Common Noradrenergic Mechanisms in Parkinson´s Disease and L-DOPA Induced Dyskinesia and Healthy Age Matched Controls; [11C]Yohimbine and [11C]MeNER PET

Introduction: The major source of NE in the central nervous system (CNS) is the locus coeruleus (LC), which sends projections to virtually all parts of the CNS, integrating cognitive and autonomic functions with the state of arousal (Sara SJ 2009).

With the onset of pathogenesis of PD in the lower brainstem, early symptoms of PD that include sleep disorder, cognitive deficits, and autonomic dysfunction, may appear prior to the motor symptoms of PD, and these symptoms have been linked to the degeneration of the LC and subsequent loss of noradrenergic innervations in the peripheral and central nervous systems (Rascol et al., 2009, Hawkes et al., 2010, Braak et al., 2003).

The loss of neurons in the LC exceeds that of the substantia nigra in some studies (Zarow et al. 2003), in which it is also argued that the loss may be related to the symptoms of endogenous depression in 40% of patients with PD. In these patients, the severity of motor symptoms also may be aggravated by loss of NE as release of dopamine (DA) and firing of dopaminergic neurons normally are both facilitated by activation of noradrenergic neurons.

Lesion of the LC and the subsequent loss of this facilitation reduces nigrostriatal DA release. Similarly, lesions to both dopaminergic and noradrenergic neurons induce more severe motor deficits, compared to lesions of dopaminergic neurons alone (Mavridis M et al., 1999). This relation suggests direct and indirect roles for NE in the emergence and severity of both motor and non-motor symptoms in PD, including depression.

The effects of NE are mediated by stimulation of the three receptor subtypes alpha-1, alpha-2, and ß. In the proposed studies, the investigators focus on alpha-2 and ß-receptors. Of the alpha-2 receptors, the alpha2C subtype is densely expressed in structures of the basal ganglia and therefore may mediate the direct effects of alpha-2 receptors on motor behavior.