Frye et al.1 published a study in Translational Psychiatry that indicated that treatment with sapropterin, which is a synthetic form of tetrahydrobiopterin (BH4), improved metabolic outcomes in patients with autism spectrum disorder (ASD). They explained that BH4 is a critical co-factor for the production of precursors of many monoamine neurotransmitters, including dopamine (DA)2 and norepinephrine (NE),3 and is vital in nitric oxide (NO) production. The author of this letter has published an ecological investigation that may shed light on the existence of BH4 in ASD and why supplementation appears to ameliorate behavioral and metabolic outcomes in ASD, as shown by Frye et al.1
The increase in NO levels that is often noted in ASD may have to do with the parasympathetic dominant state that arises from chronic gestational exposure to nitrous oxide (N2O) in the environment, most especially from agricultural practices but other sources as well, as discussed elsewhere.4 This cycle may start, given that N2O, at clinically relevant doses, inhibits the human (alpha 7) nicotinic acetylcholine receptor (alpha 7 nAChR)5 and results in elevated central levels of DA and NE, as discussed previously.4 Others have found this particular nicotinic ACh receptor subtype to be altered in ASD.6, 7 Low concentrations of monoamine uptake inhibitors (that is, elevated synaptic NE) enhanced cerebral vasodilation mediated by alpha 7 nAChR,8 suggesting that elevated central NE levels may overcome central N2O-mediated inhibition of this receptor. Alpha 7 nAChR also acts as an anti-inflammatory in the periphery, and activation of the receptor prevented H2O2-mediated cell damage,9 suggesting that early gestational inhibition of alpha 7 nAChR may contribute to a higher oxidative stress baseline in ASD subjects.
Therefore, if gestational exposure to N2O perturbs, among many targets,4 alpha 7 nAChR activity, an uncoupling from eNOS may also occur,10 facilitating the production of H2O2, which can enhance cerebral endothelial ‘agonist-induced vasodilation’ induced by acetylcholine.11, 12 The cholinergic system may, therefore, have a key etiological role in a mouse model of ASD.13 This cascade is dependent upon increased superoxide dismutase and decreased catalase, which characterize oxidative stress profiles in patients with ASD.14 H2O2 has been shown to induce a long-lasting bradycardia in rats that was inhibited by catalase activity15 and stimulated BH4 synthesis in vascular endothelial cells,16 although the magnitude of alpha 7 nAChR impairment during gestational N2O exposure may impact the capacity of central stimulation in ASD patients.17 Nevertheless, higher H2O2 production (indicative of gestational N2O burden) may help to explain increased plasma levels of NO18 in ASD. Moreover, Wu et al.19 reported that GTS-21, an alpha 7 nAChR agonist, ‘inhibited the production of IFN-γ by PBMCs from patients with RA in a dose-dependent manner and reduced the levels of IFN-γ to levels similar to, or even below, those found in healthy volunteers’, suggesting that inhibition of this particular nAChR subtype may contribute to not only elevated plasma NO in ASD but also increased inflammatory markers, like IFNγ, as has been shown.18 These studies support the claim by Frye et al.1 that ‘the increase in NO metabolism seen in some individuals with ASD is associated with greater morbidity and a less favorable prognosis’.
The author has previously discussed the other physiological roles of N2O, including the inhibition of dopamine 4 receptor (DR4) activity through impairment of methionine synthase.4 The elegant studies of Yuen and Yan20 suggest that DR4 activation exerts an activity-dependent control of calcium homeostasis that then has a bi-directional impact on glutamatergic signaling in pyramidal neurons of prefrontal cortex, potentially contributing to autonomic dysregulation. Furthermore, Koyanagi et al.21 reported that the antinociceptive effect of N2O was mediated in part by dopamine receptor 2, and activation of this receptor could be expected to promote parasympathetic tone.22, 23 Therefore, disruption of these many intricate control mechanisms, perhaps through chronic gestational environmental N2O exposure, may confer a parasympathetic dominance.
