Advertisement

Metabolic Brain Disease

, Volume 27, Issue 4, pp 453–458 | Cite as

Inhibition of acetylcholinesterase activity in brain and behavioral analysis in adult rats after chronic administration of fenproporex

  • Gislaine T. Rezin
  • Giselli Scaini
  • Gabriela K. Ferreira
  • Mariane R. Cardoso
  • Cinara L. Gonçalves
  • Larissa S. Constantino
  • Pedro F. Deroza
  • Fernando V. Ghedim
  • Samira S. Valvassori
  • Wilson R. Resende
  • João Quevedo
  • Alexandra I. Zugno
  • Emilio L. Streck
Original Paper

Abstract

Fenproporex is an amphetamine-based anorectic and it is rapidly converted in vivo into amphetamine. It elevates the levels of extracellular dopamine in the brain. Acetylcholinesterase is a regulatory enzyme which is involved in cholinergic synapses and may indirectly modulate the release of dopamine. Thus, we investigated whether the effects of chronic administration of fenproporex in adult rats alters acquisition and retention of avoidance memory and acetylcholinesterase activity. Adult male Wistar rats received repeated (14 days) intraperitoneal injection of vehicle or fenproporex (6.25, 12.5 or 25 mg/kg i.p.). For behavioral assessment, animals were submitted to inhibitory avoidance (IA) tasks and continuous multiple trials step-down inhibitory avoidance (CMIA). Acetylcholinesterase activity was measured in the prefrontal cortex, hippocampus, hypothalamus and striatum. The administration of fenproporex (6.25, 12.5 and 25 mg/kg) did not induce impairment in short and long-term IA or CMIA retention memory in rats. In addition, longer periods of exposure to fenproporex administration decreased acetylcholinesterase activity in prefrontal cortex and striatum of rats, but no alteration was verified in the hippocampus and hypothalamus. In conclusion, the present study showed that chronic fenproporex administration decreased acetylcholinesterase activity in the rat brain. However, longer periods of exposure to fenproporex did not produce impairment in short and long-term IA or CMIA retention memory in rats.

Keywords

Acetylcholinesterase Fenproporex Behavioral Memory 

Notes

Acknowledgements

This study was supported by grants from Conselho Nacional de Pesquisa e Desenvolvimento (CNPq), Fundação de Apoio à Pesquisa Científica e Tecnológica do Estado de Santa Catarina (FAPESC) and Universidade do Extremo Sul Catarinense (UNESC).

