ABOUT ME: I am board certified in internal medicine, have been diagnosed with CFS and POTS in the past, and have spent the last few years diving deep in my own study of neurobiology and the art of “neurohacking”. I usually keep my theories to myself but when I stumbled on this one, I felt that it was too intriguing not to share with others.
Trace amines are biologically related to major amines such as norepinephrine and dopamine but they are present in much smaller concentrations. Trace amines molecules include phenythylamine (PEA), tyramine, octopamine, tryptamine, 3-iodothyronamine (T1AM) and a number of others.
Trace amine-associated receptor 1 (TAAR1) is a G-coupled protein receptor that was discovered in 2001, and since then at least eight more species of this receptor type have been identified in various tissues (stomach, small intestine, liver, kidneys, lymphocytes, astrocytes, monoaminergic neurons). In the past few years, there has been a rapidly emerging understanding about the important the role trace amines in the regulation of nervous system, metabolism and olfaction (sense of smell).
Before TAAR1 was identified, trace amines were thought to have little biological function but in recent years, their role as very powerful neuromodulators has emerged. Via their action on TAAR receptors trace amines act as “master ” that essentially influence all other aminergic neurotransmitters (NE, DA, SE) in the central nervous system. TAAR receptors also appear to be involved in the neuromodulation of glutamate, histamine, and GABA.
Their most profound influence appears to be on the release of catecholamines (norepinephrine and dopamine). TAAR1 is widely expressed in the primary monoaminergic areas of the brain and well positioned to modulate locomotor, emotional, and motivated behaviors that are traditionally associated with monoaminergic activity.
Trace amines are also believed to inhibit transporters of these molecules (NET transporter deficiency has been observed in some POTS patients). They can also affect a marked effect on the release histamine, which is another common problem in many patients. TAAR receptors are also involved in the neuromodulation of glutamate, GABA and serotonin.
So here are the top ten reasons that led me to believe that trace amines and TAAR receptors deserve a full investigation regarding their possible role in etiology of CFS and POTS. (My guess is that there is likely either a primary hypersensitivity or down regulation of the receptors depending on clinical picture, although abnormalities in the synthesis or breakdown of trace amines are also a possibility).
TAAR receptors have been found in leukocytes and B lymphocytes, and are thought to be directly involved in regulation of immunity. This would explain the underlying immune system abnormalities found in CFS/POTS patients.
3. TAAR1 and TAAR 2 receptors are present in large numbers in play a crucial role in olfaction (smell), in particular detection of volatile amines, which would explain the hallmark sensitivity to chemical smells.
4. Trace amines molecules act as indirect sympathomimetic agents involved in regulation of sympathetic system. They also have been shown to have a direct effect on alpha1 and alpha2 receptors. It is possible, that the over-activation of sympathetic nervous system combined with the catecholamine depletion due to the persistent release (a phenomenon known as “tachyphylaxis” is what causes the infamous “tired but wired” state, when it feels like nerve cells are pushing on the gas pedal while running on an empty gasoline tank.
5. Trace amines synthesis (in particular conversion of T4 to 3-iodothyronamine (T1AM)) appears to be closely related to the metabolism of thyroid hormones, and due to its synthesis within intestinal lumen, also possibly to gut flora. (Hartmut et al, 2017).
6. High levels of 3-iodothyronamine (T1AM) have been shown to induce a state of “torpor/immobility” in rodents. This would correlated with a physiological signature of “dauer’ described by R. Naviaux (Naviaux et al, 2016) et al in their recent CFS metabolomics study. It appears that T1AM plays a pivotal role in orchestrating neuronal energy balance in conjunction with thyroid hormone. (I don’t know about you but I like the word “torpor”, to me it sounds like a very apt description of what I’ve experienced on my worst days).
7. Overstimulation of TAAR receptors has been linked to the oxidative damage to neurons and a decrease in glutamate clearance (Cisneros IE, Ghorpade A, 2014).
