PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

(1)一系列11种高效多巴胺（DA）的效力

(1) The potencies of a series of 11 highly efficacious dopamine (DA) agonists for in vivo inhibition of DA single cell firing correlate better with in vitro binding affinities at D3 than at D2 receptors in CHO cells transfected with cDNAs encoding for D3 and D2L receptors, respectively. These results support a functional contribution of the D3 receptor subtype in the autoreceptor-mediated regulation of DA cell activity. However, infusion of DA D2 and D3 receptor antisense oligonucleotides into rat substantia nigra has, to date, produced no selective modifications of firing which can be distinguished from nonselective effects. (2) In models of basal ganglia organization, DA receptor stimulation is thought to indirectly decrease neural activity in the subthalamic nucleus due to disinhibition of the globus pallidus. However, systemic administration of the nonselective DA agonist apomorphine has been found to double the average firing rate of subthalamic neurons. Two D1 agonists also increased the firing rate of subthalamic neurons, a D2-D3 agonist produced smaller effects. Local infusion of D1 agonists also stimulated pallidal activity, indicating a potential excitatory role of DA locally in the subthalamic nucleus. Investigation of possible sites of action of D1 and D2 agonists in 6-OHDA-lesioned rats through local infusions has demonstrated short-term plasticity and indicates effects vary depending on whether D1 receptors and D2-D3 are stimulated simultaneously or 5 to 10 min apart. (3) Cannabinoid receptor distribution suggests that cannabinoids may influence basal ganglia motor function by actions on the striatal output pathways. The finding that cannabinoid agonists attenuate DA agonist- induced rotation in rats with 6-OHDA-induced DA cell lesions indicate that cannabinoid receptor stimulation influences both D1- and D2-mediated processes, although D1 processes appear to be affected to a greater degree. (4) We have found a high level of AP-1 binding in the rat striatum which is enhanced after DA depletion by reserpine treatment or by 6-OHDA- induced DA cell lesion. Binding was further enhanced by combinations of D1 and D2 DA agonists in the 6-OHDA-lesioned rats but only by D1 agonists in normal rats. The observations indicate that AP-1-mediated changes in gene expression may contribute to alterations in agonist sensitivity in the striatum after DA cell lesion.