Abstract
Fluoride exposure caused anxiety- and depression-like behavior in mice. Meanwhile, exercise contributes to relieve anxiety and depression. However, the effects of exercise on anxiety- and depression-like behavior in fluorosis mice remain unclear. In the current study, thirty-six Institute of Cancer Research (ICR) female mice were randomly assigned to four groups: control group (C, gavage with distilled water); exercise group (E, gavage with distilled water and treadmill exercise (speed, 10 m/min; time, 30 min/day)); fluoride group (F, gavage with 24 mg/kg sodium fluoride (NaF)); and exercise plus fluoride group (EF, gavage with 24 mg/kg NaF and treadmill exercise). All treatments lasted for 8 weeks. A number of entries into and time spent in the open zone in the elevated zero maze (EZM), resting time in the tail suspension test (TST) and levels of serotonin (5-HT) and gamma-aminobutyric acid (GABA), were significantly altered in F when compared to C. Meanwhile, the anxiety-like behavior in the EZM and the depression-like behavior in the TST were significantly improved in EF when compared to group F. Exercise significantly enhanced fluoride-induced low GABA level, with less effect on the concentration of 5-HT. Moreover, the mRNA and protein expressions of GABA synthesis and transport-related proteins of glutamic acid decarboxylase (GAD) 65 and GAD67 and vesicular GABA transporter (VGAT) were all strikingly decreased in F, while those in EF were increased. In conclusion, exercise ameliorates anxiety- and depression-like behavior in fluorosis mice through increasing the expressions of GABA synthesis and transport-related proteins, rather than 5-HT system.
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All data generated or analyzed during this study are included in the published article and its supplementary information files. The raw data of the paper are available upon request from the corresponding author.
References
Ten Cate JM, Buzalaf MAR (2019) Fluoride mode of action: once there was an observant dentist. J Dent Res 98:725–730
Dec K, Łukomska A, Maciejewska D, Jakubczyk K, Baranowska-Bosiacka I, Chlubek D, Wasik A, Gutowska I (2017) The influence of fluorine on the disturbances of homeostasis in the central nervous system. Biol Trace Elem Res 177:224–234
Buzalaf MAR (2018) Review of fluoride intake and appropriateness of current guidelines. Adv Dent Res 29:157–166
Sun Z, Niu R, Wang B, Jiao Z, Wang J, Zhang J, Wang S, Wang J (2011) Fluoride-induced apoptosis and gene expression profiling in mice sperm in vivo. Arch Toxicol 85:1441–1452
Liu J, Wang HW, Lin L, Miao CY, Zhang Y, Zhou BH (2019) Intestinal barrier damage involved in intestinal microflora changes in fluoride-induced mice. Chemosphere 234:409–418
Ma Y, Niu R, Sun Z, Wang J, Luo G, Zhang J, Wang J (2012) Inflammatory responses induced by fluoride and arsenic at toxic concentration in rabbit aorta. Arch Toxicol 86:849–856
Yan X, Dong N, Hao X, Xing Y, Tian X, Feng J, Xie J, Lv Y, Wei C, Gao Y, Qiu Y, Wang T (2019) Comparative transcriptomics reveals the role of the toll-like receptor signaling pathway in fluoride-induced cardiotoxicity. J Agric Food Chem 67:5033–5042
Niu R, Chen H, Manthari RK, Sun Z, Wang J, Zhang J, Wang J (2018) Effects of fluoride on synapse morphology and myelin damage in mouse hippocampus. Chemosphere 194:628–633