References

  1. Appleyard ME (1992) Secreted acetylcholinesterase: non-classical aspects of a classical enzyme. Trends Neurosci 15:485–490PubMedCrossRefGoogle Scholar
  2. Ballard CG, Greig NH, Guillozet-Bongaarts AL, Enz A, Darvesh S (2005) Cholinesterases: Roles in the brain during health and disease. Curr Alzheimer Res 2:307–318PubMedCrossRefGoogle Scholar
  3. Bartus RT, Dean RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414PubMedCrossRefGoogle Scholar
  4. Berman JA, Talmage DA, Role LW (2007) Cholinergic Circuits and signaling in the pathophysiology of Schizophrenia. Int Rev Neurobiol 78:193–223PubMedCrossRefGoogle Scholar
  5. Bray GA, Tartaglia LA (2000) Medicinal strategies in the treatment of obesity. Nature 404:672–677PubMedGoogle Scholar
  6. Cody JT, Valtier S, Stillman S (1999) Amphetamine and fenproporex levels following multidose administration of fenproporex. J Anal Toxicol 23:187–194PubMedGoogle Scholar
  7. Coutts RT, Nazarali AJ, Baker GB, Pasutto FM (1986) Metabolism and disposition of N-(2-cyanoethyl)-amphetamine (fenproporex) and amphetamine: study in the rat brain. Can J Physiol Pharmacol 64:724–728PubMedCrossRefGoogle Scholar
  8. Cragg SJ (2006) Meaningful silences: How dopamine listens to the ACh pause. Trends Neurosci 29:125–131PubMedCrossRefGoogle Scholar
  9. Das A, Kapoor K, Sayeepriyadarshini AT, Dikshit M, Palit G, Nath C (2000) Immobilization stress-induced changes in acetylcholinesterase activity and cognitive function in mice. Pharmacol Res 42:213–217PubMedCrossRefGoogle Scholar
  10. Ellman GI, Courtney KD, Andres V Jr, Feather-Stone RM (1961) A New and Rapid Colorimetric Determination of Acetylcholinesterase Activity. Biochem Pharmacol 7:88–95PubMedCrossRefGoogle Scholar
  11. Gilboa-Geffen A, Hartmann G, Soreq H (2012) Stressing hematopoiesis and immunity: an acetylcholinesterase window into nervous and immune system interactions. Front Mol Neurosci 5:30. doi: 10.3389/fnmol.2012.00030 PubMedCrossRefGoogle Scholar
  12. Gotti C, Clementi F (2004) Neuronal nicotinic receptors: From structure to pathology. Prog Neurobiol 74:363–396PubMedCrossRefGoogle Scholar
  13. Grisaru D, Sternfeld M, Eldor A, Glick D, Soreq H (1999) Structural roles of acetylcholinesterase variants in biology and pathology. Eur J Biochem 264:672–686PubMedCrossRefGoogle Scholar
  14. Gurevich-Panigrahi T, Panigrahi S, Wiechec E, Los M (2009) Obesity: Pathophysiology and Clinical Management. Curr Med Chem 16:506–521PubMedCrossRefGoogle Scholar
  15. Hyde TM, Crook JM (2001) Cholinergic systems and schizophrenia: Primary pathology or epiphenomena? J Chem Neuroanat 22:53–63PubMedCrossRefGoogle Scholar
  16. Klegeris A, Korkina LG, Greenfield SA (1995) A possible interaction between acetylcholinesterase and dopamine molecules during autoxidation of the amine. Free Radic Biol Med 18:223–230PubMedCrossRefGoogle Scholar
  17. Kleijn J, Wiskerke J, Cremers TI, Schoffelmeer AN, Westerink BH, Pattij T (2012) Effects of amphetamine on dopamine release in the rat nucleus accumbens shell region depend on cannabinoid CB1 receptor activation. Neurochem Int. Mar 10. [Epub ahead of print]Google Scholar
  18. Kraemer T, Theis GA, Weber AA, Maurer HH (2000) Studies on the metabolism and toxicological detection of the amphetamine-like anorectic fenproporex in human urine by gas chromatography-mass spectrometry and fluorescence polarization immunoassay. J Chromatogr B 738:107–118CrossRefGoogle Scholar
  19. Kuczenski R, Segal DS (1997) Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: Comparison with amphetamine. J Neurochem 68:2032–2037PubMedCrossRefGoogle Scholar
  20. Kuczenski R, Segal DS (2001) Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate: Relative roles of dopamine and norepinephrine. J Pharmacol Exper Ther 296:876–883Google Scholar
  21. Kuczenski R, Segal DS (2002) Exposure of adolescent rats to oral methylphenidate: Preferential effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine. J Neurosci 22:7264–7271PubMedGoogle Scholar
  22. Kuhl DE, Koeppe RA, Minoshima S, Snyder SE, Ficaro EP, Foster NL, Frey KA, Kilbourn MR (1999) In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer’s disease. Neurology 52:691–699PubMedCrossRefGoogle Scholar
  23. LaVoie MJ, Hastings TG (1999) Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine. J Neurosci 19:1484–1491PubMedGoogle Scholar
  24. Liu J, Olivier K, Pope CN (1999) Comparative neurochemical effects of repeated methyl parathion or chlorpyrifos exposures in neonatal and adult rats. Toxicol Appl Pharmacol 158:186–196PubMedCrossRefGoogle Scholar
  25. Lowry OH, Rosebough NG, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
  26. Mattei R, Carlini EA (1996) Acomparative study of the anorectic and behavioral effects of fenproporex on male and female rats. Braz J Med Biol Res 29:1025–1030PubMedGoogle Scholar
  27. Mesulam MM (2004) The cholinergic innervation of the human cerebral cortex. Progr Brain Res 145:67–78CrossRefGoogle Scholar
  28. Milatovic D, Dettbarn WD (1996) Modification of acetylcholinesterase during adaptation to chronic, subacute paraoxon application in rat. Toxicol Appl Pharmacol 136:20–28PubMedCrossRefGoogle Scholar
