Medical Physiology

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Browsing Medical Physiology by browse.metadata.advisor "Daniels, William M. U."

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    The effects of physical and psychological stress on the behaviour and neurochemistry of rats
    (Stellenbosch : University of Stellenbosch, 2005-12) Van Vuuren, Petra J.; Daniels, William M. U.; Du Toit, E. F.; University of Stellenbosch. Faculty of Health Sciences. Dept. of Biomedical Sciences. Medical Physiology.
    Stress is considered one of the major factors involved in the pathogenesis of affective disorders, for example, direct and indirect exposure to terrorist attacks or being subjected to subtle victimization. There is a long history of development of procedures to determine anxiety responses in animals in order to find new or better treatments for patients. Prior stress exposure is known to alter the activation response to a subsequent stressor and the means of coping with stress can influence health and disease. This orchestrated process, usually referred to as the “stress response”, involves various mechanisms, which allow the body to make the necessary physical, psychological and the neuro-endocrine adjustments required to cope with the demands of a homeostatic challenge. The communication box method is a useful model to investigate the physiological changes that occur under psychological stress, since it can produce an experimental anxiety based on psychological communication between two or more animals, without the direct physical stress. In this animal model, the psychologically stressed rats are exposed to the visual, olfactory, auditory stimuli (such as struggling, vocalization, defecating, urinating and jumping) from the foot shock rat (Oishi et al., 2003). In the present study, we examined the neuro-endocrine and behavioural responses after different durations of inescapable foot shock and the subsequent effect of citalopram (10 milligram/kilogram, intraperitoneal once a day for 10 days), a selective serotonin reuptake inhibitor in reversing these responses. We have subjected rats to a number of stress paradigms (varying in duration), and assessed the effects thereof on behaviour at two different time points. Physically stressed rats were subjected to 10 unpredicted electric foot shocks (0.5 milliampere), in 10 minutes, while the psychologically stressed rats witnessed everything. The behavioural responses were assessed 5 days and 10 days after the last stress session. The rats were decapitated and corticosterone concentrations were determined one day after the open field and elevated plus-maze tests were performed. The behavioural and endocrine responses in the rats subjected to physical and psychological stress in this study showed that single stress exposure may lead to different outcomes as repetitive stress exposure and that the consequences of stress exposure develop over time and persist for an extended time period. These consequences of direct stress exposure versus indirect stress exposure show a grading in stress intensity and perception, similar to that observed in humans. In the experiment where the rats where treated with citalopram, it showed that citalopram is effective in reversing anxious-like behaviours, but not locomotor deficits. In all the animals basal plasma corticosterone concentrations were comparable and physically and psychologically stressed rats displayed a hyposensitive hypothalamic-pituitary-adrenal axis following acute restraint stress. These findings are interesting in a number of ways. It showed that our stress models propose to be useful in elucidating the complex interrelationship between an external event or stressor, and the organism experiencing it. Simultaneously it presents a promising platform for the finding of new or better treatments for patients.
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    A proteomic analysis of the ventral and dorsal hippocampal brain areas of serotonin knockout rats
    (Stellenbosch : Stellenbosch University, 2008-03) Fairbairn, Lorren R.; Daniels, William M. U.; Stein, Dan J.; Stellenbosch University. Faculty of Health Sciences. Dept. of Biomedical Sciences. Medical Physiology.
    For many centuries, scientists have engaged in a theoretical debate concerning the etiology of mood disorders, with very few ancient scholars speculating about the importance of genetic factors and affective temperaments as factors in the etiology of depression. Mood, emotion and cognition have been shown to be modulated by the serotonergic midbrain raphe system; implicated in the pathogenesis of psychiatric disorders like those of the affective spectrum. Evidence from neuroscience, genetics, and clinical investigation demonstrate that depression is a disorder of the brain. Brain imaging research is revealing that in depression, neural circuits responsible for moods, thinking, sleep, appetite, and behavior fail to function properly, and that the regulation of critical neurotransmitters is impaired. Genetics research, including studies of twins, indicates that genes play a role in depression. Vulnerability to depression appears to result from the influence of multiple genes acting together with environmental factors. Other research has shown that stressful life events, particularly in the form of loss such as the death of a close family member, may trigger major depression in susceptible individuals. Depression and anxiety have often been successfully treated by means of selective serotonin reuptake inhibitors. However, selective serotonin reuptake inhibitors do not solve all the problems inherent to the treatment of depression, for approximately 30 % of depressed patients do not respond to treatment and 20 % experience relapses whilst on treatment. Of consideration is the fact that the majority of drugs today are based on proteins, with 50 % of therapeutics on the market targeting cell membrane proteins. Up to this day the precise pathophysiology of mood disorders remains obscure, as does the neurobiology of normal mood regulation. Accordingly, there is a need for methods to identify the structural and/or signaling components which lead to changes in the brain, particularly the hippocampus, of subjects having mood disorders such as bipolar depressive disorder, chronic major depressive disorder and the like. Similarly, there is a need for the early detection, screening and diagnosis of individuals at risk for a mood disorder. As the serotonin tranpsorter is the primary target for therapeutic intervention in the treatment of numerous psychiatric disorders and considering the fact that at the structural level this protein’s function as transporter in membranes remains incompletely understood, investigating its function in psychiatric disorders are of importance . The objective of this study was to determine the role of the serotonin transporter in wild type and serotonin knockout rats, with regards to the hippocampus. Rat hippocampi were fractionated into cytosolic and membrane components, which were run and further separated in two dimensions. Firstly separation occurred by isoelectrical focusing (pI), follwed by gel iii electrophoresis (molecular weight). Gels were compared to see whether protein spots have changed between animals that have been differentially bred. Differentially expressed protein spots, as determined by PD Quest software, were excised, digested and analyzed by means of mass spectrometry. Our results indicated that metabolic, structural and cell signaling proteins were differentially expressed in both the ventral and dorsal hippocampus of the serotonin knockout rat. Futhermore, cellular stress proteins were found to be only differentially expressed in the ventral hippocampus. The majority of proteins identified in both hippocampal areas as well as both fractions, were assigned to energy metabolism. The cytosolic protein profile mirrored the pattern of the membrane protein profile. In conclusion, this proteomic study identified various protein groups that interacted with one another, thus establishing compensation for disrupted serotonin homeostasis.