Although the profound deficits of parkinsonism attest to the importance of dopamine in normal function, the action of dopamine on information transmission t rough the basal ganglia has received little attention in awake, trained animals. It is well-documented, however, that neurons in the basal ganglia have both D1-class and D2-class receptors, and there is evidence that dopamine acting ont he two receptor classes has reciprocal effects and that its action int he striatum is important for some forms of learning. The proposed projects will make use of a new type of permselective tubing that will allow administration of dopamine receptor-active agents locally in the striatum of monkeys trained in a variety of arm movement tasks. The experiments will test models of dopaminergic action via D1-class vs. D2- class receptors (1) on the activity of output neurons in the internal pallidal segment (GPi), (2) on the activity of neurons in the external pallidal segment (GPe), which is in the """"""""indirect path"""""""" to GPi, (3) on tonic vs. phasic signals transmitted through the basal ganglia, and (4) on the changes in pallidal activity (and task behavior) when the animal must learn a series of movements to a sequence of spatial targets. The models have been derived largely from anatomic studies and observed changes in the expression of peptide markers after lesions and/or pharmacologic manipulation of the dopaminergic system. They predict (1) that dopamine exerts reciprocal actions on """"""""direct"""""""" vs. """"""""indirect"""""""" paths from the striatum to GPi, and (2) that these reciprocal actions are differentially exerted via D1-class vs. D1-class vs. D2-class receptors. In addition, the low discharge rate of inhibitory striatal neurons predicts that (3) blockade of inhibitory vs. facilitatory actions of dopamine in the striatum would have quite different effects on tonic and phasic signals carried by pallidal neurons. Finally, striatal dopamine has been shown to play an important role in some forms of classical conditioning. Studies of the conditions in which dopaminergic neurons are active and the necessity of dopamine for production of long-term depression in the striatal predict that (4) striatal dopamine may play an important role to enable other forms of learning. The proposed studies, to be carried out in monkeys trained to do motor sequence tasks, will test all of these predictions regarding the influence of dopamine on information transmission in the basal ganglia. They are of importance both for an understanding of basal ganglia function and for consideration of appropriate clinical interventions in disorders such as Parkinsonism.
