Anatomy and function of dopamine receptors: understanding the pathophysiology of fluctuations in Parkinson's disease

The principal dopamine (DA) receptors mediating the antiparkinson effects o f levodopa are D1 and D2, which are anatomically and functionally segregate d. We hypothesize that DA receptor-mediated effects are critical for the de velopment of treatment-related fluctuations in Parkinson's disease (PD). We suggest that two sequential processes occur to permit the emergence of the so-called short duration response and dyskinesias: (1) functional uncoupli ng of D1 and D2 receptor-mediated effects with shift to the left of the dos e-response curve; and, (2) sensitization of the D1-mediated striatal output due to repetitive, primarily D1 receptor stimulation by DA. These mechanis ms result in excessive, pathological inhibition of basal ganglia output neu rons in the GPi producing dyskinesias and the short duration response. (C) 2001 Elsevier Science Ltd. All rights reserved.