Serotonin and the central nervous system: An autoradiographic study

Grome, John Joseph (1983) Serotonin and the central nervous system: An autoradiographic study. PhD thesis, University of Glasgow.

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The use of behavioural models and electrophysiology are two commonly used approaches for studying the effects of the substance serotonin and serotonin-like drugs on the central nervous system. The behavioural tests were developed following the discovery that pharmacological manipulations resulted in an increase in serotonin concentration in the central nervous system and led to the production of a definable behavioural syndrome. However, this is a gross measure of central serotoninergic interactions in the brain since it does not provide any information on the precise location of the cerebral regions involved. The measurement of electrical activity has proved a powerful tool for directly measuring the functional activity of neurones and their responses to the micro-iontophoretic application of serotonin or serotonin- mimetic drugs. This technique is limited, in a practical sense, by the number of cells which can be measured in any one area of the brain and as an inevitable consequence of the use of anaesthesia in these preparations. In recent years, a more direct measurement of regional cerebral function in the conscious rat has been developed. As glucose is the sole energy substrate for the brain under non-pathological conditions, its measurement is a direct index of cerebral function. The method in question uses 14C-2 deoxyglucose to measure local cerebral glucose utilisation by quantitative autoradiography. It provides, due to the unique properties of 2 deoxyglucose, a measure of the integrated response of the central nervous system to pharmacological manipulation. The results of this thesis are presented in four parts. In the first, (Chapter III), serotonin, when administered, into the carotid artery of halothane anaesthetised rats was found to have no effect on glucose utilisation unless the animal was first treated with the monoamine oxidase inhibitor, clorgyline. When these substances were combined, a number of regions were found to have decreased rates of glucose use, particularly in the cortex. The problem associated with this model will be discussed, particularly in relation to the depressive actions of halothane anaesthesia. The second part (Chapters IV and V) of this thesis deals with the actions of two structurally-differing sets of putative serotonin agonists on the local cerebral glucose utilisation, behaviour and cardiovasculature of conscious rats. Lysergic acid diethylamide and 5 methoxy-N,N-dimethyltryptamine both contain indeleamine portions to their structures; as does serotonin itself. Quipazine and chloropiperazinylpyrazine contain piperazine moeities which make them structurally similar to tricyclic antidepressants. In the majority of brain areas studied, these two sets of putative serotonin agonists produced a depression in glucose use; and therefore functions. However, in a select number of structures in the anterior thalamus and in some extrapyramidal areas, the piperazine-containing compounds were capable of producing significant increases in glucose use. A pattern quite different from that produced by the indoleamine containing substances. The third section (Chapter VI) deals with the use of substances which have been suggested as serotonin antagonists in the central nervous system., These compounds, metergoline, methysergide and cyproheptadine, have all been shown to be potent antagonists at serotonin receptors in the periphery. In the present experiments they were found to produce decreases in local cerebral glucose utilisation at relatively high doses. These results have implications with regard to the "classical" concept of receptor antagonists . In the final section of results, (Chapters VII and VIII) data are provided on the actions of the four putative serotonin agonists following the pretreatment of metergoline and methysergide. The consequence of this combination of treatment was that some but not all agonist effects were inhibited. On the contrary, in certain cerebral areas the functional response to the serotonin agonist was either unaffected or potentiated by the pretreatment of metergoline or methysergide. Thus, the combination of "agonist" and "antagonist" produced a pattern of response which was very different from that produced by either set of compounds alone. In the subsequent discussion a synthesis of this information is attempted in the light of previous in vivo and in vitro information.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Alexander Murray-Harper
Keywords: Neurosciences, Endocrinology
Date of Award: 1983
Depositing User: Enlighten Team
Unique ID: glathesis:1983-72789
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 11 Jun 2019 11:06
Last Modified: 11 Jun 2019 11:06

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