Symptom's Associated with Abnormal Norepinephrine Levels
Affective Disorders and Mood
Depression. Norepinephrine – and specifically, norepinephrine deficiency - is implicated in depression, but the exact role that norepinephrine plays in depression is unclear.1,2
There appears to be blunted response in growth hormone following challenge with clonidine (which lowers norepinephrine), which has been identified as the most convincing evidence of the role of norepinephrine abnormalities in depression.1,3–5 Other evidence for a role of epinephrine in depression include:2
- the limbic system, which has a role in emotional regulation, is innervated by norepinephrine projections from the locus coeruleus.
- postmortem brains of depressed patients often show abnormalities of the norepinephrine system.
- preclinical research shows that genetically engineered mice with enhancements in the norepinephrine system are protected from depression-like behaviors that result from stress.
- several antidepressants work by inhibiting the reuptake of norepinephrine or by acting as antagonists for the inhibitory presynaptic norepinephrine receptors.
- following successful treatment with antidepressant drugs that impact the norepinephrine system, depleting the brain of norepinephrine makes depressive symptoms return.
Stress and Anxiety. The norepinephrine system affects anxiety, likely owing to its role in the stress response.6–8 However, norepinephrine can either enhance or reduce anxiety, depending on the context. For this reason, anxiety medications that influence the norepinephrine system may paradoxically increase anxiety in certain patients.
Mood. The impact that norepinephrine has on mood may be mediated by corticotropin-releasing factor (CRF), which regulates central norepinephrine and is involved with stress.1 Like selective serotonin reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (NRIs) have been shown in preclinical research to attenuate stress-induced alterations in the activity of tyrosine hydroxylase (TH), which synthesizes norepinephrine.
Norepinephrine has differential effects on cognition through its distinct effects on a1 and a2 receptors.9
Executive Functioning. Norepinephrine is implicated in executive functioning, owing largely to its role in modulating prefrontal cognition.2,9
Attention. Norepinephrine has an established role in waking and arousal.10 Research on the impact of norepinephrine on attention suggests that the responsiveness of the norepinephrine system contributes to attention.11
Lowered norepinephrine neurotransmission is associated with attention problems and lack of focus.2,10,11 On the other hand, in contexts where norepinephrine release is high, as in response to stress, attention may become more flexible.9 For instance, in the context of novel environmental stimuli, enhanced norepinephrine transmission reduces attention to individual objects and increases scanning of environment.12
Memory. Hippocampal memory consolidation and retrieval requires norepinephrine.10
The effects of norepinephrine on working memory appear to work through its impact on arousal levels.9 Specifically, high affinity post-synaptic α2 receptors appear to promote working memory in the context of moderate rates of norepinephrine release. In contrast, lower affinity α1 receptors are associated with higher levels of arousal that occur in response to stress, which impairs working memory performance.
Cognition-Related Disease. Norepinephrine has been implicated in cognition-related disease such as Alzheimer’s disease and mild cognitive impairment (MCI). 10,13 The locus coeruleus (which is where norepinephrine is synthesized) is a source of tau, a hallmark of Alzheimer’s disease.10
It has been hypothesized that norepinephrine cell death in the locus coeruleus may contribute to Alzheimer’s disease progression. Preclinical studies also suggest that restoring norepinephrine functioning may help to slow the neurodegeneration observed in Alzheimer’s disease through neuroprotective effects such as reducing inflammation and clearing amyloid.13 Similarly, it has been proposed that the cognitive deficits observed in Parkinson’s disease may result from a loss of norepinephrine function in the locus coeruleus.14
Social behavior. Through its role in motivation, intellect, and cognition, norepinephrine can impact social relationships.2 Norepinephrine has been specifically implicated in infant attachment learning as well as aversion learning.15
Drug Abuse. Norepinephrine may play a role in the abuse of drugs and other substances such as alcohol and caffeine. The relationship between norepinephrine and substance seeking may be mediated by the effects of stress on norepinephrine release.6 Clonidine (which lowers norepinephrine levels) reduces symptoms of withdrawal.
