Manipulation of Metabotropic and AMPA Glutamate Receptors in the Brain

Lam, Amy G. M (1999) Manipulation of Metabotropic and AMPA Glutamate Receptors in the Brain. PhD thesis, University of Glasgow.

Abstract

The consequences of the pharmacological manipulation of metabotropic and AMPA glutamate receptor-mediated events in the rat brain were investigated in this thesis. [14C]2- deoxyglucose autoradiography was used to explore modifications in physiological brain function following the systemic administration of two novel selective agonists with actions on group II metabotropic glutamate receptors (mGluRs) and following the intracerebral manipulation of the hippocampus using a selective AMPA antagonist. The putative role of group II mGluRs in neuroprotection was also examined. An in vivo model of cerebral ischaemia together with two in vitro models of neurotoxicity with group II mGluR agonist intervention were used to study the potential of group II mGluR agonists in protecting cellular elements from neurotoxic insults. Mapping brain function with group II selective mGluR agonists Local rates of cerebral glucose use were measured using the [14C]2-deoxyglucose autoradiographic technique to examine the functional consequences of the systemic administration of the novel mGluR agonist LY3 54740, and a related analogue LY3 79268, in the conscious rat. Both LY354740 (0.3, 3.0, 30 mg/kg) and LY379268 (0.1, 1.0, 10 mg/kg) produced dose-dependent changes in glucose utilisation. LY3 54740 produced anatomically widespread reductions in glucose use, while LY3 79268 affected a smaller number of brain regions which displayed increases in glucose metabolism. After LY354740 (3.0mg/kg) administration, 4 out of 42 brain regions demonstrated statistically significant changes from vehicle treated controls; red nuclei (-16%), mammillary body (-25%), anteroventral thalamic nucleus (-29%) and the superficial layer of the superior colliculus (+50%). An additional 15 regions displayed significant reductions in function-related glucose use (P<0.05) in animals treated with LY354740 (30mg/kg). In contrast, LY379268 (0.1, 1.0, l0mg/kg) produced changes in glucose metabolism in only 20% of the brain regions analysed. Significant increases in glucose use (P<0.05) were evident in the superficial layer of the superior colliculus (+81%), locus coeruleus (+57%), genu of the corpus callosum (+31%), cochlear nucleus (+26%), inferior colliculus (+20%) and the molecular layer of the hippocampus (+14%). Three regions displayed significant decreases: mammillary body (-34%), anteroventral thalamic nucleus (-28%) and the lateral habenular nucleus (-24%>). Both compounds displayed a similar anatomical pattern of altered glucose metabolism in the limbic system. Reductions were noted in the anteroventral thalamic nucleus, lateral habenular nucleus, molecular layer of the hippocampus and the mammillary body (P < 0.05) following both agonists Glucose utilisation in components of different sensory systems were altered following the activation of mGluR2/3. In animals treated with LY354740, reductions in function-related glucose use were observed in areas associated with vision, while those treated with LY3 79268 demonstrated elevated glucose utilisation in primary auditory areas. This study has demonstrated that the [14C]2-deoxyglucose autoradiographic technique provides a reliable means of mapping functional events in the brain. It has highlighted fundamental differences in the regional effects of the two agonists and has served to demonstrate the important functional involvement of the limbic system together with the participation of components of different sensory systems in response to the activation of mGluR2 and mGluR3 with LY354740 and LY379268. Regional mapping of cerebral function following hippocampal manipulation The [14C]2-deoxyglucose autoradiographic technique was used to investigate changes in brain function during, and following, the localised 7 day infusion of the selective AMPA/kainate receptor antagonist LY326325 in the conscious rat. During the period of drug infusion, anatomically circumscribed changes in glucose use were measured in animals treated with LY326325 compared with aCSF (artificial cerebrospinal fluid) treated control animals. Reductions in glucose utilisation were demonstrated in the molecular layer of the dorsal hippocampus (-23%, P<0.002) but not in the molecular layer of the ventral hippocampus. The maximal reduction in glucose use measured in the molecular layer of the hippocampus was observed adjacent to the implant site, along a dorsal axis relative to the implant site. Other than a marked elevation in function-related glucose use in the superficial layers of the entorhinal cortex, rates of glucose utilisation in the remaining regions of the CNS were minimally affected during the period of drug infusion. (Abstract shortened by ProQuest.).

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: David Lodge
• Keywords: Neurosciences
• Date of Award: 1999
• Depositing User: Enlighten Team
• Unique ID: glathesis:1999-74869
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 27 Sep 2019 15:45
• Last Modified: 27 Sep 2019 15:45
• URI: https://theses.gla.ac.uk/id/eprint/74869