Neurotoxicity Research

, Volume 19, Issue 1, pp 55–62 | Cite as

Memory Impairment Induced by Sodium Fluoride is Associated with Changes in Brain Monoamine Levels

  • Marcela Pereira
  • Patrícia A. Dombrowski
  • Estela M. Losso
  • Lea R. Chioca
  • Cláudio Da Cunha
  • Roberto AndreatiniEmail author


Previous studies suggest that sodium fluoride (NaF) can impair performance in some memory tasks, such as open-field habituation and two-way active avoidance. In the present study, we evaluated the effect of NaF intake (100 ppm in drinking water for 30 days) and its short-term (15 days) withdrawal on open-field habituation and brain monoamine level. Adult male rats were allocated to three groups: tap water (NaF 1.54 ppm) for 45 days (control group); 15 days of tap water followed by NaF for 30 days; and NaF for 30 days followed by 15 days of tap water. The results showed that NaF impairs open-field habituation and increases noradrenaline (NA) and serotonin (5-HT) in the striatum, hippocampus and neocortex. Dopamine (DA) increase was restricted to the striatum. Short-term NaF withdrawal did not reverse these NaF-induced changes, and both NaF treatments led to a mild fluorosis in rat incisors. No treatment effect was seen in body weight or fluid/water consumption. These results indicate that sodium fluoride induces memory impairment that outlasts short-term NaF withdrawal (2 weeks) and may be associated with NA and 5-HT increases in discrete brain regions.


Cognitive impairment Dopamine Memory Monoamines Open-field habituation Serotonin Sodium fluoride 







Sodium fluoride




Dihydroxyphenylacetic acid


5-Hydroxyindoleacetic acid




Homovanilic acid



This research was partially supported by Fundação Araucária. MP, RA and CC are recipient of CNPq fellowships; PAD and LRC are recipients of CAPES fellowships.


