Fletcher, Alan Edward; (1991) Studies on the modulatory role of glycine at the NMDA receptor complex in supraspinal regions of rodent brain. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A quantitative autoradiographical technique has been employed to investigate the regional distribution of the strychnine-insensitive glycine receptor in rat brain. A heterogenous pattern of binding was observed throughout the regions studied, the highest binding being localized in the CAl stratum radiatum and the dentate gyrus molecular layer. An evaluation of the pharmacological specificity of the receptor revealed a single population of sites, which displayed a complex agonist/antagonist structure activity relationship. Quantitative autoradiography has been used to evaluate the enhancement of 3H-MK-801 binding produced by glutamate and glycine in a number of discrete brain regions. The study was extended to include the effect of extended preincubation times on the regional enhancement. In addition, the effects of the NMDA antagonists, 3-[(±)-2-carboxypiperazin-4-yl]-l-phosphonic acid (CPP) and 7 chlorokynurenic acid (7 CIKYN) on the regional binding of 3H-MK-801 has been evaluated, together with an autoradiographical demonstration of the competitive nature of these antagonists. The lack of regional variation observed throughout the studies suggest that, at least in the regions studied, the relationship between the sites on the NMDA receptor complex is uniform. An in vitro slice preparation has been used to evaluate the nature of glycine release in rat cerebellum and hippocampus. High K+ (30-55mM) stimulated release of endogenous and tritiated glycine from cerebellar slices was calciumm dependent. In contrast 3H-glycine release from hippocampal slices was calcium independent. Excitatory amino acid stimulated release of endogenous and tritiated glycine release from cerebellar slices in a dose dependent manner. In addition a pharmacological and autoradiographical determination of the strychnine-insensitive glycine receptor in the cerebellum was localised (> 90%) in the granule cell layer. A preliminary investigation of NMDA receptor mediated enhancement of cGMP levels in slices (chopped and handcut) of rat (8-day and adult) and gerbil is described, together with an evaluation of NMDA-mediated enhancement in cortical cell cultures.

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