PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

1) Dl和D2多巴胺受体在基底神经节中的作用。机制

1) Roles of Dl and D2 Dopamine Receptors in Basal Ganglia. Mechanisms underlying the synergistic interactions of Dl and D2 receptors are being studied in striatal slices via intracellular recording techniques, an approach new to the Section this year. Cathodal pulses induce at least two types of response in the striatal neurons; relevance to striatal mechanisms will be studied. Focal stimulation elicits EPSP's composed of at least three potentials; the fastest appears to involve a non-NMDA receptor, the slower potentials involve NMDA receptors. Focal electrical stimulation also appears to release a modulatory factor which induces changes in current-voltage relationships. First results show that dopamine is not this modulatory factor but dopamine does appear to be a modulator of the voltage-dependent conductances and may regulate repetitive firing in striatal neurons. 2) D2 Autoreceptor / D2 Postsynaptic Receptor Studies. N-0923 and N-0924 are two stereoisomers of current clinical interest; we find N-0923 is a potent and efficacious D2 agonist and N-0924 acts as a partial D2 agonist. Differences in spare receptor number at pre- and post-synaptic D2 receptor sites account for why a partial dopamine agonist can be fully efficacious at D2 autoreceptors while providing a "clamp" at postsynaptic D2 receptors, stimulating weakly while blocking further stimulation. In fact, maintaining therapeutic levels of postsynaptic dopamine receptor stimulation or blockade may be more effectively done with partial dopamine agonists than by adjustment of blood levels of more efficacious agents. 3) Consequences of Dopamine Cell Degeneration in the Basal Ganglia. Changes in dopamine receptor function following chronic reserpine treatment are different from those seen in control but in the opposite direction from those seen in long term 6-hydroxydopamine lesioned rats. Similar changes are being found in rats with relatively short-term lesions of the striatonigral pathway. This evidence for a biphasic pattern in dopamine receptor-mediated effects after dopamine depletion indicates a greater range and complexity in the compensatory responses to dopamine loss than previously appreciated. 4) Role of the Pedunculopontine Tegmental Nucleus (PPN). We have found the PPN exerts effects on substantia nigra dopamine cell activity which appear mediated by both indirect and direct mechanisms. This raises questions about the role of PPN degeneration shown occurring in certain neurological disorders including progressive supranuclear palsy, Parkinson's disease and Alzheimer's disease.