  1. Beck KD, Luine VN (1999) Food deprivation modulates chronic stress effects on object recognition in male rats: role of monoamines and amino acids. Brain Res 830:56–71CrossRefPubMedGoogle Scholar
  2. Bera I, Sabatini R, Auteri P, Flace P, Sisto G, Montagnani M, Potenza MA, Marasciulo FL, Carratu MR, Coluccia A, Borracci P, Tarullo A, Cagiano R (2007) Neurofunctional effects of developmental sodium fluoride exposure in rats. Eur Rev Med Pharmacol Sci 11(4):211–224PubMedGoogle Scholar
  3. Bhatnagar M, Rao P, Saxena A, Bhatnagar R, Meena P, Barbar S, Chouhan A, Vimal S (2006) Biochemical changes in brain and other tissues of young adult female mice from fluoride in their drinking water. Fluoride 39(4):280–284Google Scholar
  4. Boulton IC, Cooke JA, Johnson MS (1995) Fluoride accumulation and toxicity in laboratory populations of wild small mammals and white mice. J Appl Toxicol 15:423–431CrossRefPubMedGoogle Scholar
  5. Brudevold F, Bakhos Y, Aasenden R (1978) Dental fluorosis as related to the concentration of fluoride in teeth and bone. JADA 96:459–463PubMedGoogle Scholar
  6. Buhot HC, Martin S, Segu L (2000) Role of serotonin in memory impairment. Ann Med 32:210–221CrossRefPubMedGoogle Scholar
  7. Buzalaf MA, Granjeiro JM, Duarte JL, Taga ML (2002) Fluoride content of infant foods in Brazil and risk of dental fluorosis. ASDC J Dent Child 69(2):196–200, 125–126Google Scholar
  8. Buzalaf MA, de Almeida BS, Cardoso VE, Ollympio KP, de Furlani TA (2004) Total and acid soluble fluoride content of infant cereals, beverages and biscuits from Brazil. Food Addit Contam 21:210–215CrossRefPubMedGoogle Scholar
  9. Canal CE, Chang Q, Gold PE (2008) Intra-amygdala injections of CREB antisense impair inhibitory avoidance memory: role of norepinephrine and acetylcholine. Learn Mem 15:677–686CrossRefPubMedGoogle Scholar
  10. Carey RJ, Dai H, Gui J (1998) Effects of dizocilpine (MK-801) on motor activity and memory. Psychopharmacology (Berl) 137(3):241–246CrossRefGoogle Scholar
  11. Chamberlain SR, Muller U, Blackwell AD, Robbins TW, Sahakian BJ (2006) Noradrenergic modulation of working memory and emotional memory in humans. Psychopharmacology 188:397–407CrossRefPubMedGoogle Scholar
  12. Chioca LR, Raupp IM, da Cunha C, Losso EM, Andreatini R (2008) Subchronic fluoride intake induces impairment in habituation and active avoidance tasks in rats. Eur J Pharmacol 579(1–3):196–201CrossRefPubMedGoogle Scholar
  13. Chirumari K, Reddy PK (2007) Dose-dependent effects of fluoride on neurochemical milieu in the hippocampus and neocortex of rat brain. Fluoride 40(2):101–110Google Scholar
  14. Da Cunha C, Wietzikoski EC, Dombrowski P, Santos LM, Bortolanza M, Boschen SL, Miyoshi E (2009) Learning processing in the basal ganglia: a mosaic of broken mirrors. Behav Brain Res 199:156–169Google Scholar
  15. Degroot A, Salhoff C, Davis RJ, Nomikos GG (2005) Genetic deletion of CB1 receptors improves non-associative learning. Behav Brain Res 162(1):161–164CrossRefPubMedGoogle Scholar
  16. Ekambaram P, Paul V (2001) Calcium preventing locomotor behavioral and dental toxicities of fluoride by decreasing serum fluoride level in rats. Environ Toxicol Pharmacol 9:141–146CrossRefPubMedGoogle Scholar
  17. Ekambaram P, Paul V (2003) Effect of vitamin D on chronic behavioral and dental toxicities of sodium fluoride in rats. Fluoride 36:189–197Google Scholar
  18. Gevaerd MS, Miyoshi E, Silveira R, Canteras NS, Takahashi RN, da Cunha C (2001) L-Dopa restores striatal dopamine level but fails to reverse MPTP-induced memory deficits in rats. Int J Neuropsychopharmacol 4:361–370CrossRefPubMedGoogle Scholar
  19. Izquierdo I, Da Cunha C, Rosat R, Jerusalinsky D, Ferreira MBC, Medina JH (1992) Neurotransmitter receptors involved in post-training memory processing by the amygdala, medial septum, and hippocampus of the rat. Behav Neural Biol 58:16–26CrossRefPubMedGoogle Scholar
  20. Kawahara H, Yoshida M, Yokoo H, Nishi M, Tanaka M (1993) Psychological stress increases serotonin release in the rat amygdala and prefrontal cortex assessed by in vivo microdialysis. Neurosci Lett 162:81–84CrossRefPubMedGoogle Scholar
  21. Leussis MP, Bolivar VJ (2006) Habituation in rodents: a review of behavior, neurobiology, and genetics. Neurosci Biobehav Rev 30:1045–1064CrossRefPubMedGoogle Scholar
  22. Levy SM (1994) Review of fluoride exposures and ingestion. Community Dent Oral Epidemiol 22(3):173–180CrossRefPubMedGoogle Scholar
  23. Long YG, Wang YN, Chen J, Jiang SF, Nordberg A, Guana ZZ (2002) Chronic fluoride toxicity decreases the number of nicotinic acetylcholine receptors in rat brain. Neurotoxicol Teratol 24:751–757CrossRefPubMedGoogle Scholar
