A dissertation submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg, in fulfilment of requirements for the degree of Medicine in Psychiatry. Johannesburg, March 1991. / In the first part of the dissertation a literature survey is done, looking at 1. An overview of dysthymic disorder. 2. An overview of serotonin and its involvement in psychiatric disorder [Abbreviated Abstract. Open document to view full version]

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Serotonin (5HT) is an indoleamine with potent j vitro and in vivo effects on aldosterone biosynthesis in the adrenal zona glomerulosa of several species including Man and the rat. Its physiological role in the control of aldosterone secretion however, is not well understood. The purpose of these studies was to clarify its possible role in aldosterone biosynthesis using the rat as an experimental model. Attempts to localise 5HT within the adrenal gland using a specific monoclonal antibody to 5HT with the avidin-biotin detection technique, suggested, that serotonergic nerves are not present in the adrenal cortex although appreciable levels of 5HT were measured by HPLC in adrenal tissue ( 1.7 # 0.2 μg/ g wet weight). The storage and metabolism of 5HT in isolated zona glomerulosa cells and inner cortical and, medullary cells was investigated using [3 H]-5HT as a marker. Zona glomerulosa cells rapidly metabolised 5HT, whereas the inner zones were able to store or retain 5HT to a greater extent. Stimulation of steroidogenesis by 5HT however, was confined to the zona glomerulosa cells of the adrenal cortex. The interaction of 5HT with specific 5HT receptors was investigated by studying the effects of the 5HT antagonists, methysergide and ketanserin on the steroidogenic response to 5HT in isolated zona glomerulosa cell suspensions. Methysergide (10-6M) inhibited the corticosterone and aldosterone responses to 5HT (10-9M - 10-6)and angiotensin II (10-9M, 10-8M). In addition, it significantly inhibited the corticosterone response to ACTH. Ketanserin (10-6M) also inhibited the corticosterone and aldosterone responses to 5HT (10-9M, 10-8M) and All (10-9M, 10-8M) but did not affect ACTHstimulated steroidogenesis. Neither antagonist affected the steroidogenic responses to potassium. A change in dietary salt intake of rats did not lead to any significant change in either the blood levels or adrenal contents of 5HT. The in vitro- responsiveness of adrenal cells to 5HT however, was altered by changing the sodium status. An overall view of changing endogenous levels of 5HT in vivo in the rat was explored using the 5HT-depleting agent, PCPA and the immediate 5HT-precursor, 5-hydroxytryptophan (5HTP). Treatment with PCPA led to a decrease in blood 5HT levels and a loss of in vitro responsiveness to 5HT and All in subsequent preparations of zona glomerulosa cells. Treatment with 5HTP produced higher blood levels of 5HT and an enhanced responsiveness of subsequent preparations of zona glomerulosa cells. These studies suggest that 5HT from central and/or peripheral sources such as platelets or mast cells, could exert a tonic effect on aldosterone secretion from the rat adrenal zona glomerulosa, which is mediated by the activation of specific receptors for 5HT.

The nervous system copes with variability in the external and internal environment by using neuromodulators to adjust the efficacy of neural circuits. The role of serotonin (5HT) as a neuromodulator of olfactory processing in the antennal lobe (AL) of Manduca sexta was examined. Serotonin has been hypothesized as a circadian modulator of sensitivity of AL neurons, so the coding of odor concentration in the AL was first examined without the manipulation of 5HT levels. Reponses of the AL to different concentrations of odors were recorded using multi-electrode extracellular arrays. As odor concentration increased, more AL units responded and the AL was best able to discriminate odors at high concentrations, a finding that was replicated in matched behavioral assays. Multi-electrode recordings were then used to examine the effects of 5HT on responses to stimuli that varied in chemical structure and concentration. Serotonin enhanced AL unit responses by increasing response duration and firing rate, which in turn increased the amount of coincident firing between units. Due to the increased activation of units as concentration increased, and the greater effect of 5HT on stronger responses, serotonin had the greatest effect on overall ensemble activation at higher odor concentrations. Additionally, response thresholds shifted to lower odor concentrations for some units, suggesting that 5HT increases the sensitivity of AL units. Serotonin enhanced AL discrimination of single odors at different concentrations and structurally dissimilar odors at a single concentration. In order to predict which insects share a similar role for 5HT in the AL, immunocytochemistry was used to compare the ALs of different insects. All holometabolous insects (except the Euhymenoptera) had 5HT-immunoreactive AL neurons that were morphologically similar to those of M. sexta. These combined studies implicate 5HT as a modulator of sensitivity and efficacy in the AL of M. sexta and suggest that 5HT may play this role for most of the Holometabola. This proposed role of 5HT in the AL of the Holometabola is reminiscent of the hypothesized involvement of serotonergic neurons from the Raphe nucleus in vertebrates that seem to gate activity in the olfactory bulb in the context of behavioral arousal.

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Thesis (M.A.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Serotonin (5-hydroxytryptamine), one of the biologically active amines, has been found in rather large quantities in the dorsal skin of Rana pipiens. Quantitative determination of the endogenous levels of the amine in the whole dorsal skin homogenate extracts were made on a Farrand spectroflourometer, and ranges of 120-200 micrograms per gram of fresh tissue were established. Comparison of whole skin homogenates and homogenates of just the dorsal cutaneous ridges, or dermal plicae, indicated that the amine is localized in these ridges. Acid treatment of the denser more fibrous portions of the homogenate prior to extraction more then noublcc the yields of serotonin. This result showed that the amine is found primarily in the deeper portions of the skin, very likely in the poison glands which are concentrated in the dermal plicae. Skin homogenates were also studied to determine if serotonin is actually synthesized in the skin. A precursor of the amine, 5-hydroxytryptophan, decarboxylates in tne presence of 5-hydroxytryrtophan decarooxylase to produce the amine. 5-hydroxytryrtophan was incubated with the homogenate, under nitrogen, for two hours to determine enzymic activity. Under the conditions of the experiment, no enzymic activity could be shown, indicating that serotonin is not produced in the skin of the frog in detectable amounts. The fact that serotonin levels are so high, and the lack of enzymic activity indicates that once synthesized serotonin is stored in an inactive form or is synthesized elsewhere and transnorted to the skin. / 2031-01-01