8. There is some evidence that TAAR receptors may play a role in regulation of ACTH, and as we all know hypothalamic dysregulation of cortisol levels is common in patients with CFS, POTS and fibromyalgia. (Zucci et al, 2006)
9. TAAR receptors regulate cellular cAMP accumulation via their effect on adenylyl cyclase. The rank order of potency for cAMP production is
p-tyramine> β-phenylethylamine>tryptamine>octopamine>m-tyramine>>dopamine (Zucci et al, 2006).
Thus, the energetic abnormalities observed in at least some CFS patients (I do believe it is a heterogeneous diagnosis right now) may be due to mitochondrial impairment of energy production but rather to disordered intracellular cAMP regulation (which would explain why the Stanford study did not find any mitochondrial impairment in CFS patients).
10. Recent study identified TAAR1 gene SNPs as one of several abnormal genes in fibromyalgia patients cohort. Trace amines and TAAR receptors have been shown to be involved in regulation of nociceptive (pain) pathways and locomotion in spinal cord neuronal pathways (Smith SB et al 2012).
REFERENCES:
1. Nelson DA, Tolbert MD, Singh SJ, Bost KLJ. Expression of neuronal trace amine-associated receptor (Taar) mRNAs in leukocytes. Neuroimmunol. 2007 Dec;192(1-2):21-30. Epub 2007 Sep 27.
2. Hochman S. Metabolic recruitment of spinal locomotion: intracellular neuromodulation by trace amines and their receptors. Neural Regeneration Research. 2015;10(12):1940-1942. doi:10.4103/1673-5374.169625.
3. Ju H, So H, Ha K, Park K, Lee JW, Chung CM, et al. Sustained torpidity following multi-dose administration of 3-iodothyronamine in mice. J Cell Physiol (2011) 226(4):853–8. doi:10.1002/jcp.22573
4. Pacifico R, Dewan A, Cawley D, Guo C, Bozza T. An Olfactory Subsystem that Mediates High Sensitivity Detection of Volatile Amines. Cell reports. 2012;2:76-88. doi:10.1016/j.celrep.2012.06.006.)
5. Saraiva LR, Kondoh K, Ye X, Yoon K, Hernandez M, Buck LB. Combinatorial effects of odorants on mouse behavior. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(23):E3300-E3306. doi:10.1073/pnas.1605973113.
6. Zucchi R, Accorroni A, Chiellini G. Update on 3-iodothyronamine and its neurological and metabolic actions. Frontiers in Physiology. 2014;5:402. doi:10.3389/fphys.2014.00402.
7.Miller GM. The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J. Neurochem. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101 Freely accessible. PMID 21073468.
8. Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186.
9. Maguire JJ, Davenport AP (19 July 2016). "Trace amine receptor: TA1 receptor". IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. Retrieved 22 September 2016.
10. Rogers TJ (2012). "The molecular basis for neuroimmune receptor signaling". J Neuroimmune Pharmacol. 7 (4): 722–724. doi:10.1007/s11481-012-9398-4. PMC 4011130 Freely accessible. PMID 22935971
11. Xie Z, Westmoreland SV, Bahn ME, Chen GL, Yang H, Vallender EJ, Yao WD, Madras BK, Miller GM (April 2007). "Rhesus monkey trace amine-associated receptor 1 signaling: enhancement by monoamine transporters and attenuation by the D2 autoreceptor in vitro". The Journal of Pharmacology and Experimental Therapeutics. 321 (1): 116–127. doi:10.1124/jpet.106.116863. PMID 17234900.
