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 alpha1 and alpha2 adrenergic receptors (ARs), we show that STN neurons have functional alpha1- and alpha2-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 in STN activity. Our data challenge assumptions about the role of alpha1-AR and alpha2-AR in the regulation of STN neurons in both intact and 6-OHDA-lesioned rats and further ground the rationale for using alpha2-AR noradrenergic antagonists in Parkinson's disease, albeit via an unexpected mechanism.
Belujon
Pauline
P
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5227, Université Victor Segalen, 33076 Bordeaux Cedex, France.
Bezard
Erwan
E
Taupignon
Anne
A
Bioulac
Bernard
B
Benazzouz
Abdelhamid
A
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004594:Electrophysiology; D018476:Hypokinesia / Q000139:chemically induced / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D009924:Organ Culture Techniques; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism; D020531:Subthalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects