Symptom's Associated with Abnormal GABA Levels

From brainmatrix

Gamma-aminobutyric acid (GABA) plays a major role in neuronal inhibition. It occurs naturally in several foods, but it is found in higher levels in fermented food products.[1] In Japan, it is used deliberately as a functional food ingredient for health benefits. Research on the safety of using GABA as a supplement has shown that taking 18 grams per day for 4 days or 120 mg per day for 12 weeks does not produce adverse events.[2] Some studies have shown that a moderate drop in blood pressure has occurred with GABA intake. The ubiquity of GABA within the central nervous system makes it difficult to delineate its specific effects.

See Paredes and Agmo for deeper information on most of the following.21

Affective Disorders and Mood[edit]

Anxiety. GABA has a clear role in fear and anxiety disorders.3–6 GABA administration has been shown to reduce anxiety and worry and to induce relaxation in humans.1,7 At the same time, negative modulators of GABA receptors are known to have anxiogenic-like effects.4 The specific mechanism by which GABA mediates fear appears to be gender dependent.8

One way GABA may impact anxiety is via its impact on fear memory.9 Drugs that facilitate the transmission of GABA have been shown to interrupt fear memory formation and storage.9

Depression. GABA appears to play a role in depression.4,10–12 The GABA hypothesis of depression posits that modulators of the α2/α3 GABAA receptor may be valuable antidepressants.5 Reduced GABAergic functioning is generally associated with depression, and thus antidepressants that leverage the GABA system aim to increase GABA.4

Mood. Emrich first postulated a role for GABA in mood in 1980.13 GABA has since been shown to play a role in mood and to be capable of stabilizing mood.1,4,14 For instance, sodium valproate, which blocks GABA transmission, is used to treat bipolar disorder.15

Stress. Stress is known to deplete GABA and requires replacement of the metabolite through, for instance, enriched functional foods.1 Thus unsurprisingly, the administration of GABA is known to reduce stress.3

Psychosis. Psychosis may be influenced by GABA functioning.16

Autism. GABA inhibition is implicated in autism spectrum disorder as well as other developmental disorders.17

Cognition[edit]

Cognition. Altered GABA transmission is linked to cognitive functions.18 Specifically, whereas lowered GABA is associated with reduced cognitive control, GABA has been shown to enhance memory.3,19

Attention. GABA is implicated in scattered attention and difficulty in focusing on one task.17,19 For instance, altered levels of GABA have been observed in children with attention-deficit/hyperactivity disorder, ADHD, potentially owing to its impact on dopaminergic transmission in the striatum.19,20 Specifically, children with ADHD have lower GABA concentrations than those without the disorder.17

Behavior[edit]

Different GABA receptor subtypes have distinct impacts on behavior.21

Impulsivity. GABA is implicated in self-control and behavioral inhibition.19,22,23 Low GABA levels are associated with increased impulsivity, as well as impaired response inhibition.19

GABA levels have been shown to be lower in patient groups – like those with Prader-Willi syndrome – who display significant behavioral disturbances that may be related to lack of self-control and a tendency toward impulsivity.24 These behavioral problems include temper outbursts, social interaction difficulties, skin-picking, and a tendency to be self-absorbed.

Compulsivity. GABA levels in the orbitofrontal cortex of those with obsessive-compulsive disorder (OCD) is significantly lower than what is observed in those without the disorder.25

Sleep. It is well established that GABA enhances sleep and is involved in circadian rhythm.3 It is also implicated in insomnia and other sleep disturbances.

Physical Symptoms[edit]

Pain. GABA is implicated in pain, though activation of GABA can enhance or minimize pain, depending on the location of activation.3,7,26,27

However, generalized activation of GABA appears to reduce the overall response to painful stimuli.7,26 As such, therapeutic strategies aimed at leveraging the GABA system are developed to increase GABA synthesis.27 Agonists for both GABAA and GABAB receptors act as analgesics.21,28

Headaches. Headaches are one of the manifestations related to changes in GABA transmission that involves pain.29,30

Immunity. GABA administration may bolster immunity through its anxiolytic effects.1 It may also have antimicrobial and anti-allergy effects.31 Additionally, GABA appears to have anti-inflammatory properties that may provide health benefits.2,31

Cardiovascular function. GABA regulates cardiovascular functions and can impact heart rate.1,32–36 Research into its ability to combat hypertension is ongoing.2,31

Respiration. GABA is found not only in the brain but also in peripheral tissues and in other locations, such as the lungs. Baclofen (a GABAB agonist) has been shown preclinically to inhibit neurally mediated bronchoconstriction.37

Motility. Administration of GABA leads to hypomotility, reduced ambulatory activity, and sedation.21 On the other hand, reduced GABA in the motor cortex is associated with muscle rigidity and spasms, as seen in stiff-person syndrome.38,39 

Cancer. GABA may provide antioxidant effects and has been shown to contribute to inhibiting cancer cell metastasis.1,2,31,16,21