12. Liberles SD, Buck LB (August 2006). "A second class of chemosensory receptors in the olfactory epithelium". Nature. 442 (7103): 645–650. doi:10.1038/nature05066. PMID 16878137
13. Dinter J, Mühlhaus J, Jacobi SF, Wienchol CL, Cöster M, Meister J, Hoefig CS, Müller A, Köhrle J, Grüters A, Krude H, Mittag J, Schöneberg T, Kleinau G, Biebermann H (June 2015). "3-iodothyronamine differentially modulates α-2A-adrenergic receptor-mediated signaling". J. Mol. Endocrinol. 54 (3): 205–216. doi:10.1530/JME-15-0003
14. Sotnikova TD, Caron MG, Gainetdinov RR (August 2009). "Trace amine-associated receptors as emerging therapeutic targets". Mol. Pharmacol. 76 (2): 229–235. doi:10.1124/mol.109.055970. PMC 2713119 Freely accessible. PMID 19389919
15. Smith SB, Maixner DW, Fillingim RB, Slade G, Gracely RH, Ambrose K, Zaykin DV, Hyde C, John S, Tan K, Maixner W, Diatchenko L (February 2012). "Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia". Arthritis and Rheumatism. 64 (2): 584–593. doi:10.1002/art.33338. PMC 3237946 Freely accessible. PMID 21905019
16. Robert K. Naviaux, Jane C. Naviaux, Kefeng Li, A. Taylor Bright, William A. Alaynick, Lin Wang, Asha Baxter, Neil Nathan, Wayne Anderson and Eric Gordon. Metabolic features of chronic fatigue syndrome. PNAS 2016 September, 113 (37) E5472-E5480. https://doi.org/10.1073/pnas.1607571113
17. Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, Durkin MM, Lakhlani PP, Bonini JA, Pathirana S, Boyle N, Pu X, Kouranova E, Lichtblau H, Ochoa FY, Branchek TA, Gerald C (2001). "Trace amines: identification of a family of mammalian G protein-coupled receptors". PNAS. 98 (16): 8966–71. doi:10.1073/pnas.151105198. PMC 55357 Freely accessible. PMID 11459929
18. Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK (2001). "Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor". Mol. Pharmacol. 60 (6): 1181–8. doi:10.1124/mol.60.6.1181. PMID 11723224
19. Pei Yue, Asif-Malik Aman, Canales Juan J. Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications. Frontiers in Neuroscience 2016.
20. Cisneros IE, Ghorpade A (October 2014). "Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes". Neuropharmacology. 85: 499–507. doi:10.1016/j.neuropharm.2014.06.011. PMC 4315503 Freely accessible. PMID 24950453.
21. Hartmut H. Glossmann1 and Oliver M. D. Lutz2 Torpor: The Rise and Fall of 3-Monoiodothyronamine from Brain to Gut—From Gut to Brain?. Frontiers in Endocrinology. Review published: 31 May 2017. doi: 10.3389/fendo.2017.00118
Trace amines are biologically related to major amines such as norepinephrine and dopamine but they are present in much smaller concentrations. Trace amines molecules include phenythylamine (PEA), tyramine, octopamine, tryptamine, 3-iodothyronamine (T1AM) and a number of others.
Trace amine-associated receptor 1 (TAAR1) is a G-coupled protein receptor that was discovered in 2001, and since then at least eight more species of this receptor type have been identified in various tissues (stomach, small intestine, liver, kidneys, lymphocytes, astrocytes, monoaminergic neurons). In the past few years, there has been a rapidly emerging understanding about the important the role trace amines in the regulation of nervous system, metabolism and olfaction (sense of smell).
Before TAAR1 was identified, trace amines were thought to have little biological function but in recent years, their role as very powerful neuromodulators has emerged. Via their action on TAAR receptors trace amines act as “master ” that essentially influence all other aminergic neurotransmitters (NE, DA, SE) in the central nervous system. TAAR receptors also appear to be involved in the neuromodulation of glutamate, histamine, and GABA.
Their most profound influence appears to be on the release of catecholamines (norepinephrine and dopamine). TAAR1 is widely expressed in the primary monoaminergic areas of the brain and well positioned to modulate locomotor, emotional, and motivated behaviors that are traditionally associated with monoaminergic activity.
Trace amines are also believed to inhibit transporters of these molecules (NET transporter deficiency has been observed in some POTS patients). They can also affect a marked effect on the release histamine, which is another common problem in many patients. TAAR receptors are also involved in the neuromodulation of glutamate, GABA and serotonin.
So here are the top ten reasons that led me to believe that trace amines and TAAR receptors deserve a full investigation regarding their possible role in etiology of CFS and POTS. (My guess is that there is likely either a primary hypersensitivity or down regulation of the receptors depending on clinical picture, although abnormalities in the synthesis or breakdown of trace amines are also a possibility).
