Noradrenergic modulation of subthalamic nucleus activity: Behavioral and electrophysiological evidence in intact and 6-hydroxydopamine-lesioned rats

The subthalamic nucleus ( STN) plays a key role in the pathophysiology of Parkinson's disease. The modulation of the STN by norepinephrine, however, is unknown. The present study aims at characterizing the effects of systemic administration of noradrenergic agents on locomotor activity and on in vivo extracellularly recorded STN neuronal activity in intact and 6-hydroxydopamine ( 6-OHDA)-lesioned rats. Using selective agonists and antagonists of alpha 1 and alpha 2 adrenergic receptors ( ARs), we show that STN neurons have functional alpha 1- and alpha 2-AR controlling STN firing with an impact on locomotor activity. We further demonstrate that those systemic effects are supported, at least in part, by a direct modulation of STN neuronal activity, using patch-clamp recordings of STN neurons in brain slices. These findings support the premise that hypokinesia is associated with an increased STN neuronal activity, and that improvements of parkinsonian motor abnormalities are associated with a decrease inSTNactivity. Our data challenge assumptions about the role of alpha 1-AR and alpha 2-AR in the regulation of STN neurons in both intact and 6-OHDA-lesioned rats and further ground the rationale for using alpha 2-AR noradrenergic antagonists in Parkinson's disease, albeit via an unexpected mechanism.