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A biochemical and behavioural study of the toxic effects of 3-nitropropionic acid and methamphetamine in the rat

Eradiri, Oweikumo Lambert; (2000) A biochemical and behavioural study of the toxic effects of 3-nitropropionic acid and methamphetamine in the rat. Doctoral thesis (Ph.D.), University College London (United Kingdom). Green open access

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Abstract

The effective treatment of Parkinson's disease (PD) has been hindered by a variety of factors including the lack of a precise understanding of the aetiology of the disease, as well as the loss of efficacy of the mainstay therapeutic agent, L-3,4 dihydroxyphenylalanine (L-DOPA). This work was embarked upon with the aim of producing parkinsonian conditions in a rat by harnessing various theories proposed for the aetiology of the disorder. In addition, it was intended to take a closer look at the mechanism(s) of action of L-DOPA, to determine if there are additional ways of enhancing and prolonging its effectiveness. An over-view of the theories put forward for the cause and progression of PD reveals two schools of thought: Metabolic Stress and Oxidative Stress. While these groups of factors are independent in their own rights, they are often cyclical and inter-related. The Metabolic Stress theories suggest that PD is a consequence of an acquired or inherent metabolic defect that triggers off a variety of reactions that ultimately lead to neuron death. Proponents of the Oxidative Stress theories tend to suggest that an internal or external trigger factor impinges on and overwhelms the body's anti-oxidative mechanisms, causing metabolic failure and, ultimately, cell death. However, the specific reason(s) why the dopaminergic cell bodies of the substantia nigra pars compacta (SNpc) begin to die in PD patients remain(s) cryptic. Methamphetamine (METH), a common drug of abuse, has been shown to induce the release of dopamine and glutamate in the basal ganglia. Its ability to reverse the dopamine (DA) transporter localises its effects to catecholaminergic neurones, while its glutamate-releasing characteristic gives it an excitotoxic potential. 3-nitropropionic acid (3-NP) is a food contaminant commonly found in mildewed sugar-cane. Its ability to inhibit succinate dehydrogenase in the electron transport chain makes it a good inducer of metabolic stress. By combining both agents, we created a metabolically impaired environment in the basal ganglia with 3-NP, and localized this to dopaminergic neurones with METH. The incorporation of METH introduced the excitotoxic effects of glutamate on these metabolically impaired DA neurones, causing further dopaminergic dysfunction. The mutual potentiation of 3-NP and METH exploited in this regimen (which we have termed the 3-NPM model), yielded animals with alterations in tissue levels of DA and 5-hydroxytryptamine (5-HT), but not those of aspartate and glutamate in the nucleus accumbens septi (NAcc), prefrontal cortex (PFC), substantia nigra (SN) and the corpus striatum (ST). The activity of the enzyme L-DOPA decarboxylase (DDC) was not significantly altered in the four brain regions analysed, whereas the enzyme 5-hydroxytryptophan decarboxylase (5-HTPDC) was significantly reduced in the nigrostriatal tract. The results suggest that 3-NPM treatment compromises nigrostriatal dopamine function in a way that could mimic the preclinical stages of parkinsonism. The spontaneous motility of 3-NPM-treated rats did not differ significantly from unlesioned animals, but they exhibited an enhanced sensitivity to the motor stimulant effects of direct and indirect DA agonists. There was an enhanced response to the D2 agonist RU 24213, but not to the D1 agonist, SKF 38393. A biphasic response to the D1/D2, agonist, apomorphine was observed, while the indirect DA receptor agonist, MK 801, significantly enhanced and prolonged locomotor activity in these rats. Administration of L-DOPA in conjunction with the peripheral aromatic 1-amino acid decarboxylase (AADC) inhibitor, benserazide, has been the mainstay of PD therapy. It was possible to render a threshold dose of L-DOPA (for reversing rigidity in reserpinised rats, 100 mg/kg) effective by combining it with the antiparkinson drug budipine. This drug has been shown to raise DA levels by stimulating AADC. Addition of the central AADC inhibitor, NSD 1015, to this combination further enhanced the locomotor stimulating effects of L-DOPA. These experiments were conducted in saline-treated control animals and 3-NPM-treated rats. In the third paradigm, we used rats that had their brain monoamine content depleted, as a model of parkinsonism. The choice of reserpine for this purpose was made, to present a uniform basis for comparing the results of parallel studies in our laboratory. This work suggests the use of the 3-NPM model as a paradigm for the early stages of PD, and emphasizes the importance of the D2 receptor pathways in the treatment of the disease. In addition, it indicates a DA-independent motor stimulant effect of L-DOPA, that can be manipulated by NMDA antagonists like budipine, as well as by various DA receptor antagonists.

Type: Thesis (Doctoral)
Qualification: Ph.D.
Title: A biochemical and behavioural study of the toxic effects of 3-nitropropionic acid and methamphetamine in the rat
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: (UMI)AAI10104902; Health and environmental sciences; Acid; Behavioural; Biochemical; Methamphetamine; Toxic
URI: https://discovery.ucl.ac.uk/id/eprint/10102401
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