Skip to main content
SpringerLink
Log in

Clozapine Administration Modifies Neurotensin Effect on Synaptosomal Membrane Na+, K+ -ATPase Activity

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Na+, K+-ATPase is inhibited by neurotensin, an effect which involves the peptide high affinity receptor (NTS1). Neurotensin effect on cerebral cortex synaptosomal membrane Na+, K+-ATPase activity of rats injected i.p. with antipsychotic clozapine was studied. Whereas 3.5 × 10−6 M neurotensin decreased 44% Na+, K+-ATPase activity in the controls, the peptide failed to modify enzyme activity 30 min after a single 3.0, 10.0 and 30.0 mg/kg clozapine dose. Neurotensin decreased Na+, K+-ATPase activity 40 or 20% 18 h after 3.0 or 5.6 mg/kg clozapine administration, respectively, and lacked inhibitory effect 18 h after 17.8 and 30.0 mg/kg clozapine doses. Results indicated that the clozapine treatment differentially modifies the further effect of neurotensin on synaptosomal membrane Na+, K+-ATPase activity according to time and dose conditions employed. Taken into account that clozapine blocks the dopaminergic D2 receptor, findings obtained favor the view of an interplay among neurotensinergic receptor, dopaminergic D2 receptor and Na+, K+-ATPase at synaptic membranes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Carraway R, Leeman SE (1973) The isolation of a new hypotensive peptide neurotensin from bovine hypothalami. J Biol Chem 248:6854–6861

    CAS  PubMed  Google Scholar 

  2. Vincent JP, Mazella J, Kitabgi P (1999) Neurotensin and neurotensin receptors. Trends Pharmacol 20:302–309

    Article  CAS  Google Scholar 

  3. Pelaprat D (2006) Interactions between neurotensin receptors and G proteins. Peptides 27:2476–2487

    Article  CAS  PubMed  Google Scholar 

  4. Dobner PR (2005) Multitasking with neurotensin in the central nervous system. Cell Mol Life Sci 62:1946–1963

    Article  CAS  PubMed  Google Scholar 

  5. Nemeroff CB, Cain ST (1985) Neurotensin-dopamine interactions in the CNS. Trends Pharmacol 6:201–205

    Article  CAS  Google Scholar 

  6. Kasckow J, Nemeroff CB (1991) The neurobiology of neurotensin: focus on neurotensin-dopamine interactions. Regul Pept 36:153–164

    Article  CAS  PubMed  Google Scholar 

  7. Beauregard M, Ferron A, Descarries L (1992) Oppossite effects of neurotensin on dopamine inhibition in different regions of the rat brain: an iontophoretic study. Neuroscience 47:613–619

    Article  CAS  PubMed  Google Scholar 

  8. Binder EB, Kinkead B, Owens MJ et al (2001) Neurotensin and dopamine interactions. Pharmacol Rev 53:453–486

    CAS  PubMed  Google Scholar 

  9. Baldesarini RJ, Tarazi FI (2006) Pharmacotherapy of psychosis and mania. In: Brunton LL, Lazo JS, Parker KL (eds) Goodman & Gilman′s. The pharmacological basis of therapeutics, 11th edn. McGraw-Hill, New York, pp 461–500

    Google Scholar 

  10. Farah A (2005) Atypicality of atypical antipsychotics. J Clin Psychiatry 7:268–274

    Google Scholar 

  11. Binder EB, Kinkead B, Owens MJ et al (2001) Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: evidence from animal models of sensorimotor gating. J Neurosci 21:601–608

    CAS  PubMed  Google Scholar 

  12. Albers RW, Siegel GJ (2006) Membrane transport. In: Siegel GJ, Albers RW, Brady ST et al (eds) Basic neurochemistry. Molecular, cellular, and medical aspect, 7th edn. Elsevier Academic Press, MA, pp 73–94

    Google Scholar 

  13. Rodríguez de Lores Arnaiz G (2007) Na+, K+-ATPase in the brain: structure and function. In: Lajtha A (ed) Neural membranes and transport; handbook of neurochemistry and molecular neurobiology, Reith MEA, vol 11. Springer, Berlin, pp 209–224

    Google Scholar 

  14. Sweadner KJ (1989) Isozymes of Na+, K+-ATPase. Biochim Biophys Acta 988:185–220

    CAS  PubMed  Google Scholar 

  15. Arystarkhova E, Donnet C, Muñoz Matta A et al (2007) Multiplicity of expression of FXYD proteins in mammalian cells: dynamic exchange of phospholemman and gamma-subunit in response to stress. Am J Physiol Cell Physiol 292:C1179–C1191

    Article  CAS  PubMed  Google Scholar 

  16. Rodríguez de Lores Arnaiz G (1983) Neuronal Na+, K+-ATPase and its regulation by catecholamines. Intern Brain Res Org Monogr Ser 10:147–158

    Google Scholar 

  17. López Ordieres MG, Rodríguez de Lores Arnaiz G (2000) Neurotensin inhibits neuronal Na+, K+-ATPase activity through high affinity peptide receptor. Peptides 21:571–576

    Article  PubMed  Google Scholar 

  18. López Ordieres MG, Rodríguez de Lores Arnaiz G (2001) K+-p-nitrophenyl-phosphatase inhibition by neurotensin involves high affinity neurotensin receptor: influence of potassium concentration and enzyme phosphorylation. Regul Pept 101:183–187

    Article  PubMed  Google Scholar 

  19. López Ordieres MG, Rodríguez de Lores Arnaiz G (2005) The inhibitory effect of neurotensin on synaptosomal membrane Na+, K+-ATPase is altered by antipsychotic administration. Regul Pept 129:177–182

    Article  PubMed  Google Scholar 

  20. Feifel D, Melendez G, Shilling PD (2004) Reversal of sensorimotor gating deficits in Brattleboro rats by acute administration of clozapine and a neurotensin agonist, but not haloperidol: a potential predictive model for novel antipsychotic effects. Neuropsychopharmacology 4:731–738

    Article  Google Scholar 

  21. Feifel D, Mexal S, Melendez G, Liu PY, Goldenberg JR, Shilling PD (2009) The Battleboro rat displays a natural deficit in social discrimination that is restored by clozapine and a neurotensin analog. Neuropsychopharmacology 34:2011–2018

    Article  CAS  PubMed  Google Scholar 

  22. Rodríguez de Lores Arnaiz G, Alberici M, De Robertis E (1967) Ultrastructural and enzymic studies of cholinergic and non-cholinergic synaptic membranes isolated from brain cortex. J Neurochem 14:215–225

    Article  Google Scholar 

  23. Albers RW, Rodríguez de Lores Arnaiz G, De Robertis E (1965) Sodium-potassium-activated ATPase and potassium-activated p-nitrophenylphosphatase: a comparison of their subcelullar localizations in rat brain. Proc Natl Acad Sci 53:557–564

    Article  CAS  PubMed  Google Scholar 

  24. Lowry OH, López JA (1946) Determination of inorganic phosphate in presence of labile P ester. J Biol Chem 162:421–428

    CAS  Google Scholar 

  25. Lowry OH, Rosebrough NJ, Farr AL et al (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  26. Arnt J, Skarsfeldt T (1998) Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 18:63–101

    Article  CAS  PubMed  Google Scholar 

  27. Remington G, Kapur S (2000) Atypical antipsychotics: are some more atypical than others? Psychopharmacology (Berlin) 148:3–15

    Article  CAS  Google Scholar 

  28. Baldessarini RJ, Centorrino F, Flood JG et al (1993) Tissue concentrations of clozapine and its metabolites in the rat. Neuropsychopharmacology 9:117–124

    CAS  PubMed  Google Scholar 

  29. Strange PG (2001) Antipsychotic drugs: importance of dopamine receptors for mechanisms of therapeutic actions and side effects. Pharmacol Rev 53:119–133

    CAS  PubMed  Google Scholar 

  30. Kinkead B, Shahid S, Owens MJ et al (2000) Effects of acute and subchronic administration of typical and atypical antipsychotic drugs on the neurotensin system of the rat brain. J Pharmacol Exp Ther 295:67–73

    CAS  PubMed  Google Scholar 

  31. Rodríguez de Lores Arnaiz G (1987) The inhibition of neuronal Na+, K+-ATPase by dopamine is not prevented by the neuroleptics haloperidol, droperidol or spiperone. Com Biol (Buenos Aires) 5:275–283

    Google Scholar 

  32. Cáceda R, Kinkead B, Nemeroff CB (2003) Do neurotensin receptor agonists represent a novel class of antipsychotic drugs? Semin Clin Neuropsychiatry 8:94–108