Zhao Q, Niu Q, Chen JW, Xia T, Zhou GY, Li P, Dong LX, Xu CY, Tian ZY, Luo C et al (2019) Roles of mitochondrial fission inhibition in developmental fluoride neurotoxicity: mechanisms of action in vitro and associations with cognition in rats and children. Arch Toxicol 93:709–726
Yang L, Jin PY, Wang XY, Zhou Q, Lin XL, Xi SH (2018) Fluoride activates microglia, secretes inflammatory factors and influences synaptic neuron plasticity in the hippocampus of rats. Neurotoxicology 69:108–120
Li X, Zhang J, Niu R, Manthari RK, Yang K, Wang J (2019) Effect of fluoride exposure on anxiety- and depression-like behavior in mouse. Chemosphere 215:454–460
Agalakova NI, Nadei OV (2020) Inorganic fluoride and functions of brain. Crit Rev Toxicol 50:28–46
Liu F, Ma J, Zhang H, Liu P, Liu YP, Xing B, Dang YH (2014) Fluoride exposure during development affects both cognition and emotion in mice. Physiol Behav 124:1–7
Zachariassen KE, Flaten TP (2009) Is fluoride-induced hyperthyroidism a cause of psychosis among East African immigrants to Scandinavia? Med. Hypotheses 72:501–503
Ayuso-Mateos JL, Vazquez-Barquero JL, Dowrick C, Lehtinen V, Dalgard OS, Casey P, Wilkinson C, Lasa L, Page H, Dunn G et al (2001) Depressive disorders in Europe: prevalence figures from the ODIN study. Br J Psychiatry 179:308–316
Zhang M, Liu Y, Zhao M, Tang W, Wang X, Dong Z, Yu S (2017) Depression and anxiety behaviour in a rat model of chronic migraine. J Headache Pain 18:27
Chang C, Guo H, Tsai W, Yang K, Lin L, Cheng T, Chuu J (2015) Subchronic arsenic exposure induces anxiety-like behaviors in normal mice and enhances depression-like behaviors in the chemically induced mouse model of depression. Biomed Res Int 2015:159015
Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT (2001) Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 50:260–265
Richards EM, Mathews DC, Luckenbaugh DA, Ionescu DF, Machado-Vieira R, Niciu MJ, Duncan WC, Nolan NM, Franco-Chaves JA, Hudzik T, Maciag C, Li S, Cross A, Smith MA, Zarate CA Jr (2016) A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression. Psychopharmacology 233:1119–1130
Grace AA (2016) Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci 17:524–532
Gross C, Zhuang X, Stark K, Ramboz S, Oosting R, Kirby L, Santarelli L, Beck S, Hen R (2002) Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416:396–400
Luscher B, Fuchs T (2015) GABAergic control of depression-related brain states. Adv Pharmacol 73:97–144
Reddy YP, Tiwari S, Tomar LK, Desai N, Sharma VK (2020) Fluoride-induced expression of neuroinflammatory markers and neurophysiological regulation in the brain of wistar rat model. Biol Trace Elem Res. https://doi.org/10.1007/s12011-020-02362-x
Kaur T, Bijarnia RK, Nehru B (2009) Effect of concurrent chronic exposure of fluoride and aluminum on rat brain. Drug Chem Toxicol 32:215–221
Pal S, Sarkar C (2014) Protective effect of resveratrol on fluoride induced alteration in protein and nucleic acid metabolism, DNA damage and biogenic amines in rat brain. Environ Toxicol Pharmacol 38:684–699
Guth S, Hüser S, Roth A, Degen G, Diel P, Edlund K, Eisenbrand G, Engel KH, Epe B, Grune T, Heinz V, Henle T, Humpf HU, Jäger H, Joost HG, Kulling SE, Lampen A, Mally A, Marchan R, Marko D, Mühle E, Nitsche MA, Röhrdanz E, Stadler R, van Thriel C, Vieths S, Vogel RF, Wascher E, Watzl C, Nöthlings U, Hengstler JG (2020) Toxicity of fluoride: critical evaluation of evidence for human developmental neurotoxicity in epidemiological studies, animal experiments and in vitro analyses. Arch Toxicol 94:1375–1415
