Symptoms Associated with Abnormal Norepinephrine Levels

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Affective Disorders and Mood[edit]

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][4][5] Other evidence for a role of norepinephrine 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][7][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.

Cognition[edit]

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][11][12][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]

Behavior[edit]

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]

Physical Symptoms[edit]

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][21][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]

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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

References[edit]

  1. ↑ 1.0 1.1 1.2 Leonard, Brian E. (2002). "Stress, norepinephrine and depression". Acta Neuropsychiatrica. 14 (4): 173–180. doi:10.1034/j.1601-5215.2002.140403.x. ISSN 0924-2708.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Moret, Chantal; Briley, Mike (2011). "The importance of norepinephrine in depression". Neuropsychiatric Disease and Treatment. 7 (Supplement 1): 9–13. doi:10.2147/NDT.S19619. PMC 3131098. PMID 21750623.
  3. ↑ Mitchell, P. B.; Bearn, J. A.; Corn, T. H.; Checkley, S. A. (1988). "Growth Hormone Response to Clonidine After Recovery in Patients with Endogenous Depression". The British Journal of Psychiatry. 152 (1): 34–38. doi:10.1192/bjp.152.1.34. ISSN 0007-1250.
  4. ↑ Charney, Dennis S. (1982). "Adrenergic Receptor Sensitivity in Depression: Effects of Clonidine in Depressed Patients and Healthy Subjects". Archives of General Psychiatry. 39 (3): 290. doi:10.1001/archpsyc.1982.04290030030005. ISSN 0003-990X.
  5. ↑ Checkley, S. A.; Slade, A. P.; Shur, E. (1981). "Growth Hormone and other Responses to Clonidine in Patients with Endogenous Depression". British Journal of Psychiatry. 138 (1): 51–55. doi:10.1192/bjp.138.1.51. ISSN 0007-1250.
  6. ↑ 6.0 6.1 Fitzgerald, Paul J. (2013). "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. 7: SART.S13019. doi:10.4137/SART.S13019. ISSN 1178-2218. PMC 3798293. PMID 24151426.CS1 maint: PMC format (link)
  7. ↑ Goddard, Andrew W.; Ball, Susan G.; Martinez, James; Robinson, Michael J.; Yang, Charles R.; Russell, James M.; Shekhar, Anantha (2010). "Current perspectives of the roles of the central norepinephrine system in anxiety and depression". Depression and Anxiety. 27 (4): 339–350. doi:10.1002/da.20642.
  8. ↑ 8.0 8.1 Yaribeygi, Habib; Panahi, Yunes; Sahraei, Hedayat; Johnston, Thomas P.; Sahebkar, Amirhossein (2017). "The impact of stress on body function: a review" (PDF). EXCLI Journal; 16:Doc1057; ISSN 1611-2156. doi:10.17179/EXCLI2017-480. PMC 5579396. PMID 28900385.CS1 maint: PMC format (link)
  9. ↑ 9.0 9.1 9.2 9.3 Berridge, Craig W.; Spencer, Robert C. (2016). "Differential cognitive actions of norepinephrine a2 and a1 receptor signaling in the prefrontal cortex". Brain Research. 1641: 189–196. doi:10.1016/j.brainres.2015.11.024. PMC 4876052. PMID 26592951.CS1 maint: PMC format (link)
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 Borodovitsyna, Olga; Flamini, Matthew; Chandler, Daniel (2017). "Noradrenergic Modulation of Cognition in Health and Disease". Neural Plasticity. 2017: 1–14. doi:10.1155/2017/6031478. ISSN 2090-5904. PMC 5450174. PMID 28596922.CS1 maint: PMC format (link)
