Norepinephrine deficiency in Parkinson's disease: the case for noradrenergic enhancement

Mov Disord. 2014 Dec;29(14):1710-9. doi: 10.1002/mds.26048. Epub 2014 Oct 9.


The dramatic response of most motor and some nonmotor symptoms to dopaminergic therapies has contributed to maintaining the long-established identity of Parkinson's disease (PD) as primarily a nigrostriatal dopamine (DA) deficiency syndrome. However, DA neurotransmission may be neither the first nor the major neurotransmitter casualty in the neurodegenerative sequence of PD. Growing evidence supports earlier norepinephrine (NE) deficiency resulting from selective degeneration of neurons of the locus coeruleus and sympathetic ganglia. Dopaminergic replacement therapy therefore would seem to neglect some of the motor, behavioral, cognitive, and autonomic impairments that are directly or indirectly associated with the marked deficiency of NE in the brain and elsewhere. Therapeutic strategies to enhance NE neurotransmission have undergone only limited pharmacological testing. Currently, these approaches include selective NE reuptake inhibition, presynaptic α2 -adrenergic receptor blockade, and an NE prodrug, the artificial amino acid L-threo-3,4-dihydroxyphenylserine. In addition to reducing the consequences of deficient noradrenergic signaling, enhancement strate gies have the potential for augmenting the effects of dopaminergic therapies in PD. Furthermore, early recognition of the various clinical manifestations associated with NE deficiency, which may precede development of motor symptoms, could provide a window of opportunity for neuroprotective interventions.

Keywords: Parkinson's disease; autonomic; cognitive; locus coeruleus; norepinephrine; sleep disorders.

Publication types

  • Review

MeSH terms

  • Animals
  • Autonomic Nervous System Diseases / metabolism
  • Dopamine / metabolism
  • Dopamine beta-Hydroxylase / deficiency*
  • Dopamine beta-Hydroxylase / drug effects
  • Dopamine beta-Hydroxylase / metabolism
  • Humans
  • Locus Coeruleus / drug effects*
  • Locus Coeruleus / metabolism
  • Motor Activity / drug effects*
  • Norepinephrine / deficiency*
  • Norepinephrine / metabolism
  • Norepinephrine / pharmacology*
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / genetics


  • Dopamine beta-Hydroxylase
  • Dopamine
  • Norepinephrine

Supplementary concepts

  • dopamine beta hydroxylase deficiency