Pharmacological and Pathological Alterations in Hippocampal Function: An Autoradiographic Analysis of Glutamatergic and Cholinergic Transmitter Systems

The effects of pharmacological and pathological manipulation of hippocampal cholinergic and glutamatergic neurotransmitter receptor systems were examined using quantitative in vivo [14C]-deoxyglucose autoradiography and in vitro ligand binding autoradiography. In three series of rats, local cerebral glucose utilisation was assessed in 76 anatomically defined hippocampal, limbic and other structures following administration of three novel cholinergic or glutamatergic agents in order to assess the physiological changes in cerebral metabolism in response to pharmacological challenge. Secondly, to assess the plastic responses of hippocampal cholinergic and glutamatergic transmitter systems in the hippocampus to cholinergic denervation, ligand binding to N-methyl-D-aspartate (NMDA), AMPA-sensitive quisqualate, kainate and muscarinic receptors was performed in rats which had received surgery to lesion the medial septum three weeks previously. The status of cholinergic systems was further investigated using biochemical techniques to estimate muscarinic-stimulated second messenger turnover following septal lesions. Local cerebral glucose utilisation was measured in rats using the deoxyglucose technique three weeks after medial septal lesion as an index of function. Finally, the effects of acute experimental subdural haematoma, a novel ischaemic technique, on functional activity in the hippocampus and associated limbic regions were assessed using deoxyglucose autoradiography. The ability of a novel glutamate antagonist to prevent functional disturbances produced by subdural haematoma were also assessed, with a view to potential clinical treatment of ischaemia. These studies demonstrate that manipulation of cholinergic and glutamatergic transmitter systems in the CNS may result in widespread functional alterations in the brain, and suggest that cholinergic and glutamatergic systems may interact in the plastic modifications which accompany cholinergic denervation in the limbic system. The results provide an in vivo perspective of the functional disturbances which accompany ischaemia, and support the glutamatergic hypothesis of ischaemia; further, these results suggest that glutamatergic antagonists may be of benefit in the clinical treatment of ischaemia. The results presented in this thesis highlight the advantages of in vivo mapping of cerebral events, particularly in situations where dynamic alterations in function are likely to occur, such as acute pharmacological, or pathological challenge. Furthermore, the use of receptor autoradiography provides insights into the processes of modification following denervation, and suggest that in the hippocampus, both cholinergic and glutamatergic systems are involved in synaptic modifications which accompany cholinergic denervation. (Abstract shortened by ProQuest.)