| Summary: | 碩士 === 台北醫學院 === 醫學研究所 === 88 === 1. Dextromethorphan, a non-competitive antagonist of N-methyl-D- aspartate (NMDA) receptor, attenuate NMDA receptor-mediated response by binding to a site in the receptor-coupled ion channel. [3H]N-(1-[2-thienyl]cyclohexyl)-3,4- piperidine（[3H]TCP）, a radiolabelled ligand binding to the phencyclidine binding site in the NMDA receptor-coupled channel, has been widely used to determine the expression of the NMDA receptor in the brain tissues. Our previous study has demonstrated a ontogenic change in the affinity of [3H]TCP binding in developing rat brain. In particularly, combined prenatal and post-natal exposure to morphine induced a time-specific change in the density of the NMDA receptor in cortex and hippocampus. We further asked whether this specific change is a fundamental alteration in the property of the NMDA receptor-coupled channel, including a parallel change in the affinity of DM in binding into this channel. To address this issues we determine the potency of DM in displacing the binding of [3H]TCP in cortical tissues derived from rats with age of 7, 14, 30 and 60 days. Morphine group rats were rats born to dams rats received bi-daily injection of morphine since one week before mating till the end of first month after delivery. Control group rats were rats born to dams rats received saline injection only. Our results showed that no change of affinity for TCP binding and Ki for DM in inhibiting [3H]TCP was found between control and morphine group rats during these examined post-natal days. Furthermore, we determined whether the two major metabolites of DM, namely the dextrorphan (DT) and 3-methoxymorphinol (MM), may be also potent in inhibiting the [3H]TCP in the NMDA receptor-coupled channel, in the membrane prepared from cortex tissues of adult normal rats. We found DT and MM can concentration dependently inhibiting [3H]TCP binding with IC50 similar to that of DM, but no significant difference between DM, DT and MM in displacing the [3H]TCP binding.
Amphetamine, a psychostimulant, has been found by our previous study to have antagonist effect by directly acting at multiple sites on the NMDA receptor. We further demonstrate the stero-specifity of this antagonizing effect by exam the methamphetamine（MA）,d-amphetamine（DA） and l-amphetamine（LA）in displacing [3H]TCP binding to study its stereo-specify. The results suggested that all these drugs could inhibit [3H]TCP binding with two potencies. The rank order of inhibiting affinity of high potency effect is LA=DA=MA, and of low potency effect is LA=DA>MA, suggest that the stereo-specific of the two potency effect of amphetamine is different, and the binding sites for these two effects of amphetamine on the NMDA receptor is not identical.
2. Administration of MPTP（N-methyl-4- phenyl-1,2,3,6- tetrahydropyridine）to mammals causes damage to the dopaminergic pathway and produce symptoms similar to that observed in Parkinson’s disease. Glial cell line-derived neurotrophic factor（GDNF）has been proposed as a useful therapeutic agent in the treatment of Parkinson’s disease. The gene expression of GDNF was enhanced following various brain insults. So the objective of the present study was to exam the expression of GDNF mRNA following MPTP treatment in C57BL/6J mice. We also investigated alterations in cell death effector gene expression, bax, and the immediate-early genes, c-fos and c-jun, induced by MPTP in C57BL/6J mice cortex, striatum and cerebellum. In conclusion, MPTP-induced dopaminergic neurotoxicity does not elicit any changes in the expression of endogenous GDNF mRNA in the adult mouse cortex, striatum and cerebellum. And we found that MPTP could induce a transient increase in the c-fos expression and induce a late onset increase in the bax gene expression in all brain regions examined. This results indicate that MPTP-induced neurotoxicity involve apoptosis process which could occur in brain regions not related to the dopaminergic system.
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