The BH4 dysregulation in ASD may be a manifestation of this parasympathetic dominance to accommodate a low-grade N2O (that is, κ-opioid) dependence developed in utero. Recent studies that intimate a sympathetic dominance in ASD24, 25, 26 may actually be revealing the paradigm of opiate withdrawal in ASD subjects,27 especially given the seasonality of agricultural N2O emissions.28 Given that 3CT is a known inhibitor of tyrosine hydroxylase,29 a rate-limiting enzyme involved in catecholamine synthesis, the significant decrease in 3CT after supplementation1 may indicate the role of BH4 in the restoration of myogenic and central catecholaminergic activity, much like naltrexone,30, 31 an opioid antagonist. These contributions may help to explain the amelioration of behavioral (that is, irritability, hyperactivity) and metabolic (that is, NO) outcomes characteristic of ASD patients.
References
Frye RE, DeLatorre R, Taylor HB, Slattery J, Melnyk S, Chowdhury N et al. Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study. Transl Psychiatry 2013; 3: e237.
van Vliet D, Anjema K, Jahja R, de Groot MJ, Liemburg GB, Heiner-Fokkema MR et al. BH4 treatment in BH4-responsive PKU patients: preliminary data on blood prolactin concentrations suggest increased cerebral dopamine concentrations. Mol Genet Metab 2015; 114: 29–33.
Kapatos G, Hirayama K, Hasegawa H . Tetrahydrobiopterin turnover in cultured rat sympathetic neurons: developmental profile, pharmacologic sensitivity, and relationship to norepinephrine synthesis. J Neurochem 1992; 59: 2048–2055.
Fluegge KR, Fluegge KR . Retraction: Glyphosate use predicts ADHD hospital discharges in the Healthcare Cost and Utilization Project Net (HCUPnet): a two-way fixed-effects analysis. PLoS One 2015; 10: e0133525.
Suzuki T, Ueta K, Sugimoto M, Uchida I, Mashimo T . Nitrous oxide and xenon inhibit the human (alpha 7)5 nicotinic acetylcholine receptor expressed in Xenopus oocyte. Anesth Analg 2003; 96: 443–448.
Deutsch SI, Burket JA, Benson AD, Urbano MR . The 15q13.3 deletion syndrome: deficient α7-containing nicotinic acetylcholine receptor-mediated neurotransmission in the pathogenesis of neurodevelopmental disorders. Prog Neuropsychopharmacol Biol Psychiatry 2016; 64: 109–117.
Ray MA, Graham AJ, Lee M, Perry RH, Court JA, Perry EK . Neuronal nicotinic acetylcholine receptor subunits in autism: an immunohistochemical investigation in the thalamus. Neurobiol Dis 2005; 19: 366–377.
Long C, Chen MF, Sarwinski SJ, Chen PY, Si M, Hoffer BJ et al. Monoamine uptake inhibitors block alpha7-nAChR-mediated cerebral nitrergic neurogenic vasodilation. Am J Physiol Heart Circ Physiol 2006; 291: H202–H209.
Li DJ, Zhao T, Xin RJ, Wang YY, Fei YB, Shen FM . Activation of α7 nicotinic acetylcholine receptor protects against oxidant stress damage through reducing vascular peroxidase-1 in a JNK signaling-dependent manner in endothelial cells. Cell Physiol Biochem 2014; 33: 468–478.
Haberberger RV, Henrich M, Lips KS, Kummer W . Nicotinic receptor alpha 7-subunits are coupled to the stimulation of nitric oxide synthase in rat dorsal root ganglion neurons. Histochem Cell Biol 2003; 120: 173–181.
Yokoyama M, Hirata K . Endothelial nitric oxide synthase uncoupling: Is it a physiological mechanism of endothelium-dependent relaxation in cerebral artery? Cardiovasc Res 2007; 73: 8–9.
Drouin A, Thorin-Trescases N, Hamel E, Falck JR, Thorin E . Endothelial nitric oxide synthase activation leads to dilatory H2O2 production in mouse cerebral arteries. Cardiovasc Res 2007; 73: 73–81.
Karvat G, Kimchi T . Acetylcholine elevation relieves cognitive rigidity and social deficiency in a mouse model of autism. Neuropsychopharmacology 2014; 39: 831–840.
Zoroglu SS, Armutcu F, Ozen S, Gurel A, Sivasli E, Yetkin O et al. Increased oxidative stress and altered activities of erythrocyte free radical scavenging enzymes in autism. Eur Arch Psychiatry Clin Neurosci 2004; 254: 143–147.
Máximo Cardoso L, de Almeida Colombari DS, Vanderlei Menani J, Alves Chianca D Jr, Colombari E . Cardiovascular responses produced by central injection of hydrogen peroxide in conscious rats. Brain Res Bull 2006; 71: 37–44.