  29. Moser VC, Padilla S (1998) Age- and gender-related differences in the time course of behavioral and biochemical effects produced by oral chlorpyrifos in rats. Toxicol Appl Pharmacol 149:107–119PubMedCrossRefGoogle Scholar
  30. Moussavi N, Gavino V, Receveur O (2008) Could the Quality of Dietary Fat, and Not Just Its Quantity, Be Related to Risk of Obesity? Obesity 16:7–15PubMedCrossRefGoogle Scholar
  31. Musial A, Bajda M, Malawska B (2007) Recent developments in cholinesterases inhibitors for Alzheimer’s disease treatment. Curr Med Chem 14:2654–2679PubMedCrossRefGoogle Scholar
  32. Namba H, Iyo M, Fukushi K, Shinotoh H, Nagatsuka S, Suhara T, Sudo Y, Suzuki K, Irie T (1999) Human cerebral acetylcholinesterase activity measured with positron emission tomography: procedure, normal values and effect of age. Eur J Nucl Med 26:135–143PubMedCrossRefGoogle Scholar
  33. Page G, Peeters M, Najimi M, Maloteaux JM, Hermans E (2001) Modulation of the neuronal dopamine transporter activity by the metabotropic glutamate receptor mGluR5 in rat striatal synaptosomes through phosphorylation mediated processes. J Neurochem 76:1282–1290PubMedCrossRefGoogle Scholar
  34. Rezin GT, Jeremias IC, Ferreira GK, Cardoso MR, Morais MO, Gomes LM, Martinello OB, Valvassori SS, Quevedo J, Streck EL (2011) Brain energy metabolism is activated after acute and chronic administration of fenproporex in young rats. Int J Dev Neurosci 29:937–942Google Scholar
  35. Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res Rev 11:157–198CrossRefGoogle Scholar
  36. Roesler R, Vianna MR, De-Paris F, J Q (1999) Memory-enhancing treatments do not reverse the impairment of inhibitory avoidance retention induced by NMDA receptor blockade. Neurobiol Learn Mem 72:252–258PubMedCrossRefGoogle Scholar
  37. Sarter M, Parikh V (2005) Choline transporters, cholinergic transmission and cognition. Nat Rev Neurosci 6:48–56PubMedCrossRefGoogle Scholar
  38. Schetinger MRC, Porto NM, Moretto MB, Morsch VM, Rocha JBT, Vieira V, Moro F, Neis RT, Bittencourt S, Bonacorso HG, Zanatta N (2000) New benzodiazepines alter acetylcholinesterase and ATP-Dase activities. Neurochem Res 25:949–955PubMedCrossRefGoogle Scholar
  39. Silman I, Sussman JL (2005) Acetylcholinesterase: ‘classical’ and ‘non-classical’ functions and pharmacology. Curr Opin Pharmacol 5:293–302PubMedCrossRefGoogle Scholar
  40. Smythies J (2005) Section I: The cholinergic system. Int Rev Neurobiol 64:1–122PubMedCrossRefGoogle Scholar
  41. Spina MB, Cohen G (1989) Dopamine turnover and glutathione oxidation: implications for Parkinson disease. Proc Natl Acad Sci USA 86:1398–1400PubMedCrossRefGoogle Scholar
  42. Steriade M (2004) Acetylcholine systems and rhythmic activities during the waking–sleep cycle. Prog Brain Res 145:179–196PubMedCrossRefGoogle Scholar
  43. Tse MT, Cantor A, Floresco SB (2011) Repeated amphetamine exposure disrupts dopaminergic modulation of amygdala-prefrontal circuitry and cognitive/emotional functioning. J Neurosci 31(31):11282–94PubMedCrossRefGoogle Scholar
  44. United Nations International Narcotics Control Board (UNINCB). Report of the International Narcotics Control Board for 2007 (E/INCB/2007/1). Available at: http://www.incb.org/incb/annual-report-2007.html.
  45. Volkow ND, Wang G, Fowler JS, Logan J, Gerasimov M, Maynard L (2001) Therapeutic doses of oral methylphenidate significantly increases extracellular dopamine in the human brain. J Neurosci 2:121–125Google Scholar
  46. Wonnacott S, Sidhpura N, Balfour DJ (2005) Nicotine: From molecular mechanisms to behavior. Curr Opin Pharmacol 5:53–59PubMedCrossRefGoogle Scholar
  47. Woolf N (1991) Cholinergic systems in mammalian brain and spinal cord. Prog Neurobiol 37:475–524PubMedCrossRefGoogle Scholar
  48. Zheng Q, Olivie, K, Won YK, Pope CN (2000) Comparative cholinergic neurotoxicity of oral chlorpyrifos exposures in preweanling and adult rats. Toxicol Sci 55:124–132Google Scholar
  49. Zhu J, Reith ME (2008) Role of the dopamine transporter in the action of psychostimulants, nicotine, and other drugs of abuse. CNS Neurol Disord Drug Targets 7:393–409PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Gislaine T. Rezin
    • 1
    • 3
  • Giselli Scaini
    • 1
    • 3
  • Gabriela K. Ferreira
    • 1
    • 3
  • Mariane R. Cardoso
    • 1
    • 3
  • Cinara L. Gonçalves
    • 1
    • 3
  • Larissa S. Constantino
    • 1
    • 3
  • Pedro F. Deroza
    • 2
    • 3
  • Fernando V. Ghedim
    • 2
    • 3
  • Samira S. Valvassori
    • 2
    • 3
  • Wilson R. Resende
    • 2
    • 3
  • João Quevedo
    • 2
    • 3
  • Alexandra I. Zugno
    • 2
    • 3
  • Emilio L. Streck
    • 1
    • 3
  1. 1.Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da SaúdeUniversidade do Extremo Sul CatarinenseCriciúmaBrazil
  2. 2.Laboratório de Neurociências, Programa de Pós-graduação em Ciências da SaúdeUniversidade do Extremo Sul CatarinenseCriciúmaBrazil
  3. 3.Instituto Nacional de Ciência e Tecnologia em Medicina Translacional (INCT-TM)Porto AlegreBrazil

Personalised recommendations