Eating. Norepinephrine plays a role in feeding behavior. Preclinical studies have long shown that injecting norepinephrine and alpha adrenoreceptor agonists can induce vigorous feeding behavior.16 Further investigations into the way that norepinephrine contributes to feeding behavior have demonstrated that norepinephrine helps to maintain the consummatory process.
Agitation and Aggression. It has been suggested that norepinephrine may play a role not only in the cognitive symptoms of Alzheimer’s disease but also in the noncognitive behavioral disturbances observed in the disease.17 These behaviors include agitation, aggression, and akathisia, which are linked to increased levels of norepinephrine.
Motivation. Norepinephrine appears to influence motivation, though as with attention, context dictates whether norepinephrine enhances or reduces motivation. Reduced norepinephrine has been shown to be accompanied by reductions in motivation.2 However, at the same time, selective norepinephrine reuptake inhibitors have also been shown to induce apathy, suggesting that high levels of norepinephrine may also reduce motivation.18
Pain. Norepinephrine is implicated in intrinsic pain control.19 Particularly in neuropathic conditions or in the case of inflammation, noradrenergic pain inhibitory mechanisms provide antinociceptive effects. As such, administration of certain adrenoreceptor agonists has been shown to alleviate chronic pain.
Fibromyalgia. Norepinephrine is implicated in fibromyalgia, and selective norepinephrine reuptake inhibitors are often used in the treatment of the disorder.20–22 Lowered levels of norepinephrine in the descending anti-nociceptive pathways of the spinal cord have been observed in people with fibromyalgia, which could help explain the aberrant pain processing that those with fibromyalgia experience.21
Restless Leg Syndrome. Selective norepinephrine reuptake inhibitors have been implicated in restless leg syndrome, suggesting a potential role of norepinephrine in the disorder.23 However, the evidence on the relationship is relatively scarce and contradictory.
Hypoglycemia. Norepinephrine averts hypoglycemia progression and is normally secreted in response to low blood glucose concentration.24,25
Sleep Disorders. Norepinephrine is implicated in sleep disorders, likely owing to its role in waking and arousal.10,26
Energy. Reduced neurotransmission of norepinephrine is associated with low energy.2
Blood pressure. Norepinephrine is implicated in blood pressure, with changes in blood pressure observed in response to certain drugs that affect the norepinephrine system.27,28
These observations have led to the development of dietary guidelines for patients who are taking drugs that boost norepinephrine. Those recommendations can be viewed in this table (Table 3) from Calvi et al.27
Sweating. Norepinephrine affects apocrine sweat glands, thereby contributing to emotional sweating that occurs in response to things like pain, fear, stress, or sexual stimulation.29
Color Vision. It has been suggested that norepinephrine may impact color vision, but the research is inconclusive.30
Heart Health. Norepinephrine can affect heart health.31 Patients with chronic heart failure have been shown to have norepinephrine spillover, and norepinephrine has also been shown to lead to cardiac apoptosis.
