Excitatory Amino Acid Receptor-Mediated Events in the Brain: Quantitative Autoradiographic Studies

Browne, Susan E (1993) Excitatory Amino Acid Receptor-Mediated Events in the Brain: Quantitative Autoradiographic Studies. PhD thesis, University of Glasgow.

Abstract

The effects of pharmacological and pathological manipulations of excitatory amino acid receptor-mediated events in the rat brain were investigated using quantitative in vivo autoradiographic procedures. [14C]-2-Deoxyglucose in vivo autoradiography was used to measure local rates of cerebral glucose utilisation in discrete brain regions, following systemic administration of agents acting at AMPA and NMDA receptor subtypes, to assess physiological changes in cerebral metabolism occurring in response to pharmacological challenge. Secondly, in order to assess in vivo the effects of systemic administration of an agent which putatively modulates NMDA receptor activity, [125I]-MK-801 in vivo autoradiography was used to measure levels of NMDA receptor activation throughout the brain. Thirdly, [14C]-2-deoxyglucose in vivo autoradiography was used to assess the chronic and acute cerebral metabolic effects of manipulating discrete populations of neurones by microinjections of excitatory amino acid agonists into the basal forebrain. AMPA Receptor Blockade Local cerebral glucose utilisation was examined in 50 discrete CNS regions acutely after intravenous administration of the AMPA receptor antagonists NBQX (10, 30 and 100mg/kg) and the novel agent LY-293558 (10, 30 and 100mg/kg) to conscious rats. Both agents markedly depressed glucose use throughout the brain, producing anatomically widespread, dose-dependent reductions in glucose use in the majority of regions examined. No elevations in glucose use were seen in any of the regions examined following administration of either agent. Following NBQX (100mg/kg), statistically significant decreases in glucose use were seen in 48 of the 50 regions investigated, while significant reductions following LY-293558 (100mg/kg) occurred in 43 regions. The magnitudes of the glucose use depression seen following both NBQX (100mg/kg) and LY-293558 (100mg/kg) were as great as any previously reported with any pharmacological intervention. Rates of glucose utilisation were reduced by 50-68% in many auditory, cortical and limbic regions by the highest dose of the AMPA antagonists. For example, NBQX (100mg/kg) and LY-293558 (100mg/kg) reduced glucose use by -64% and -68% respectively in the inferior colliculus; -64% and -64% respectively in the posterior cingulate cortex; and -50% and -55% respectively in sensory motor cortex (layer IV). The anatomical patterns of reduced glucose use following NBQX and LY-293558 were essentially similar. However, in a number of regions subtle anomalies were evident in the nature of the response to the two AMPA antagonists. For example, LY-293558 was more potent than NBQX by a factor of 2-3 in auditory structures, and in a number of limbic and cortical regions. In addition, LY-293558 at any dose failed to significantly affect glucose use in 7 of the regions examined, whereas glucose use was unchanged in 2 regions following NBQX. In one of the CNS regions examined, the superficial layer of the superior colliculus, glucose utilisation was insensitive to both NBQX and LY- 293558 within the dose ranges studied. In this study, the advantages of using the [14C]-2-deoxyglucose autoradiography technique to map dynamic functional events in vivo are highlighted by its ability to discern subtle dissimilarities in the regional effects of the two AMPA antagonists. The glucose use depression produced by AMPA receptor blockade is in marked contrast to the previously reported heterogeneous effects of competitive and non-competitive NMDA antagonists. NMDA Receptor Manipulation Local cerebral glucose utilisation was investigated in conscious rats acutely after intravenous administration of D-cycloserine (0.3, 3 and 30mg/kg), a partial agonist at the glycine regulatory site on the NMDA receptor complex. The concentration range employed was chosen on the basis of reported dose- dependent agonist and antagonist properties of D-cycloserine in vivo. D-Cycloserine failed to significantly alter glucose use in any of the 51 brain regions examined. In a separate study, [125Il-MK-801 in vivo autoradiography was used to assess NMDA receptor potentiation in the brain by a putative agonist dose of D-cycloserine (3mg/kg, i.v.). Results were compared with levels of [125I]-MK- 801 binding in conscious and anaesthetised rats following intravenous administration of vehicle. The studies in this thesis serve to highlight both the strengths and weaknesses of using autoradiographic approaches to map functional events in vivo. In particular, it is evident that the unique opportunity afforded by the [14C]-2-deoxyglucose technique, to assess alterations in cerebral metabolic activity in terms of local cerebral glucose use, is optimally exploited in conditions of acute pharmacological or pathological challenge where dynamic functional changes are likely to occur. (Abstract shortened by ProQuest.).

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Christine Stirton
• Keywords: Neurosciences, Pharmacology, Medical imaging
• Date of Award: 1993
• Depositing User: Enlighten Team
• Unique ID: glathesis:1993-74766
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 27 Sep 2019 16:34
• Last Modified: 27 Sep 2019 16:34
• URI: https://theses.gla.ac.uk/id/eprint/74766