PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

(1)基底神经节D1和D2多巴胺受体的体外研究：

(1) D1 and D2 Dopamine (DA) Receptors in Basal Ganglia-~ in vitro Studies: Studies in striatal slices were undertaken to investigate mechanisms which might account for different effects of D1 agonists on striatonigral activity in normal, 6-OHDA-lesioned, and reserpine-treated rats. Experiments utilizing intra-cellular recording techniques find, following DA cell lesion, that fenoldopam's effects on striatal neuronal excitability are not altered, but SKF 38393 exhibited both excitatory and inhibitory effects. The D1 antagonist SCH 23390 failed to reverse SKF 38393-induced changes in excitability indicating they are not mediated through D1 receptors; results raise concern about use in vitro neurophysiological studies of SKF 38393 as a prototypic D1 agonist. In contrast, SKF 38393 and fenoldopam induced comparable changes in phosphoinositide accumulation in striatal slices from control and 6-OHDA-lesioned rats; this accumulation is greater after DA cell lesion. (2) D1 and D2 Receptors in Basal Ganglia - in vivo Studies: Whether the lesion alters the steady-state levels of striatal D2 mRNA remains controversial. Solution hybridization-ribonuclease protection assays found no significant differences in absolute counts for D2 long or D2 short mRNAs or in ratios of D2/beta-actin mRNAs between lesioned and unlesioned striata in rats studied 2, 4, 8 or 19 weeks after lesion, indicating that postsynaptic changes induced by DA denervation are not associated with alterations in steady-state levels of D2 mRNA. (3) Effects of DA Agonists - Subthalamic Nucleus: Examination of effects of excitatory amino acids and DA on the activity of subthalamic neurons using extracellular single unit recording techniques showed that blockade of NMDA or AMPA receptors had no significant effect on average on the firing of subthalamic neurons. The DA agonist, apomorphine, significantly increased the firing of subthalamic neurons, effects unexpected in light of current models of basal ganglia organization that predict increased inhibitory pallidosubthalamic activity following DA agonist administration. (4) Effects of DA Agonists - DA Cells: Agonists were ranked for relative potency at D2 and D3 receptors and examined for ability to inhibit DA cell firing. Although D2 receptors are expressed in greater numbers by DA cells, to date potency at D3 receptors correlates better with the ED50 for DA cell inhibition of these agonists.