Headaches. Norepinephrine is implicated in headaches including migraine.32 Evidence for a role in migraine comes from the clinical evidence of the efficacy of selective norepinephrine reuptake inhibitors in preventing migraine and vestibular migraine. However, though not observed in episodic cluster headaches, increased levels of norepinephrine are observed in chronic cluster headaches.33
Immune Function. Norepinephrine appears to impact the immune system. Higher levels of plasma norepinephrine that occur in response to stress have been shown to diminish immune function, specifically with respect to phagocytes and lymphocytes.8
Note: Paper with a lot more information when we want more: Borodovitsyna
1. Leonard BE. Stress, norepinephrine and depression. Journal of Psychiatry & Neuroscience : JPN. 2001;26(Suppl):S11. doi:10.1034/j.1601-5215.2002.140403.x
2. Moret C, Briley M. The importance of norepinephrine in depression. Neuropsychiatr Dis Treat. 2011;7(Suppl 1):9-13. doi:10.2147/NDT.S19619
3. Mitchell PB, Bearn JA, Corn TH, Checkley SA. Growth hormone response to clonidine after recovery in patients with endogenous depression. Br J Psychiatry. 1988;152(JAN.):34-38. doi:10.1192/BJP.152.1.34
4. Charney DS, Heninger GR, Sternberg DE, Hafstad KM, Giddings S, Landis DH. Adrenergic receptor sensitivity in depression. Effects of clonidine in depressed patients and healthy subjects. Arch Gen Psychiatry. 1982;39(3):290-294. doi:10.1001/ARCHPSYC.1982.04290030030005
5. Checkley SA, Slade AP, Shur E. Growth hormone and other responses to clonidine in patients with endogenous depression. Br J Psychiatry. 1981;138(1):51-55. doi:10.1192/BJP.138.1.51
6. Fitzgerald PJ. Elevated Norepinephrine may be a Unifying Etiological Factor in the Abuse of a Broad Range of Substances: Alcohol, Nicotine, Marijuana, Heroin, Cocaine, and Caffeine. Substance Abuse: Research and Treatment. 2013;7:171. doi:10.4137/SART.S13019
7. Goddard AW, Ball SG, Martinez J, et al. Current perspectives of the roles of the central norepinephrine system in anxiety and depression. Depress Anxiety. 2010;27(4):339-350. doi:10.1002/DA.20642
8. Yaribeygi H, Panahi Y, Sahraei H, Johnston TP, Sahebkar A. The impact of stress on body function: A review. EXCLI Journal. 2017;16:1057. doi:10.17179/EXCLI2017-480
9. Berridge CW, Spencer RC. Differential Cognitive Actions of Norepinephrine α2 and α1 Receptor Signaling in the Prefrontal Cortex. Brain Res. 2016;1641(Pt B):189. doi:10.1016/J.BRAINRES.2015.11.024
10. Borodovitsyna O, Flamini M, Chandler D. Noradrenergic modulation of cognition in health and disease. Neural Plasticity. 2017;2017. doi:10.1155/2017/6031478
11. Dahl MJ, Mather M, Sander MC, Werkle-Bergner M. Noradrenergic responsiveness supports selective attention across the adult lifespan. J Neurosci. 2020;40(22):4372-4390. doi:10.1523/JNEUROSCI.0398-19.2020
12. Viggiano D, Ruocco LA, Arcieri S, Sadile AG. Involvement of norepinephrine in the control of activity and attentive processes in animal models of attention deficit hyperactivity disorder. Neural Plast. 2004;11(1-2):133-149. doi:10.1155/NP.2004.133
13. Chalermpalanupap T, Kinkead B, Hu WT, et al. Targeting norepinephrine in mild cognitive impairment and Alzheimer’s disease. Alzheimer’s Research & Therapy. 2013;5(2):21. doi:10.1186/ALZRT175
14. Vazey EM, Aston-Jones G. The emerging role of norepinephrine in cognitive dysfunctions of Parkinson’s disease. Front Behav Neurosci. 2012;6(JULY). doi:10.3389/FNBEH.2012.00048