  24. McGaugh JL (2004) The amygdale modulates the consolidation of memories of emotionally arousing experiences. Annu Rev Neurosci 27:1–28CrossRefPubMedGoogle Scholar
  25. McGaugh JL, Roozendaal B (2009) Drug enhancement of memory consolidation: historical perspective and neurobiological implications. Psychopharmacology 202:3–14CrossRefPubMedGoogle Scholar
  26. Mello e Souza T, Rohden A, Meinhardt M, Goncalves CA, Quillfeldt JA (2000) S100B infusion into the rat hippocampus facilitates memory for the inhibitory avoidance task but not for the open-field habituation. Physiol Behav 71:29–33CrossRefPubMedGoogle Scholar
  27. Mendl M (1999) Performing under pressure: stress and cognitive function. Appl Anim Behav Sci 65:221–244CrossRefGoogle Scholar
  28. Pedrazza EL, Riboldi GP, Pereira GS, Izquierdo I, Bonan CD (2007) Habituation to an open field alters ecto-nucleotidase activities in rat hippocampal synaptosomes. Neurosci Lett 413(1):21–24CrossRefPubMedGoogle Scholar
  29. Perez-Garcia G, Meneses A (2008) Memory formation, amnesia, improved memory and reversed amnesia: 5-HT role. Behav Brain Res 195:17–29CrossRefPubMedGoogle Scholar
  30. Roozendaal B, Castello NA, Vedana G, Barsegyan A, McGaugh JL (2008) Noradrenergic activation of the basolateral amygdala modulates consolidation of object recognition memory. Neurobiol Learn Mem 90:576–579CrossRefPubMedGoogle Scholar
  31. Sarri E, Claro E (1999) Fluoride-induced depletion of polyphosphoinositides in rat brain cortical slices: a rationale for the inhibitory effects on phospholipase C. Int J Dev Neurosci 17:357–367CrossRefPubMedGoogle Scholar
  32. Segovia G, Del Arco A, de Blas M, Garrido P, Mora F (2008) Effects of an enriched environment on the release of dopamine in the prefrontal cortex produced by stress and on working memory during aging in the awake rat. Behav Brain Res 187:304–311CrossRefPubMedGoogle Scholar
  33. Shan KR, Qi XL, Long YG, Nordberg A, Guan ZZ (2004) Decreased nicotinic receptors in PC12 cells and rat brains influenced by fluoride toxicity: a mechanism relating to a damage at the level in post-transcription of the receptor genes. Toxicology 200(2–3):169–177CrossRefPubMedGoogle Scholar
  34. Smith CE, Nanci A, Denbesten PK (1993) Effects of chronic fluoride exposure on morphometric parameters defining the stages of amelogenesis and ameloblast modulation in rat incisors. Anat Rec 237:243–258CrossRefPubMedGoogle Scholar
  35. Spittle B (1994) Psycopharmacology of fluoride: a review. Int Clin Psychopharmacol 9:79–82CrossRefPubMedGoogle Scholar
  36. Thiel CM, Huston JP, Schwarting RKW (1998) Hippocampal acetylcholine and habituation learning. Neuroscience 4:1253–1262CrossRefGoogle Scholar
  37. Tsunoda M, Aizawa Y, Nakano K, Liu Y, Horiuchi T, Itai K, Tsunoda H (2005) Changes in fluoride levels in the liver, kidney, and brain and in neurotransmitters of mice after subacute administration of fluoride. Fluoride 38(4):284–292Google Scholar
  38. Vianna MR, Alonso M, Viola H, Quevedo J, de Paris F, Furman M, de Stein ML, Medina JH, Izquierdo I (2000) Role of hippocampal signaling pathways in long-term memory formation of a nonassociative learning task in the rat. Learn Mem 7(5):333–340CrossRefPubMedGoogle Scholar
  39. Wang J, Ge Y, Ning H, Wang S (2004) Effects of high fluoride and low iodine on biochemical indexes of the brain and learning-memory of offspring rats. Fluoride 37:201–208Google Scholar
  40. Watt MJ, Burke AR, Renner KJ, Forster GL (2009) Adolescent male rats exposed to social defeat exhibit altered anxiety behavior and limbic monoamines as adults. Behav Neurosci 123:564–576CrossRefPubMedGoogle Scholar
  41. Wu C, Gu X, Ge Y, Zhang J, Wang J (2006) Effects of high fluoride and arsenic on brain biochemical indexes and learning-memory in rats. Fluoride 39(4):274–279Google Scholar
  42. Yuan SD, Xie QW, Lu FY (1993) Changes of serotonin content and turnover rate in hypothalamus of female rat during fluorosis. Fluoride 26(1):57–60Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Marcela Pereira
    • 1
  • Patrícia A. Dombrowski
    • 1
  • Estela M. Losso
    • 2
  • Lea R. Chioca
    • 1
  • Cláudio Da Cunha
    • 1
  • Roberto Andreatini
    • 1
    Email author
  1. 1.Laboratório de Fisiologia e Farmacologia do Sistema Nervoso Central, Departamento de Farmacologia, Setor de Ciências BiológicasUniversidade Federal do Paraná, Centro PolitécnicoCuritibaBrazil
  2. 2.Health Division, PedodonticsUniversidade PositivoCuritibaBrazil

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