Lapmanee S, Charoenphandhu J, Teerapornpuntakit J, Krishnamra N, Charoenphandhu N (2017) Agomelatine, venlafaxine, and running exercise effectively prevent anxiety- and depression-like behaviors and memory impairment in restraint stressed rats. PLoS One 12:e0187671
Morgan JA, Singhal G, Corrigan F, Jaehne EJ, Jawahar MC, Baune BT (2018) The effects of aerobic exercise on depression-like, anxiety-like, and cognition-like behaviours over the healthy adult lifespan of C57BL/6 mice. Behav Brain Res 337:193–203
Cassilhas RC, Tufik S, de Mello MT (2016) Physical exercise, neuroplasticity, spatial learning and memory. Cell Mol Life Sci 73:975–983
Bloor CM (2005) Angiogenesis during exercise and training. Angiogenesis 8:263–271
D'Ascola A, Bruschetta G, Zanghì G, Campo S, Medica P, Campana S, Ferlazzo G, Gibbs BF, Ferlazzo AM (2018) Changes in plasma 5-HT levels and equine leukocyte SERT expression in response to treadmill exercise. Res Vet Sci 118:184–190
Yuan TF, Paes F, Arias-Carrión O, Ferreira Rocha NB, de Sá Filho AS, Machado S (2015) Neural mechanisms of exercise: anti-depression, neurogenesis, and serotonin signaling. CNS Neurol Disord Drug Targets 14:1307–1311
Maddock RJ, Casazza GA, Fernandez DH, Maddock MI (2016) Acute modulation of cortical glutamate and GABA content by physical activity. J Neurosci 36:2449–2457
Shepherd JK, Grewal SS, Fletcher A, Bill DJ, Dourish CT (1994) Behavioural and pharmacological characterisation of the elevated "zero-maze" as an animal model of anxiety. Psychopharmacology 116:56–64
Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370
Murrough JW, Yaqubi S, Sayed S, Charney DS (2015) Emerging drugs for the treatment of anxiety. Expert Opin Emerg Drugs 20:393–406
Baruch N, Burgess J, Pillai M, Allan CL (2019) Treatment for depression comorbid with dementia. Evid Based Ment Health 22:167–171
Otto MW, Tuby KS, Gould RA, McLean RY, Pollack MH (2001) An effect-size analysis of the relative efficacy and tolerability of serotonin selective reuptake inhibitors for panic disorder. Am J Psychiatry 158:1989–1992
Peng GJ, Tian JS, Gao XX, Zhou YZ, Qin XM (2015) Research on the pathological mechanism and drug treatment mechanism of depression. Curr Neuropharmacol 13:514–523
Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE (2013) Exercise for depression. Cochrane Database Syst Rev (9):CD004366
Segura-Aguilar J, Paris I, Muñoz P, Ferrari E, Zecca L, Zucca FA (2014) Protective and toxic roles of dopamine in Parkinson's disease. J Neurochem 129:898–915
Gu Z, Chu L, Han Y (2019) Therapeutic effect of resveratrol on mice with depression. Exp Ther Med 17:3061–3064
Borroto-Escuela DO, Narváez M, Ambrogini P, Ferraro L, Brito I, Romero-Fernandez W, Andrade-Talavera Y, Flores-Burgess A, Millon C, Gago B et al (2018) Receptor-receptor interactions in multiple 5-HT1A heteroreceptor complexes in raphe-hippocampal 5-HT transmission and their relevance for depression and its treatment. Molecules 23:1341
Li X, Fan Y, Xiao S, Peng S, Dong X, Zheng X, Liu CC, Li H, Xiao Z (2015) Decreased platelet 5-hydroxytryptamin (5-HT) levels: a response to antidepressants. J Affect Disord 187:84–90
Gabbay V, Mao X, Klein RG, Ely BA, Babb JS, Panzer AM, Alonso CM, Shungu DC (2012) Anterior cingulate cortex gamma-aminobutyric acid in depressed adolescents: relationship to anhedonia. Arch Gen Psychiatry 69:139–149
Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J, Drevets WC (2007) Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry 64:193–200