TAAR receptors have been found in leukocytes and B lymphocytes, and are thought to be directly involved in regulation of immunity. This would explain the underlying immune system abnormalities found in CFS/POTS patients.
3. TAAR1 and TAAR 2 receptors are present in large numbers in play a crucial role in olfaction (smell), in particular detection of volatile amines, which would explain the hallmark sensitivity to chemical smells.
4. Trace amines molecules act as indirect sympathomimetic agents involved in regulation of sympathetic system. They also have been shown to have a direct effect on alpha1 and alpha2 receptors. It is possible, that the over-activation of sympathetic nervous system combined with the catecholamine depletion due to the persistent release (a phenomenon known as “tachyphylaxis” is what causes the infamous “tired but wired” state, when it feels like nerve cells are pushing on the gas pedal while running on an empty gasoline tank.
5. Trace amines synthesis (in particular conversion of T4 to 3-iodothyronamine (T1AM)) appears to be closely related to the metabolism of thyroid hormones, and due to its synthesis within intestinal lumen, also possibly to gut flora. (Hartmut et al, 2017).
6. High levels of 3-iodothyronamine (T1AM) have been shown to induce a state of “torpor/immobility” in rodents. This would correlated with a physiological signature of “dauer’ described by R. Naviaux (Naviaux et al, 2016) et al in their recent CFS metabolomics study. It appears that T1AM plays a pivotal role in orchestrating neuronal energy balance in conjunction with thyroid hormone. (I don’t know about you but I like the word “torpor”, to me it sounds like a very apt description of what I’ve experienced on my worst days).
7. Overstimulation of TAAR receptors has been linked to the oxidative damage to neurons and a decrease in glutamate clearance (Cisneros IE, Ghorpade A, 2014).
8. There is some evidence that TAAR receptors may play a role in regulation of ACTH, and as we all know hypothalamic dysregulation of cortisol levels is common in patients with CFS, POTS and fibromyalgia. (Zucci et al, 2006)
9. TAAR receptors regulate cellular cAMP accumulation via their effect on adenylyl cyclase. The rank order of potency for cAMP production is
p-tyramine> β-phenylethylamine>tryptamine>octopamine>m-tyramine>>dopamine (Zucci et al, 2006).
Thus, the energetic abnormalities observed in at least some CFS patients (I do believe it is a heterogeneous diagnosis right now) may be due to mitochondrial impairment of energy production but rather to disordered intracellular cAMP regulation (which would explain why the Stanford study did not find any mitochondrial impairment in CFS patients).
10. Recent study identified TAAR1 gene SNPs as one of several abnormal genes in fibromyalgia patients cohort. Trace amines and TAAR receptors have been shown to be involved in regulation of nociceptive (pain) pathways and locomotion in spinal cord neuronal pathways (Smith SB et al 2012).
REFERENCES:
1. Nelson DA, Tolbert MD, Singh SJ, Bost KLJ. Expression of neuronal trace amine-associated receptor (Taar) mRNAs in leukocytes. Neuroimmunol. 2007 Dec;192(1-2):21-30. Epub 2007 Sep 27.
2. Hochman S. Metabolic recruitment of spinal locomotion: intracellular neuromodulation by trace amines and their receptors. Neural Regeneration Research. 2015;10(12):1940-1942. doi:10.4103/1673-5374.169625.
3. Ju H, So H, Ha K, Park K, Lee JW, Chung CM, et al. Sustained torpidity following multi-dose administration of 3-iodothyronamine in mice. J Cell Physiol (2011) 226(4):853–8. doi:10.1002/jcp.22573
4. Pacifico R, Dewan A, Cawley D, Guo C, Bozza T. An Olfactory Subsystem that Mediates High Sensitivity Detection of Volatile Amines. Cell reports. 2012;2:76-88. doi:10.1016/j.celrep.2012.06.006.)
5. Saraiva LR, Kondoh K, Ye X, Yoon K, Hernandez M, Buck LB. Combinatorial effects of odorants on mouse behavior. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(23):E3300-E3306. doi:10.1073/pnas.1605973113.