Shimizu S, Shiota K, Yamamoto S, Miyasaka Y, Ishii M, Watabe T et al. Hydrogen peroxide stimulates tetrahydrobiopterin synthesis through the induction of GTP-cyclohydrolase I and increases nitric oxide synthase activity in vascular endothelial cells. Free Radic Biol Med 2003; 34: 1343–1352.
Serova L, Sabban EL . Involvement of alpha 7 nicotinic acetylcholine receptors in gene expression of dopamine biosynthetic enzymes in rat brain. J Pharmacol Exp Ther 2002; 303: 896–903.
Sweeten TL, Posey DJ, Shankar S, McDougle CJ . High nitric oxide production in autistic disorder: a possible role for interferon-gamma. Biol Psychiatry 2004; 55: 434–437.
Wu S, Zhao H, Luo H et al. GTS-21, an α7-nicotinic acetylcholine receptor agonist, modulates Th1 differentiation in CD4+ T cells from patients with rheumatoid arthritis. Exp Ther Med 2014; 8: 557–562.
Yuen EY, Yan Z . Cellular mechanisms for dopamine D4 receptor-induced homeostatic regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. J Biol Chem 2011; 286: 24957–24965.
Koyanagi S, Himukashi S, Mukaida K, Shichino T, Fukuda K . Dopamine D2-like receptor in the nucleus accumbens is involved in the antinociceptive effect of nitrous oxide. Anesth Analg 2008; 106: 1904–1909.
Dyavanapalli J, Byrne P, Mendelowitz D . Activation of D2-like dopamine receptors inhibits GABA and glycinergic neurotransmission to pre-motor cardiac vagal neurons in the nucleus ambiguus. Neuroscience 2013; 5: 213–226.
Kaya D, Ellidokuz E, Onrat E, Ellidokuz H, Celik A, Kilit C . The effect of dopamine type-2 receptor blockade on autonomic modulation. Clin Auton Res 2003; 13: 275–280.
Schaaf RC, Benevides TW, Leiby BE, Sendecki JA . Autonomic dysregulation during sensory stimulation in children with autism spectrum disorder. J Autism Dev Disord 2015; 45: 461–472.
Ming X, Patel R, Kang V, Chokroverty S, Julu PO . Respiratory and autonomic dysfunction in children with autism spectrum disorders. Brain Dev 2015; 38: 225–232.
Anderson CJ, Colombo J, Unruh KE . Pupil and salivary indicators of autonomic dysfunction in autism spectrum disorder. Dev Psychobiol 2013; 55: 465–482.
Morgan MM, Christie MJ . Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human. Br J Pharmacol 2011; 164: 1322–1334.
Fluegge K . A reply to Wang T, Shan L, Du L, Feng J, Xu Z, Staal WG, Jia F. Serum concentration of 25-hydroxyvitamin D in autism spectrum disorder: a systematic review and meta-analysis. Eur Child Adolesc Psychiatry 2015; doi:10.1007/s00787-015-0803-4.
Chen QM, Smyth DD, McKenzie JK, Glavin GB, Gu JG, Geiger JD et al. Chlorotyrosine exerts renal effects and antagonizes renal and gastric responses to atrial natriuretic peptide. J Pharmacol Exp Ther 1994; 269: 709–716.
Baron SA, Testa FM, Gintzler AR . Simultaneous quantitation of norepinephrine, dopamine and serotonin in brain during and following chronic naltrexone administration. Brain Res 1985; 340: 192–198.
Roy A, Roy M, Deb S, Unwin G, Roy A . Are opioid antagonists effective in attenuating the core symptoms of autism spectrum conditions in children: a systematic review. J Intellect Disabil Res 2015; 59: 293–306.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no conflict of interest.
Rights and permissions
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
About this article
Cite this article
Fluegge, K. A reply to ‘Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study’. Transl Psychiatry 6, e793 (2016). https://doi.org/10.1038/tp.2016.24
Published:
Issue Date:
DOI: https://doi.org/10.1038/tp.2016.24
This article is cited by
-
The BTBR mouse model, cholinergic transmission, and environmental exposure to nitrous oxide
Psychopharmacology (2017)
-
The potential role of nitrous oxide in the etiology of autism spectrum disorder
Translational Psychiatry (2016)