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The origin of motor fluctuations in Parkinson’s disease

Importance of dopaminergic innervation and basal ganglia circuits

Departments of Neurology and Neurosurgery and Histology, Neuroscience Center (Drs. Obeso, Rodriguez-Oroz, Alonso, Zamarbide and Lanciego), FIMA, Clinica Universitaria and Medical School, University of Navarra, Pamplona, Spain; Experimental Neurology Laboratory, Fundacio Clinic-Hospital Clinic (Dr. Marin), IDIBAG, Barcelona, Spain; and Department of Physiology, Medical School (Dr. Rodriguez-Diaz), University of La Laguna, Tenerife, Spain.

Address correspondence and reprint requests to Dr. Jose Obeso, Neurologia-Neurociencias, Clinica Universitaria, Avenida Pio XII 36, Pamplona 31180, Spain.

The severity of dopamine depletion and the consequent pathophysiologic changes that occur in basal ganglia circuits determine the severity of parkinsonian signs. Restoring the dopamine deficit or the downstream physiologic abnormalities improves Parkinson’s Disease (PD) main motor features and as a result, attenuates the short-duration response (SDR). Therefore, both the magnitude and duration of the motor response are a function of the degree of motor severity, which is primarily governed by the loss of tonic dopaminergic activity and disruption of basal ganglia homeostatic mechanisms among which the STN-GPe/GPi circuits play a fundamental role. As neurodegeneration advances, standard levodopa administration give rises to wider oscillations in striatal dopamine availability and "pulsatile" stimulation of striatal dopamine receptors becomes predominant. This induces molecular and physiologic changes that further accentuate and aggravate the SDR that sustains motor fluctuations. Treatments capable of providing and restoring more tonic and physiologic dopaminergic stimulation may avoid many of these abnormalities and lead to better clinical outcomes.

¹Present address: Servicio de Neurologia, Fundacion Jimenez Diaz, Clinica de la Concepcion, Madrid, Spain.

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