GABAergic activity influencing cerebral function in the rat

Kelly, Paul Anthony Thomas (1982) GABAergic activity influencing cerebral function in the rat. PhD thesis, University of Glasgow.

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Currently available evidence suggests that gamma-aminobutyric acid is the major inhibitory neurotransmitter in the mammalian central nervous system. As such, a fuller knowledge of the functional role played by GABAergic neurotransmission would increase our understanding of the complexities of brain activity. Three approaches were employed to analyse GABAergic influences in cerebral function; 1) systemic administration of GABA agonists (muscimol and THIP) or related compounds (benzodiazepines), 2) specific lesioning of a known GABAergic pathway (from caudate nucleus) with subsequent pharmacological challenge and 3) local intracerebral injection of a GABA agonist (muscimol) into a region with known GABA synaptic mechanisms (caudate nucleus). All experiments were performed on restrained, conscious animals, using principally the 2-deoxyglucose quantitative autoradiographic approach to measure cerebral function (as it is reflected in rates of glucose utilisation). The intravenous administration of muscimol and THIP resulted in a heterogeneous pattern of significantly reduced glucose utilisation in the CNS. The regional hierarchy of changes in glucose utilisation was similar for both muscimol and THIP in all regions (with the exception of the superior colliculus), with muscimol being approximately six times more potent in all regions investigated. The regions in which glucose utilisation was extremely sensitive to change, displaying reductions of approximately 40% following muscimol (1.5 mg/kg) or THIP (10 mg/kg), included the neocortex and thalamic areas. In contrast, in a large number of areas, including cerebellum and related motor nuclei, hypothalamus, lateral habenula and amygdala, there were only minimal reductions in glucose use following muscimol and THIP. Regions displaying moderate reductions in glucose utilisation included most extrapyramidal regions and a number of cortical and subcortical limbic areas. In no region of the 60 CNS areas measured was a significant increase in glucose utilisation observed with any concentration of either muscimol or THIP. The regional distribution of alterations in glucose utilisation following muscimol and THIP, which do not correspond to the known topography of GABAergic neurons and receptors, provided a comprehensive description of the functional alterations, as reflected in rates of glucose utilisation, which occur in conscious rats following systemic administration of these two putative GABAergic agonists. Although benzodiazepines are thought to be active at the GABA receptor site, the response in terms of glucose use following diazepam was markedly different from that; following GABA agonists. In particular, the degree of heterogeneity of depression in glucose use was less and the hierarchy of responsiveness in diverse brain areas was different, suggesting that the responses to GABA agonists were not merely a ftinction of susceptibility to depression in general. The relationship between local cerebral blood flow (measured with iodoantipyrine) and glucose use was analysed in two groups of rats. Both blood flow and glucose use decreased in parallel in the 38 areas of the brain analysed following muscimol administration, thus maintaining the relationship observed in control rats. These studies offered no evidence for a direct vasodilatatory action for muscimol (reported by others in vitro) in the intact, conscious rat, but pointed to underlying metabolic activity as the primary determinant of cerebral blood flow. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: James McCulloch
Keywords: Neurosciences
Date of Award: 1982
Depositing User: Enlighten Team
Unique ID: glathesis:1982-72662
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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