Renal function. GABA appears to play a role in renal function.1,12

References[edit]

1. Abdou AM, Higashiguchi S, Horie K, Kim M, Hatta H, Yokogoshi H. Relaxation and immunity enhancement effects of gamma-aminobutyric acid (GABA) administration in humans. Biofactors. 2006;26(3):201-208. doi:10.1002/BIOF.5520260305

2. Oketch-Rabah HA, Madden EF, Roe AL, Betz JM. United States Pharmacopeia (USP) safety review of gamma-aminobutyric acid (GABA). Nutrients. 2021;13(8). doi:10.3390/NU13082742

3. Hepsomali P, Groeger JA, Nishihira J, Scholey A. Effects of oral gamma-aminobutyric acid (GABA) administration on stress and sleep in humans: A systematic review. Frontiers in Neuroscience. 2020;14:923. doi:10.3389/FNINS.2020.00923

4. Kalueff A v., Nutt DJ. Role of GABA in anxiety and depression. Depress Anxiety. 2007;24(7):495-517. doi:10.1002/DA.20262

5. Möhler H. The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology. 2012;62(1):42-53. doi:10.1016/J.NEUROPHARM.2011.08.040

6. Nuss P. Anxiety disorders and GABA neurotransmission: a disturbance of modulation. Neuropsychiatric Disease and Treatment. 2015;11:165. doi:10.2147/NDT.S58841

7. Jasmin L, Wu M v., Ohara PT. GABA puts a stop to pain. Curr Drug Targets CNS Neurol Disord. 2004;3(6):487-505. doi:10.2174/1568007043336716

8. Adkins JM, Lynch J, Gray M, Jasnow AM. Presynaptic GABA B receptor inhibition sex dependently enhances fear extinction and attenuates fear renewal. Psychopharmacology (Berl). 2021;238(8):2059-2071. doi:10.1007/S00213-021-05831-W

9. Makkar SR, Zhang SQ, Cranney J. Behavioral and Neural Analysis of GABA in the Acquisition, Consolidation, Reconsolidation, and Extinction of Fear Memory. Neuropsychopharmacology. 2010;35(8):1625. doi:10.1038/NPP.2010.53

10. Brambilla P, Perez J, Barale F, Schettini G, Soares JC. GABAergic dysfunction in mood disorders. Mol Psychiatry. 2003;8(8):721-737. doi:10.1038/SJ.MP.4001362

11. Leung JWC, Xue H. GABAergic functions and depression: from classical therapies to herbal medicine. Curr Drug Targets CNS Neurol Disord. 2003;2(6):363-374. doi:10.2174/1568007033482715

12. Tunnicliff G, Malatynska E. Central GABAergic systems and depressive illness. Neurochem Res. 2003;28(6):965-976. doi:10.1023/A:1023287729363

13. Emrich HM, v. Zerssen D, Kissling W, Möller HJ, Windorfer A. Effect of sodium valproate on mania. The GABA-hypothesis of affective disorders. Archiv fur Psychiatrie und Nervenkrankheiten. 1980;229(1):1-16. doi:10.1007/BF00343800

14. Krystal JH, Sanacora G, Blumberg H, et al. Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol Psychiatry. 2002;7 Suppl 1:S71-S80. doi:10.1038/SJ.MP.4001021

15. Sekhon S, Gupta V. Mood disorder. StatPearls. Published online November 20, 2021. Accessed April 17, 2022. https://www.ncbi.nlm.nih.gov/books/NBK558911/

16. Kegeles LS. Brain GABA function and psychosis. Am J Psychiatry. 2016;173(5):448-449. doi:10.1176/APPI.AJP.2016.16020165

17. Edden RAE, Crocetti D, Zhu H, Gilbert DL, Mostofsky SH. Reduced GABA concentration in attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2012;69(7):750-753. doi:10.1001/ARCHGENPSYCHIATRY.2011.2280

18. Prévot T, Sibille E. Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders. Mol Psychiatry. 2021;26(1):151-167. doi:10.1038/S41380-020-0727-3

19. Bollmann S, Ghisleni C, Poil SS, et al. Developmental changes in gamma-aminobutyric acid levels in attention-deficit/hyperactivity disorder. Transl Psychiatry. 2015;5(6). doi:10.1038/TP.2015.79

20. Tritsch NX, Ding JB, Sabatini BL. Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature. 2012;490(7419):262-266. doi:10.1038/NATURE11466

21. Paredes RG, Ågmo A. GABA and behavior: the role of receptor subtypes. Neurosci Biobehav Rev. 1992;16(2):145-170. doi:10.1016/S0149-7634(05)80177-0

22. Silveri MM, Sneider JT, Crowley DJ, et al. Frontal lobe γ-aminobutyric acid levels during adolescence: associations with impulsivity and response inhibition. Biol Psychiatry. 2013;74(4):296-304. doi:10.1016/J.BIOPSYCH.2013.01.033

