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Alteration in plasma corticosterone levels following long term oral administration of lead produces depression like symptoms in rats

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Abstract

Lead toxicity is known to induce a broad range of physiological, biochemical and behavioral dysfunctions that may result in adverse effects on several organs, including the central nervous system. Long-term exposure to low levels of lead (Pb2+) has been shown to produce behavioral deficits in rodents and humans by affecting hypothalamic-pituitary-adrenal (HPA) axis. These deficits are thought to be associated with altered brain monoamine neurotransmission and due to changes in glucocorticoids levels. This study was designed to investigate the effects of Pb2+exposure on growth rate, locomotor activity, anxiety, depression, plasma corticosterone and brain serotonin (5-HT) levels in rats. Rats were exposed to lead in drinking water (500 ppm; lead acetate) for 5 weeks. The assessment of depression was done using the forced swimming test (FST). Estimation of brain 5-HT was determined by high-performance liquid chromatography with electrochemical detection. Plasma corticosterone was determined by spectroflourimetric method. The present study showed that long term exposure to Pb2+ significantly decreased the food intake followed by the decrease in growth rate in Pb2+exposed rats as compared to control group. No significant changes in open field activity were observed following Pb2+exposure while significant increase in anxiogenic effect was observed. Increased plasma corticosterone and decreased 5-HT levels were exhibited by Pb2+exposed rats as compared to controls. A significant increase in depressive like symptoms was exhibited by Pb2+exposed rats as compared to control rats. The results are discussed in the context of Pb2+ inducing a stress-like response in rats leading to changes in plasma corticosterone and brain 5-HT levels via altering tryptophan pyrrolase activity.

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References

  • Alam N, Haleem DJ, Najam R, Haider S, Ahmed SP (2011) Hypophagic and hypolocomotive effects of metachloro phenyl piperazine in rats treated with theophylline and caffeine. Pak J Pharm Sci 24(3):251–254

    PubMed  CAS  Google Scholar 

  • Arango V, Ernsberger P, Marzuk PM, Chen J, Tierney H, Stanley M, Reis DJ, Mann JJ (1990) Autoradiographic demonstration of increased serotonin 5-HT2 and β-adrenergic receptor binding sites in the brain of suicide victims. Arch Gen Psychiatr 47(11):1038–1047

    Article  PubMed  CAS  Google Scholar 

  • Badawy AA (1977) The functions and regulation of tryptophan pyrrolase. Life Sci 21:755–768

    Article  PubMed  CAS  Google Scholar 

  • Badawy AA, Doughrty DM, Marsh-Richard DM, Steptoe A (2009) Activation of liver tryptophan Pyrrolase mediates the decrease in tryptophan availability to the brain after acute alcohol consumption by normal subjects. Alcohol Alcohol 44:267–271

    Article  PubMed  CAS  Google Scholar 

  • Carroll BJ, Iranmanesh A, Keenan DM, Cassidy F, Wilson WH, Veldhuis JD (2012) Pathophysiology of hypercortisolism in depression: pituitary and adrenal responses to low glucocorticoid feedback. Acta Psychiatr Scand 125:478–491

    Article  PubMed  CAS  Google Scholar 

  • Cory-Slechta DA (1995) Relationships between lead-induced learning impairments and changes in dopaminergic, cholinergic, and glutamatergic neurotransmitter system functions. Annu Rev Pharmacol Toxicol 35:391–415

    Article  PubMed  CAS  Google Scholar 

  • Cory-Slechta DA, Virgolini MB, Thiruchelvam M, Weston DD, Bauter MR (2004) Maternal stress modulates the effects of developmental lead exposure. Environ Health Perspect 112:717–730

    Article  PubMed  CAS  Google Scholar 

  • Cory-Slechta DA, Virgolini MB, Rossi-George A, Thiruchelvam M, Lisek R, Weston D (2008) Lifetime consequences of combined maternal lead and stress. Basic Clin Pharmacol Toxicol 102:218–227

    Article  PubMed  CAS  Google Scholar 

  • Cory-Slechta DA, Stern S, Weston D, Allen JL, Liu S (2010) Enhanced learning deficits in female rats following lifetime pb exposure combined with prenatal stress. Toxicol Sci 117:427–438

    Article  PubMed  CAS  Google Scholar 

  • de Souza Lisboa SF, Gonçalves G, Komatsu F, Queiroz CA, Almeida AA, Moreira EG (2005) Developmental lead exposure induces depressive-like behavior in female rats. Drug Chem Toxicol 28:67–77

    PubMed  Google Scholar 

  • Deakin JF, Pennell I, Upadhyaya AJ, Lofthouse R (1990) A neuroendocrine study of 5HT function in depression: evidence for biological mechanisms of endogenous and psychosocial causation. Psychopharmacol (Berl) 101:85–92

