Noradrenergic Modulation of Subthalamic Nucleus Activity: Behavioral and Electrophysiological Evidence in Intact and 6-Hydroxydopamine-Lesioned Rats

Abstract

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 ␣1 and ␣2 adrenergic receptors (ARs), we show that STN neurons have functional ␣1-and ␣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 in STN activity. Our data challenge assumptions about the role of ␣1-AR and ␣2-AR in the regulation of STN neurons in both intact and 6-OHDA-lesioned rats and further ground the rationale for using ␣2-AR noradrenergic antagonists in Parkinson's disease, albeit via an unexpected mechanism.

Inhibiting Subthalamic D5Receptor Constitutive Activity Alleviates Abnormal Electrical Activity and Reverses Motor Impairment in a Rat Model of Parkinson's Disease

“…Because D 5 Rs signaling has been shown to increase burst firing through potentiation of Cav1 channels in the STN in vitro (Baufreton et al, 2003), we tested the effect of the Cav1 channel inhibitor calciseptine using the same experimental protocol. It was purchased from Alomone Labs, and a dose of 6 ng in 20 nl of saline was injected.…”

“…It was purchased from Alomone Labs, and a dose of 6 ng in 20 nl of saline was injected. Calciseptine has been chosen for a number of reasons: (1) we showed previously that calciseptine occluded the action of SKF 81297 (6-chloro-2,3,4,5-tetrahydro-1-phenyl-1 H-3-benzazepine hydrobromide) in vitro and reduced burst competency by virtually inhibiting plateau potentials (Baufreton et al 2003);and (2) calciseptine is stable at room temperature and is not destroyed by exposition to light, a property that is necessary for using it in in vivo experiments. butaclamol, and fluphenazine on bursts (top traces) evoked by depolarizing stimuli (bottom traces) in DA-intact animals.…”

“…STN holds a pivotal position in basal ganglia circuitry, exerting an excitatory drive on the output structures (Albin et al, 1989;Surmeier and Bevan, 2003). It is now thought to mediate a top-down executive cortical control over all behavioral programs treated by basal ganglia (Cavanagh et al, 2011;Haynes and Haber, 2013).…”

“…It has been also demonstrated in vitro that D 5 Rs potentiate burst firing in STN neurons (Baufreton et al, 2003. Although the action of receptors in the D 2 family is not expected to be maintained in the DA-depleted state, the distinctive property of D 5 R of constitutive activity argues in favor of persistence of a significant part of their burst firing-potentiating action.…”

Evaluation of Metabolic State in Striatal Rat Model of Parkinson’s Disease: before and after Deep Brain Stimulation

“…The reasons that have led to ignore the role of noradrenergic neurons in the disease could be that the striatum has been the main target of the antiparkinsonian treatments. Nonetheless, noradrenergic mechanisms may also participate in the therapeutic outcome of L-DOPA and noradrenaline may act in brain regions that have a profound impact on the control of motor behaviors, including the STN and in the neurodegeneration process of PD [50][51][52][53].…”