23. Boy F, Evans CJ, Edden RAE, et al. Dorsolateral prefrontal γ-aminobutyric acid in men predicts individual differences in rash impulsivity. Biol Psychiatry. 2011;70(9):866-872. doi:10.1016/J.BIOPSYCH.2011.05.030

24. Rice LJ, Lagopoulos J, Brammer M, Einfeld SL. Reduced gamma-aminobutyric acid is associated with emotional and behavioral problems in Prader-Willi syndrome. Am J Med Genet B Neuropsychiatr Genet. 2016;171(8):1041-1048. doi:10.1002/AJMG.B.32472

25. Zhang G, Zhang K, Cui W, Hong Y, Zhang Z. The effect of early mobilization for critical ill patients requiring mechanical ventilation: a systematic review and meta-analysis. Journal of Emergency and Critical Care Medicine. 2018;2:9-9. doi:10.21037/JECCM.2018.01.04

26. Enna SJ, McCarson KE. The role of GABA in the mediation and perception of pain. Adv Pharmacol. 2006;54:1-27. doi:10.1016/S1054-3589(06)54001-3

27. Gwak YS, Hulsebosch CE. GABA and Central Neuropathic Pain following Spinal Cord Injury. Neuropharmacology. 2011;60(5):799. doi:10.1016/J.NEUROPHARM.2010.12.030

28. Sawynok J. GABAergic mechanisms of analgesia: an update. Pharmacol Biochem Behav. 1987;26(2):463-474. doi:10.1016/0091-3057(87)90148-1

29. Farmakidis C, Inan S, Milstein M, Herskovitz S. Headache and pain in Guillain-Barré Syndrome. Curr Pain Headache Rep. 2015;19(8). doi:10.1007/S11916-015-0508-X

30. Cuadrado ML, López-Ruiz P, Guerrero ÁL. Nummular headache: an update and future prospects. Expert Rev Neurother. 2018;18(1):9-19. doi:10.1080/14737175.2018.1401925

31. Ngo DH, Vo TS, Torres MD, Falqué López E. An Updated Review on Pharmaceutical Properties of Gamma-Aminobutyric Acid. Molecules 2019, Vol 24, Page 2678. 2019;24(15):2678. doi:10.3390/MOLECULES24152678

32. Bentzen BH, Grunnet M. Central and peripheral GABAA receptor regulation of the heart rate depends on the conscious state of the animal. Advances in Pharmacological Sciences. 2011;2011. doi:10.1155/2011/578273

33. Zhang J, Mifflin SW. Receptor subtype specific effects of GABA agonists on neurons receiving aortic depressor nerve inputs within the nucleus of the solitary tract. J Auton Nerv Syst. 1998;73(2-3):170-181. doi:10.1016/S0165-1838(98)00140-4

34. Blood pressure and hypothalamic NA-GABA interaction in spontaneously hypertensive rats (SHR): effect of administration DSP-4. | Semantic Scholar. Accessed July 10, 2022. https://www.semanticscholar.org/paper/Blood-pressure-and-hypothalamic-NA-GABA-interaction-Go%C5%BAli%C5%84ska-Czy%C5%BCewska-Szafran/a43ebfa68c5dc418f97d34205c5c50b89d8840c5

35. Gordon FJ, Sved AF. Neurotransmitters in central cardiovascular regulation: Glutamate and gaba. Clinical and Experimental Pharmacology and Physiology. 2002;29(5-6):522-524. doi:10.1046/J.1440-1681.2002.03666.X

36. Shizuka F, Kido Y, Nakazawa T, et al. Antihypertensive effect of gamma-amino butyric acid enriched soy products in spontaneously hypertensive rats. Biofactors. 2004;22(1-4):165-167. doi:10.1002/BIOF.5520220133

37. Dicpinigaitis P v., Nierman DM, Miller A. Baclofen-induced bronchoconstriction. Ann Pharmacother. 1993;27(7-8):883-884. doi:10.1177/106002809302700713

38. Levy LM, Dalakas MC, Floeter MK. The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of gamma-aminobutyric acid. Ann Intern Med. 1999;131(7):522-530. doi:10.7326/0003-4819-131-7-199910050-00008

39. Devlin CL, Schlosser W. Gamma-aminobutyric acid modulation of acetylcholine-induced contractions of a smooth muscle from an echinoderm (Sclerodactyla briareus). Invert Neurosci. 1999;4(1):1-8. doi:10.1007/PL00022363

  1. Abdou, A. M., Higashiguchi, S., Horie, K., Kim, M., Hatta, H., & Yokogoshi, H. (2006). Relaxation and immunity enhancement effects of γ‐aminobutyric acid (GABA) administration in humans. Biofactors, 26(3), 201-208.
  2. Oketch-Rabah, H. A., Madden, E. F., Roe, A. L., & Betz, J. M. (2021). United States Pharmacopeia (USP) safety review of gamma-aminobutyric acid (GABA). Nutrients, 13(8), 2742.