    Article  CAS  Google Scholar 

  • Donner NC, Montoya CD, Lukkes JL, Lowry CA (2012) Chronic non-invasive corticosterone administration abolishes the diurnal pattern of tph2 expression. Psychoneuroendocrinol 37:645–661

    Article  CAS  Google Scholar 

  • Dykeman R, Aguilar-Madrid G, Smith T, Juarez-Perez CA, Piacitelli GM, Hu H, Hernandez-Avila M (2002) Lead exposure in Mexican radiator repair workers. Am J Ind Med 41:179–187

    Article  PubMed  CAS  Google Scholar 

  • Elias RW (1985) Lead exposure in the human environment. In: Mahaffy KR (ed) Dietary and environmental lead. Elsevier, Amsterdam, pp 79–107

    Google Scholar 

  • Finkelstein Y, Markowitz ME, Rosen JF (1998) Low-level lead induced neurotoxicity in children: an update on central nervous system effects. Brain Res Brain Res Rev 27:168–176

    Article  PubMed  CAS  Google Scholar 

  • Gasana J, Chamorro A (2002) Environmental lead contamination in Miami inner-city area. J Expo Anal Environ Epidemiol 12:265–272

    Article  PubMed  CAS  Google Scholar 

  • Graham DL, Grace CE, Braun AA, Schaefer TL, Skelton MR, Tang PH, Vorhees CV, Williams MT (2011) Effects of developmental stress and lead (Pb) on corticosterone after chronic and acute stress, brain monoamines, and blood Pb levels in rats. Int J Dev Neurosci 29:45–55

    Article  PubMed  CAS  Google Scholar 

  • Haider S, Shameem S, Ahmed SP, Perveen T, Haleem DJ (2005) Repeated administration of lead decreases brain 5-HT metabolism and produces memory deficits in rats. Cell Mol Biol Lett 10:669–676

    PubMed  CAS  Google Scholar 

  • Haider S, Tabassum S, Ali S, Saleem S, Khan AK, Haleem DJ (2011) Age-related decreases in striatal DA produces cognitive deficits in male rats. J Pharm Nutri Sci 1(1):20–27

    Article  Google Scholar 

  • Hammond PB, Succop PA (1995) Effects of supplemental nutrition on lead-induced depression of growth and food consumption in weanling rats. Toxicol Appl Pharmacol 131:80–84

    Article  PubMed  CAS  Google Scholar 

  • Hammond PB, Minnema DJ, Succop PA (1993) Reversibility of lead-induced depression of growth. Toxicol Appl Pharmacol 123:9–15

    Article  PubMed  CAS  Google Scholar 

  • Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH (2007) Serotonin 5-HT(2C) receptors regulate anxiety-like behavior. Genes Brain Behav 6:491–496

    Article  PubMed  CAS  Google Scholar 

  • Hinkelmann K, Botzenhardt J, Muhtz C, Agorastos A, Wiedemann K, Kellner M, Otte C (2012) Sex differences of salivary cortisol secretion in patients with major depression. Stress 15:105–109

    PubMed  CAS  Google Scholar 

  • Hogg S (1996) A review of the validity and variability of the elevated plus-maze as an animal model of anxiety. Pharmacol Biochem Behav 54:21–30

    Article  PubMed  CAS  Google Scholar 

  • Jokinen J, Nordström AL, Nordström P (2010) Cholesterol, CSF 5-HIAA, violence and intent in suicidal men. Psychiatr Res 178:217–219

    Article  CAS  Google Scholar 

  • Kamali M, Saunders EF, Prossin AR, Brucksch CB, Harrington GJ, Langenecker SA, McInnis MG (2012) Associations between suicide attempts and elevated bedtime salivary cortisol levels in bipolar disorder. J Affect Disord 136:350–358

    Article  PubMed  CAS  Google Scholar 

  • Khaliq S, Haider S, Naqvi F, Perveen T, Saleem S, Haleem DJ (2012) Altered brain serotonergic neurotransmission following caffeine withdrawal produces behavioral deficits in rats. Pak J Pharm Sci 25:21–25

    PubMed  CAS  Google Scholar 

  • Kitamura Y, Araki H, Gomita Y (2002) Interaction of 5-HT and HPA axis in depression and treatment-resistant depression. Nihon Yakurigaku Zasshi 119:319–325

    Article  PubMed  CAS  Google Scholar 

  • Kuhlmann AC, McGlothan JL, Guilarte TR (1997) Developmental lead exposure causes spatial learning deficits in adult rats. Neurosci Lett 233:101–104

    Article  PubMed  CAS  Google Scholar 

  • Landrigan PJ, Schechter CB, Lipton JM, Fahs MC, Schwartz J (2002) Environmental pollutants and disease in American children: estimates of morbidity, mortality, and costs for lead poisoning, asthma, cancer, and developmental disabilities. Environ Health Perspect 110:721–728

    Article  PubMed  Google Scholar 

  • Lidsky TI, Schneider JS (2003) Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain 126:5–19