  11. ↑ 11.0 11.1 11.2 Dahl, Martin J.; Mather, Mara; Sander, Myriam C.; Werkle-Bergner, Markus (2020). "Noradrenergic Responsiveness Supports Selective Attention across the Adult Lifespan". The Journal of Neuroscience. 40 (22): 4372–4390. doi:10.1523/JNEUROSCI.0398-19.2020. ISSN 0270-6474. PMC 7252473. PMID 32317388.CS1 maint: PMC format (link)
  12. ↑ 12.0 12.1 Viggiano, D.; Ruocco, L. A.; Arcieri, S.; Sadile, A. G. (2004). "Involvement of Norepinephrine in the Control of Activity and Attentive Processes in Animal Models of Attention Deficit Hyperactivity Disorder". Neural Plasticity. 11 (1–2): 133–149. doi:10.1155/np.2004.133. ISSN 2090-5904. PMC 2565437. PMID 15303310.
  13. ↑ 13.0 13.1 Chalermpalanupap, Termpanit; Kinkead, Becky; Hu, William T; Kummer, Markus P; Hammerschmidt, Thea; Heneka, Michael T; Weinshenker, David; Levey, Allan I (2013). "Targeting norepinephrine in mild cognitive impairment and Alzheimer's disease". Alzheimer's Research & Therapy. 5 (2): 21. doi:10.1186/alzrt175. ISSN 1758-9193. PMC 3706916. PMID 23634965.CS1 maint: PMC format (link)
  14. ↑ Vazey, Elena M.; Aston-Jones, Gary (2012). "The emerging role of norepinephrine in cognitive dysfunctions of Parkinson's disease". Frontiers in Behavioral Neuroscience. 6. doi:10.3389/fnbeh.2012.00048. ISSN 1662-5153. PMC 3404393. PMID 22848194.CS1 maint: PMC format (link)
  15. ↑ Saboory, Ehsan; Ghasemi, Maedeh; Mehranfard, Nasrin (2020). "Norepinephrine, neurodevelopment and behavior". Neurochemistry International. 135: 104706. doi:10.1016/j.neuint.2020.104706.
  16. ↑ Rossi, John; Zolovick, A.J.; Davies, R.F.; Panksepp, J. (1982). "The role of norepinephrine in feeding behavior". Neuroscience & Biobehavioral Reviews. 6 (2): 195–204. doi:10.1016/0149-7634(82)90055-0.
  17. ↑ Herrmann, Nathan; Lanctôt, Krista L.; Khan, Lyla R. (2004). "The Role of Norepinephrine in the Behavioral and Psychological Symptoms of Dementia". The Journal of Neuropsychiatry and Clinical Neurosciences. 16 (3): 261–276. doi:10.1176/jnp.16.3.261. ISSN 0895-0172.
  18. ↑ Sato, Shinji; Sodeyama, Noriko; Matsuzaki, Asaki; Shiratori, Yuki (2020). "Apathy symptoms induced by low‐dose venlafaxine: Two cases". Neuropsychopharmacology Reports. 40 (2): 196–197. doi:10.1002/npr2.12104. ISSN 2574-173X. PMC 7722648 Check |pmc= value (help). PMID 32267090.
  19. ↑ Pertovaara, Antti (2006). "Noradrenergic pain modulation". Progress in Neurobiology. 80 (2): 53–83. doi:10.1016/j.pneurobio.2006.08.001.
  20. ↑ Siracusa, Rosalba; Paola, Rosanna Di; Cuzzocrea, Salvatore; Impellizzeri, Daniela (2021). "Fibromyalgia: Pathogenesis, Mechanisms, Diagnosis and Treatment Options Update". International Journal of Molecular Sciences. 22 (8): 3891. doi:10.3390/ijms22083891. ISSN 1422-0067. PMC 8068842 Check |pmc= value (help). PMID 33918736 Check |pmid= value (help).
  21. ↑ 21.0 21.1 Bhargava, J., & Hurley, J. A. (2022). Fibromyalgia–Statpearls–NCBI Bookshelf. StatPearls [Internet]. Treasure Island (FL). Accessed April 8, 2022. https://www.ncbi.nlm.nih.gov/books/NBK540974/
  22. ↑ Mease, Philip J. (2009). "Further Strategies for Treating Fibromyalgia: The Role of Serotonin and Norepinephrine Reuptake Inhibitors". The American Journal of Medicine. 122 (12): S44–S55. doi:10.1016/j.amjmed.2009.09.010.
