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Peripheral dopa decarboxylase inhibition on striatal neurone firing and dopa kinetics in the rat

Chang, Wan-Ya; (1995) Peripheral dopa decarboxylase inhibition on striatal neurone firing and dopa kinetics in the rat. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The work described in this thesis attempts to answer experimentally some questions that have arisen in the clinical treatment of Parkinson's Disease. Namely 1) Dose the time course of plasma dopa and its metabolites after systemic administration alone and after benserazide (a peripheral dopa decarboxylase inhibitor) reflect those found in the striatum and the effect on striatal neurones? 2) What is the effect of OMD, the O-methylated metabolite of dopa, on the uptake of L-dopa into the brain and the synthesis and release of dopamine? Automated high performance liquid chromatography with electrochemical detection was employed to determine the levels of dopa, dopamine and their metabolites DOPAC, HVA and OMD in plasma samples and in striatal and hippocampal perfusates (obtained by microdialysis) in halothane anaesthetized rats as well as in slices perfusates and brain tissue. Striatal neurone firing was monitored with extracellular single unit recording in intact and 6-hydroxydopamine lesioned rats. Dialysis showed that the time course of increased striatal and hippocampal L-dopa, dopamine and metabolites correlated significantly with those in plasma after 15mgKg intravenous L-dopa or 15, 50 and 100 mgKg-1 L-dopa methyl ester. After L-dopa with benserazide, plasma and CSF dopa levels were significantly higher and longer lasting although dopamine was absent from plasma and significantly lower in CSF similar CSF levels of DOPAC and HVA were obtained despite very low levels in plasma. This suggests that dopamine is formed from L-dopa crossing the blood brain barrier but it seems likely that the origin of dopamine synthesized from dopa in the presence of benserazide is different from that after L-dopa alone. This was also supported by difference in the responses of striatal neurons to L-dopa in the absence and presence of benserazide. Inhibition of such neurons did not correlate directly with CSF dopa, dopamine, DOPAC and HVA and was surprisingly less marked after benserazide. Acute lesions of the nigra striatal tract with 6-hydroxydopamine reduced the inhibitory effect of L-dopa on neuron firing and although this was restored as supersensitivity developed over two weeks. Subchronic treatment with L-dopa partially reversed it in a manner consistent with dopamine not being synthesized in dopaminergic terminal. Intravenous dopamine also inhibited striatal neurone firing and from its appearance in plasma and dialysates after L-dopa it is possible that it can cross the BBB. No evidence was obtained that high plasma OMD affected dopa entry into the brain. Superfusion of striatal slices with L-dopa (10μM) elevated tissue content of dopamine as well as increasing its spontaneous and K+- induced efflux. OMD significantly reduced both effluxes whilst significantly increasing the tissue levels of dopa and DA suggesting it reduces release of dopamine formed from exogenous L-dopa. The results are discussed in respect of the mode of action and loss of efficacy of L-dopa in Parkinsonian patients and the role of OMD.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Peripheral dopa decarboxylase inhibition on striatal neurone firing and dopa kinetics in the rat
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Parkinson's disease
URI: https://discovery.ucl.ac.uk/id/eprint/10104880
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