6. Zucchi R, Accorroni A, Chiellini G. Update on 3-iodothyronamine and its neurological and metabolic actions. Frontiers in Physiology. 2014;5:402. doi:10.3389/fphys.2014.00402.
7.Miller GM. The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J. Neurochem. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101 Freely accessible. PMID 21073468.
8. Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186.
9. Maguire JJ, Davenport AP (19 July 2016). "Trace amine receptor: TA1 receptor". IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. Retrieved 22 September 2016.
10. Rogers TJ (2012). "The molecular basis for neuroimmune receptor signaling". J Neuroimmune Pharmacol. 7 (4): 722–724. doi:10.1007/s11481-012-9398-4. PMC 4011130 Freely accessible. PMID 22935971
11. Xie Z, Westmoreland SV, Bahn ME, Chen GL, Yang H, Vallender EJ, Yao WD, Madras BK, Miller GM (April 2007). "Rhesus monkey trace amine-associated receptor 1 signaling: enhancement by monoamine transporters and attenuation by the D2 autoreceptor in vitro". The Journal of Pharmacology and Experimental Therapeutics. 321 (1): 116–127. doi:10.1124/jpet.106.116863. PMID 17234900.
12. Liberles SD, Buck LB (August 2006). "A second class of chemosensory receptors in the olfactory epithelium". Nature. 442 (7103): 645–650. doi:10.1038/nature05066. PMID 16878137
13. Dinter J, Mühlhaus J, Jacobi SF, Wienchol CL, Cöster M, Meister J, Hoefig CS, Müller A, Köhrle J, Grüters A, Krude H, Mittag J, Schöneberg T, Kleinau G, Biebermann H (June 2015). "3-iodothyronamine differentially modulates α-2A-adrenergic receptor-mediated signaling". J. Mol. Endocrinol. 54 (3): 205–216. doi:10.1530/JME-15-0003
14. Sotnikova TD, Caron MG, Gainetdinov RR (August 2009). "Trace amine-associated receptors as emerging therapeutic targets". Mol. Pharmacol. 76 (2): 229–235. doi:10.1124/mol.109.055970. PMC 2713119 Freely accessible. PMID 19389919
15. Smith SB, Maixner DW, Fillingim RB, Slade G, Gracely RH, Ambrose K, Zaykin DV, Hyde C, John S, Tan K, Maixner W, Diatchenko L (February 2012). "Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia". Arthritis and Rheumatism. 64 (2): 584–593. doi:10.1002/art.33338. PMC 3237946 Freely accessible. PMID 21905019
16. Robert K. Naviaux, Jane C. Naviaux, Kefeng Li, A. Taylor Bright, William A. Alaynick, Lin Wang, Asha Baxter, Neil Nathan, Wayne Anderson and Eric Gordon. Metabolic features of chronic fatigue syndrome. PNAS 2016 September, 113 (37) E5472-E5480. https://doi.org/10.1073/pnas.1607571113
17. Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, Durkin MM, Lakhlani PP, Bonini JA, Pathirana S, Boyle N, Pu X, Kouranova E, Lichtblau H, Ochoa FY, Branchek TA, Gerald C (2001). "Trace amines: identification of a family of mammalian G protein-coupled receptors". PNAS. 98 (16): 8966–71. doi:10.1073/pnas.151105198. PMC 55357 Freely accessible. PMID 11459929
18. Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK (2001). "Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor". Mol. Pharmacol. 60 (6): 1181–8. doi:10.1124/mol.60.6.1181. PMID 11723224
19. Pei Yue, Asif-Malik Aman, Canales Juan J. Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications. Frontiers in Neuroscience 2016.
20. Cisneros IE, Ghorpade A (October 2014). "Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes". Neuropharmacology. 85: 499–507. doi:10.1016/j.neuropharm.2014.06.011. PMC 4315503 Freely accessible. PMID 24950453.
21. Hartmut H. Glossmann1 and Oliver M. D. Lutz2 Torpor: The Rise and Fall of 3-Monoiodothyronamine from Brain to Gut—From Gut to Brain?. Frontiers in Endocrinology. Review published: 31 May 2017. doi: 10.3389/fendo.2017.00118