Davis JM, Bailey SP (1997) Possible mechanisms of central nervous system fatigue during exercise. Med Sci Sports Exerc 29:45–57
Chaouloff F, Laude D, Elghozi JL (1989) Physical exercise: evidence for differential consequences of tryptophan on 5-HT synthesis and metabolism in central serotonergic cell bodies and terminals. J Neural Transm 78:121–130
Songtachalert T, Roomruangwong C, Carvalho AF, Bourin M, Maes M (2018) Anxiety disorders: sex differences in serotonin and tryptophan metabolism. Curr Top Med Chem 18:1704–1715
MacKenzie G, Maguire J (2014) The role of ovarian hormone-derived neurosteroids on the regulation of GABAA receptors in affective disorders. Psychopharmacology 231:3333–3342
Gressier F, Calati R, Serretti A (2016) 5-HTTLPR and gender differences in affective disorders: a systematic review. J Affect Disord 190:193–207
Lee SE, Lee Y, Lee GH (2019) The regulation of glutamic acid decarboxylases in GABA neurotransmission in the brain. Arch Pharm Res 42:1031–1039
Stork O, Ji FY, Kaneko K, Stork S, Yoshinobu Y, Moriya T, Shibata S, Obata K (2000) Postnatal development of a GABA deficit and disturbance of neural functions in mice lacking GAD65. Brain Res 865:45–58
Lazarus MS, Krishnan K, Huang ZJ (2015) GAD67 deficiency in parvalbumin interneurons produces deficits in inhibitory transmission and network disinhibition in mouse prefrontal cortex. Cereb Cortex 25:1290–1296
Lau CG, Murthy VN (2012) Activity-dependent regulation of inhibition via GAD67. J Neurosci 32:8521–8531
Qi J, Kim M, Sanchez R, Ziaee SM, Kohtz JD, Koh S (2018) Enhanced susceptibility to stress and seizures in GAD65 deficient mice. PLoS One 13:e0191794
Mitchell AC, Jiang Y, Peter C, Akbarian S (2015) Transcriptional regulation of GAD1 GABA synthesis gene in the prefrontal cortex of subjects with schizophrenia. Schizophr Res 167:28–34
Fogaca MV, Duman RS (2019) Cortical GABAergic dysfunction in stress and depression: New insights for therapeutic interventions. Front Cell Neurosci 13:87
Müller I, Obata K, Richter-Levin G, Stork O (2014) GAD65 haplodeficiency conveys resilience in animal models of stress-induced psychopathology. Front Behav Neurosci 8:265
Schoenfeld TJ, Rada P, Pieruzzini PR, Hsueh B, Gould E (2013) Physical exercise prevents stress-induced activation of granule neurons and enhances local inhibitory mechanisms in the dentate gyrus. J Neurosci 33:7770–7777
Lim BV, Shin MS, Lee JM, Seo JH (2015) Treadmill exercise prevents GABAergic neuronal loss with suppression of neuronal activation in the pilocarpine-induced epileptic rats. J Exerc Rehabil 11:80–86
Ferreira-Junior NC, Ruggeri A, Silva SD Jr, Zampieri TT, Ceroni A, Michelini LC (2019) Exercise training increases GAD65 expression, restores the depressed GABAA receptor function within the PVN and reduces sympathetic modulation in hypertension. Physiol Rep 7:e14107
Funding
This work was supported by Shanxi Province Innovation Project for Graduates Students (Grant 2020SY201), Shanxi Scholarship Council of China (HGKY2019042), and the Program for the Top Young Innovative Talents of Shanxi Agricultural University (TYIT201408).
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Cao, Q., Wang, J., Hao, Y. et al. Exercise Ameliorates Fluoride-induced Anxiety- and Depression-like Behavior in Mice: Role of GABA. Biol Trace Elem Res 200, 678–688 (2022). https://doi.org/10.1007/s12011-021-02678-2
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DOI: https://doi.org/10.1007/s12011-021-02678-2