Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Parkinson's disease (PD) is a progressive neurodegenerative and movement disorder that involves specific loss of dopaminergic neurons in the substantia nigra of the brain. Exact causes of PD are unknown. However, cells affected in PD are centers of dopamine (DA) synthesis, storage, and metabolism, which implicate DA as an endogenous neurotoxin that contributes to PD. Furthermore, DA is known to undergo oxidation to radicals and quinones. These reactive species exert deleterious effects on cells through a variety of mechanisms that are relevant to the pathogenesis of PD. Another potential mechanism of toxicity for DA is metabolism to 3,4-dihydroxyphenylacetaldehyde (DOPAL). This reactive metabolite is significantly more toxic than the parent DA. DOPAL has several demonstrated mechanisms of toxicity, including formation of protein-adducts via reaction with amine-type cellular nucleophiles. However, known toxicity mechanisms do not fully account for DOPAL's high toxicity. Oxidation of DOPAL to a reactive quinone or radical could help explain its high toxicity. Therefore, the hypothesis of this work is that DOPAL is capable of undergoing oxidation that leads to increased protein modification and nucleophilic reactivity. Experimentally, oxidation of DOPAL results in formation of a semi-quinone radical and an ortho-quinone, as confirmed by electron paramagnetic resonance spectroscopy and nuclear magnetic resonance spectroscopy, respectively. In agreement with the stated hypothesis, oxidation of DOPAL enhanced its ability to induce protein cross-linking of a model protein (glyceraldehyde 3-phosphate dehydrogenase) as indicated by polyacrylamide gel-electrophoresis. Also, the presence of anti-oxidants (ascorbate, N-acetyl cysteine) attenuated the reactivity of DOPAL with the model aminenucleophile N-acetyl lysine. These results indicate that DOPAL oxidation enhances both protein cross-linking and nucleophilic reactivity. This work resulted in several other important findings. DOPAL is shown to undergo carbonyl-hydration in aqueous media, and spontaneous oxidation of DOPAL results in formation of superoxide. Furthermore, DOPAL is shown to be susceptible to oxidation by cyclooxygenase-2, an enzyme known to be involved in PD. This provides a potential mechanism for formation of the oxidized products identified here. As DA metabolism and oxidation occur in cells affected by PD, the experimental results demonstrated here are likely relevant for understanding the pathogenesis of PD.

Bibliography: leaves 317-350 / 350 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, 1986

This research project investigates the long-term consequences of perinatal exposure to high-fat (HF) on the mesocorticolimbic dopamine (DA) system. Adult offspring of mothers fed a HF diet (30% fat, compared to 5% in control mothers (C)) during the last week of gestation and throughout lactation displayed decreased locomotion in response to an acute amphetamine challenge and decreased behavioral sensitization to repeated amphetamine compared to C animals. These behavioral effects were accompanied by small increases in tyrosine hydroxylase expression in the ventral tegmental area and significant increases in DA and DOPAC content in the NAc, suggesting an elevated DA tone in this target field. In the NAc, there were no significant changes in D1, D2 receptors or DA transporter (DAT) levels between diet groups. The behavioural and biochemical data were collected in adulthood, long after the termination of the diet suggesting that a HF perinatal diet is inducing permanent changes within the DA system and might contribute to the development of metabolic disturbances.

No description available.

The extended striatum is a large, dopamine-innervated forebrain structure comprising the caudate-putamen, nucleus accumbens and olfactory tubercle (OT). The OT remains largely unexplored, despite its potentially important role in behaviour and dopamine (DA)-mediated reward. One method of studying function is examining "supersensitive" behavioural responses to DA agonists in animals after striatal DA loss. We examined whether D1 or D2 receptor supersensitivity occurs in the OT and neighbouring islands of Calleja (ICj), after unilateral 6-hydroxydopamine lesions of the medial forebrain bundle and medial OT (mOT). We also asked if the resulting DA receptor supersensitivity is anatomically heterogeneous. Our results showed D1-like receptor supersensitivity occurring in the OT with several DA agonists, and heterogeneously across the extended striatum. There is evidence of D2-like receptor supersensitivity in the ICj. Our focal mOT lesion failed to show DA receptor supersensitivity. Finally, there is little evidence for D2 supersensitivity as measured by [ 35S]GTPgammaS binding.

No description available.