    Article  PubMed  Google Scholar 

  • Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology (Berlin) 92:180–185

    CAS  Google Scholar 

  • Mattingly D (1962) A simple fluorimetric method for the estimation of free 11-hydroxycorticoids in human plasma. J Clin Pathol 15:165–171

    Article  Google Scholar 

  • Meltzer H (1989) Serotonergic dysfunction in depression. Br J Psychiatr Suppl 8:25–31

    Google Scholar 

  • Moberg T, Nordström P, Forslund K, Kristiansson M, Asberg M, Jokinen J (2011) CSF 5-HIAA and exposure to and expression of interpersonal violence in suicide attempters. J Affect Disord 132:173–178

    Article  PubMed  CAS  Google Scholar 

  • Moreira EG, Vassilieff I, Vassilieff VS (2001) Developmental lead exposure: behavioral alterations in the short and long term. Neurotoxicol Teratol 23(5):489–495

    Article  PubMed  CAS  Google Scholar 

  • Nieto-Fernandez FE, Ruiz A, Ntukogu N, Nodimelle L, Pryor SC (2006) Short term lead exposure induces a stress-like response in adult mice. Med Sci Monit 12:BR325–BR329

    PubMed  CAS  Google Scholar 

  • Pellow S, File SE (1986) Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Pharmacol Biochem Behav 24:525–529

    Article  PubMed  CAS  Google Scholar 

  • Pellow S, Chopin P, File SE, Briley M (1985) Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167

    Article  PubMed  CAS  Google Scholar 

  • Peterson RE, Pierce CE (1960) The metabolism of corticosterone in man. J Clin Invest 39:741–757

    Article  PubMed  CAS  Google Scholar 

  • Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336

    PubMed  CAS  Google Scholar 

  • Rodgers RJ (1997) Animal models of ‘anxiety’: where next? Behav Pharmacol 8:477–504

    Article  PubMed  CAS  Google Scholar 

  • Rossi-George A, Virgolini MB, Weston D, Cory-Slechta DA (2009) Alterations in glucocorticoid negative feedback following maternal Pb, prenatal stress and the combination: a potential biological unifying mechanism for their corresponding disease profiles. Toxicol Appl Pharmacol 234:117–127

    Article  PubMed  CAS  Google Scholar 

  • Sanders T, Liu Y, Buchner V, Tchounwou PB (2009) Neurotoxic effects and biomarkers of lead exposure: a review. Rev Environ Health 24(1):15–45

    Article  PubMed  CAS  Google Scholar 

  • Sargent PA, Sharpley AL, Williams C, Goodall EM, Cowen PJ (1997) 5-HT2C receptor activation decreases appetite and body weight in obese subjects. Psychopharmacology (Berlin) 133:309–312

    Article  CAS  Google Scholar 

  • Sen D, Wolfson H, Dilworth M (2002) Lead exposure in scaffolders during refurbishment construction activity--an observational study. Occup Med (Lond) 52:49–54

    Article  CAS  Google Scholar 

  • Smith SM, Vale WW (2006) The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 8:383–395

    PubMed  Google Scholar 

  • Szymańska M, Budziszewska B, Jaworska-Feil L, Basta-Kaim A, Kubera M, Leśkiewicz M, Regulska M, Lasoń W (2009) The effect of antidepressant drugs on the HPA axis activity, glucocorticoid receptor level and FKBP51 concentration in prenatally stressed rats. Psychoneuroendocrinology 34:822–832

    Article  PubMed  Google Scholar 

  • van Praag HM (1986) Biological suicide research: outcome and limitations. Biol Psychiatr 21:1305–1323

    Article  Google Scholar 

  • Virgolini MB, Chen K, Weston DD, Bauter MR, Cory-Slechta DA (2005) Interactions of chronic lead exposure and intermittent stress: consequences for brain catecholamine systems and associated behaviors and HPA axis function. Toxicol Sci 87:469–482

    Article  PubMed  CAS  Google Scholar 

  • Xu J, Yan CH, Yang B, Xie HF, Zou XY, Zhong L, Gao Y, Tian Y, Shen XM (2009) The role of metabotropic glutamate receptor 5 in developmental lead neurotoxicity. Toxicol Lett 191:223–230

    Article  PubMed  CAS  Google Scholar 

  • Young SN, Chouinard G, Annable L (1981) Tryptophan in the treatment of depression. Adv Exp Med Biol 133:727–737

    Article  PubMed  CAS  Google Scholar 

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Acknowledgement

The authors are thankful to the University of Karachi, Karachi, Pakistan for funding this project.

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The authors declare that they have no conflict of interest.

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Correspondence to Saida Haider.

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Haider, S., Saleem, S., Tabassum, S. et al. Alteration in plasma corticosterone levels following long term oral administration of lead produces depression like symptoms in rats. Metab Brain Dis 28, 85–92 (2013). https://doi.org/10.1007/s11011-012-9374-y

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  • DOI: https://doi.org/10.1007/s11011-012-9374-y

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