, and spatial phase on retinal DA release and eye growth were examined. When chicks were 8-days-old, a cone-lens imaging system was applied monocularly (+30 D, 3.3 cm cone). A short-term treatment period (6 hr) and a longer-term treatment period (4.5 days) were used. The short-term treatment tests for the acute reduction in DA release by the visual stimulus, as is seen with diffusers and lenses, whereas the 4.5 day point tests for reduction in DA release after more prolonged exposure to the visual stimulus. In the contrast study, 1.35 cyc/deg square wave grating targets of 95%, 67%, 45%, 12% or 4.2% contrast were used. Blank (0% contrast) targets were included for comparison. In the spatial frequency study, both sine and square wave grating targets with either 0.017 cyc/deg and 0.13 cyc/deg fundamental spatial frequencies and 95% contrast were used. In the spectral slope study, 30% root-mean-squared (RMS) contrast fractal noise targets with spectral fall-off of 1/f0.5, 1/f and 1/f2 were used. In the spatial alignment study, a structured Maltese cross (MX) target, a structured circular patterned (C) target and the scrambled versions of these two targets (SMX and SC) were used. Each treatment group comprised 6 chicks for ocular biometry (refraction and ocular dimension measurement) and 4 for analysis of retinal DA release. Vitreal dihydroxyphenylacetic acid (DOPAC) was analysed through ion-paired reversed phase high performance liquid chromatography with electrochemical detection (HPLC-ED), as a measure of retinal DA release. For the comparison between retinal DA release and eye growth, large reductions in retinal DA release possibly due to the decreased light level inside the cone-lens imaging system were observed across all treated eyes while only those exposed to low contrast, low spatial frequency sine wave grating, 1/f2, C and SC targets had myopic shifts in refraction. Amongst these treatment groups, no acute effect was observed and longer-term effects were only found in the low contrast and 1/f2 groups. These findings suggest that retinal DA release does not causally link visual stimuli properties to eye growth, and these target induced changes in refractive development are not dependent on the level of retinal DA release. Retinal dopaminergic cells might be affected indirectly via other retinal cells that immediately respond to changes in the image contrast of the retinal image.

Diss. (sammanfattning) Göteborg : Univ. , 2007. / Härtill 4 uppsatser.

Thesis (Ph.D.)--Auburn University, 2007. / Abstract. Vita. Includes bibliographic references.

Thesis (Ph.D. 1976) from the Dept. of Huamn Physiology and Pharmacology, University of Adelaide.

Thesis (M.D. 1979) from the Department of Obstetrics and Gynaecology, University of Adelaide.

Dissertation (Ph.D.).--University of Texas Graduate School of Biomedical Sciences at San Antonio, 2006. / Vita. Includes bibliographical references.