15. Saboory E, Ghasemi M, Mehranfard N. Norepinephrine, neurodevelopment and behavior. Neurochem Int. 2020;135. doi:10.1016/J.NEUINT.2020.104706
16. Rossi J, Zolovick AJ, Davies RF, Panksepp J. The role of norepinephrine in feeding behavior. Neurosci Biobehav Rev. 1982;6(2):195-204. doi:10.1016/0149-7634(82)90055-0
17. Herrmann N, Lanctôt KL, Khan LR. The role of norepinephrine in the behavioral and psychological symptoms of dementia. J Neuropsychiatry Clin Neurosci. 2004;16(3):261-276. doi:10.1176/JNP.16.3.261
18. Sato S, Sodeyama N, Matsuzaki A, Shiratori Y. Apathy symptoms induced by low-dose venlafaxine: Two cases. Neuropsychopharmacol Rep. 2020;40(2):196-197. doi:10.1002/NPR2.12104
19. Pertovaara A. Noradrenergic pain modulation. Prog Neurobiol. 2006;80(2):53-83. doi:10.1016/J.PNEUROBIO.2006.08.001
20. Siracusa R, di Paola R, Cuzzocrea S, Impellizzeri D. Fibromyalgia: Pathogenesis, mechanisms, diagnosis and treatment options update. International Journal of Molecular Sciences. 2021;22(8). doi:10.3390/IJMS22083891
21. Bhargava J, Hurley JA. Fibromyalgia. StatPearls. Published online October 13, 2021. Accessed April 8, 2022. https://www.ncbi.nlm.nih.gov/books/NBK540974/
22. Mease PJ. Further strategies for treating fibromyalgia: the role of serotonin and norepinephrine reuptake inhibitors. Am J Med. 2009;122(12 Suppl). doi:10.1016/J.AMJMED.2009.09.010
23. Bailey AL, Makela EH, Asberg K. Selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor use as a predictor of a diagnosis of restless Legs syndrome. J Psychiatr Pract. 2016;22(4):263-269. doi:10.1097/PRA.0000000000000166
24. Hoffman R. Sympathetic mechanisms of hypoglycemic counterregulation. Curr Diabetes Rev. 2007;3(3):185-193. doi:10.2174/157339907781368995
25. Tesfaye N, Seaquist ER. Neuroendocrine responses to hypoglycemia. Ann N Y Acad Sci. 2010;1212:12. doi:10.1111/J.1749-6632.2010.05820.X
26. Mitchell HA, Weinshenker D. Good Night and Good Luck: Norepinephrine in Sleep Pharmacology. Biochem Pharmacol. 2010;79(6):801. doi:10.1016/J.BCP.2009.10.004
27. Calvi A, Fischetti I, Verzicco I, et al. Antidepressant drugs effects on blood pressure. Frontiers in Cardiovascular Medicine. 2021;8:704281. doi:10.3389/FCVM.2021.704281
28. Regueira T, Bänziger B, Djafarzadeh S, et al. Norepinephrine to increase blood pressure in endotoxaemic pigs is associated with improved hepatic mitochondrial respiration. Crit Care. 2008;12(4). doi:10.1186/CC6956
29. Hodge BD, Sanvictores T, Brodell RT. Anatomy, skin sweat glands. StatPearls. Published online October 14, 2021. Accessed April 17, 2022. https://www.ncbi.nlm.nih.gov/books/NBK482278/
30. Keeler MH, Doehne EF. The effects of epinephrine and norepinephrine on an aspect of color vision. Psychophysiology. 1966;3(1):35-39. doi:10.1111/J.1469-8986.1966.TB02677.X
31. Lymperopoulos A, Rengo G, Koch WJ. The adrenergic nervous system in heart failure: Pathophysiology and therapy. Circ Res. 2013;113(6):739-753. doi:10.1161/CIRCRESAHA.113.300308
32. Wang F, Wang J, Cao Y, Xu Z. Serotonin-norepinephrine reuptake inhibitors for the prevention of migraine and vestibular migraine: a systematic review and meta-analysis. Reg Anesth Pain Med. 2020;45(5):323-330. doi:10.1136/RAPM-2019-101207
33. D’Andrea G, Gucciardi A, Perini F, Leon A. Pathogenesis of cluster headache: from episodic to chronic form, the role of neurotransmitters and neuromodulators. Headache. 2019;59(9):1665-1670. doi:10.1111/HEAD.13673