  23. ↑ Bailey, Anne L.; Makela, Eugene H.; Asberg, Kia (2016). "Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor Use as a Predictor of a Diagnosis of Restless Legs Syndrome". Journal of Psychiatric Practice. 22 (4): 263–269. doi:10.1097/PRA.0000000000000166. ISSN 1527-4160.
  24. ↑ Robert P. Hoffman (2007). "Sympathetic Mechanisms of Hypoglycemic Counterregulation". Current Diabetes Reviews. 3 (3): 185–193. doi:10.2174/157339907781368995.
  25. ↑ Tesfaye, Nolawit; Seaquist, Elizabeth R. (2010). "Neuroendocrine responses to hypoglycemia: Neuroendocrine responses to hypoglycemia". Annals of the New York Academy of Sciences. 1212 (1): 12–28. doi:10.1111/j.1749-6632.2010.05820.x. PMC 2991551. PMID 21039590.CS1 maint: PMC format (link)
  26. ↑ Mitchell, Heather A.; Weinshenker, David (2010). "Good night and good luck: Norepinephrine in sleep pharmacology". Biochemical Pharmacology. 79 (6): 801–809. doi:10.1016/j.bcp.2009.10.004. PMC 2812689. PMID 19833104.CS1 maint: PMC format (link)
  27. ↑ 27.0 27.1 Calvi, Anna; Fischetti, Ilaria; Verzicco, Ignazio; Belvederi Murri, Martino; Zanetidou, Stamatula; Volpi, Riccardo; Coghi, Pietro; Tedeschi, Stefano; Amore, Mario; Cabassi, Aderville (2021). "Antidepressant Drugs Effects on Blood Pressure". Frontiers in Cardiovascular Medicine. 8: 704281. doi:10.3389/fcvm.2021.704281. ISSN 2297-055X. PMC PMC8370473 Check |pmc= value (help). PMID 34414219 Check |pmid= value (help).CS1 maint: PMC format (link)
  28. ↑ Regueira, Tomas; Bänziger, Bertram; Djafarzadeh, Siamak; Brandt, Sebastian; Gorrasi, Jose; Takala, Jukka; Lepper, Philipp M; Jakob, Stephan M (2008). "Norepinephrine to increase blood pressure in endotoxaemic pigs is associated with improved hepatic mitochondrial respiration". Critical Care. 12 (4): R88. doi:10.1186/cc6956. ISSN 1364-8535. PMC 2575568. PMID 18625036.CS1 maint: PMC format (link)
  29. ↑ Hodge, B. D., Sanvictores, T., & Brodell, R. T. (2018). Anatomy, skin sweat glands.In: StatPearls. StatPearls Publishing, Treasure Island (FL). Accessed April 17, 2022. PMID: 29489179. https://www.ncbi.nlm.nih.gov/books/NBK482278/
  30. ↑ Keeler, Martin H.; Doehne, Edward F. (1966). "THE EFFECTS OF EPINEPHRINE AND NOREPINEPHRINE ON AN ASPECT OF COLOR VISION". Psychophysiology. 3 (1): 35–39. doi:10.1111/j.1469-8986.1966.tb02677.x. ISSN 0048-5772.
  31. ↑ Lymperopoulos, Anastasios; Rengo, Giuseppe; Koch, Walter J. (2013). "Adrenergic Nervous System in Heart Failure: Pathophysiology and Therapy". Circulation Research. 113 (6): 739–753. doi:10.1161/CIRCRESAHA.113.300308. ISSN 0009-7330. PMC 3843360. PMID 23989716.CS1 maint: PMC format (link)
  32. ↑ Wang, Fengzhi; Wang, Jiaoqi; Cao, Yumeng; Xu, Zhongxin (2020). "Serotonin–norepinephrine reuptake inhibitors for the prevention of migraine and vestibular migraine: a systematic review and meta-analysis". Regional Anesthesia & Pain Medicine. 45 (5): 323–330. doi:10.1136/rapm-2019-101207. ISSN 1098-7339.
  33. ↑ D'Andrea, Giovanni; Gucciardi, Antonina; Perini, Francesco; Leon, Alberta (2019). "Pathogenesis of Cluster Headache: From Episodic to Chronic Form, the Role of Neurotransmitters and Neuromodulators". Headache: The Journal of Head and Face Pain. 59 (9): 1665–1670. doi:10.1111/head.13673. ISSN 0017-8748.
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