    Article  PubMed  Google Scholar 

  33. Fuxe K, Von Euler G, Agnati LF et al (1992) Intramembrane interactions between neurotensin receptors and dopamine D2 receptors as a major mechanism for the neuroleptic-like action of neurotensin. Ann New York Acad Sci 668:186–204

    Article  CAS  Google Scholar 

  34. Calabrese EJ (2008) Hormesis and medicine. Br J Clin Pharmacol 66:594–617

    CAS  PubMed  Google Scholar 

  35. Kastin AJ, Pan W (2008) Peptides and hormesis. Crit Rev Toxicol 38:629–631

    Article  CAS  PubMed  Google Scholar 

  36. Bai M (2004) Dimerization of G-protein-coupled receptors: roles in signal transduction. Cell Signal 16:175–186

    Article  CAS  PubMed  Google Scholar 

  37. Limbird LE, Meyts PD, Lefkowitz RJ (1975) Beta-adrenergic receptors: evidence for negative cooperativity. Biochem Biophys Res Commun 64:1160–1168

    Article  CAS  PubMed  Google Scholar 

  38. Wreggett KA, Wells JW (1995) Cooperativity manifest in the binding properties of purified cardiac muscarinic receptors. J Biol Chem 270:22488–22499

    Article  CAS  PubMed  Google Scholar 

  39. Rodríguez de Lores Arnaiz G (2002) Interplay between Na+, K+-ATPase and neurotransmitter receptors. In: Richard R (ed) Current topics in neurochemistry, research trends, vol 3. Trivandrum, India, pp 189–198

    Google Scholar 

  40. Seeman P, Lee T (1975) Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188:1217–1219

    Article  CAS  PubMed  Google Scholar 

  41. Creese I, Burt DR, Snyder SH (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192:481–483

    Article  CAS  PubMed  Google Scholar 

  42. Meltzer HY, Matsubara S, Lee J-C (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin 2 pKi values. J Pharmacol Exp Ther 251:238–246

    CAS  PubMed  Google Scholar 

  43. Roth BL, Ciaranello RD, Meltzer HY (1992) Binding of typical and atypical antipsychotic agents to transiently expressed 5-HT1C receptors. J Pharmacol Exp Ther 260:1361–1365

    CAS  PubMed  Google Scholar 

  44. Seeger TF, Seymour PA, Schmidt AW et al (1995) Ziprasidone (CP-88, 059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. J Pharmacol Exp Ther 275:101–113

    CAS  PubMed  Google Scholar 

  45. Meltzer HY (1999) Suicide and schizophrenia: clozapine and the interSePT study. International Clozaril/Leponex suicide prevention trial. J Clin Psychiatry 60(suppl 12):47–50

    CAS  Google Scholar 

  46. Zeng XP, Le F, Richelson E (1997) Muscarinic m4 receptor activation by some atypical antipsychotic drugs. Eur J Pharmacol 321:349–354

    Article  CAS  PubMed  Google Scholar 

  47. Gray L, McOmish C, Scarr E et al (2008) Role of muscarinic receptors in the activity of N-desmethylclozapine: reversal of hyperactivity in the phospholipase C knockout mouse. Behav Pharmacol 19:543–547

    Article  CAS  PubMed  Google Scholar 

  48. Peroutka SJ, Snyder SH (1980) Relationship of neuroleptic drug effects at brain dopamine, serotonin, alpha-adrenergic, and histamine receptors to clinical potency. Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding. Am J Psychiatry 137:1518–1522

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

G. R. de L. A is Chief Investigator from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Financial support was provided by CONICET and Universidad de Buenos Aires, Argentina.

Author information

Authors and Affiliations

  1. Instituto de Biología Celular y Neurociencias “Prof. E. De Robertis”, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 1121, Buenos Aires, Argentina

    María G. López Ordieres & Georgina Rodríguez de Lores Arnaiz

  2. Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Junín 956, Universidad de Buenos Aires, 1113, Buenos Aires, Argentina

    María G. López Ordieres & Georgina Rodríguez de Lores Arnaiz

Authors
  1. María G. López Ordieres
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Georgina Rodríguez de Lores Arnaiz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to María G. López Ordieres.

Rights and permissions

Reprints and permissions

About this article

Cite this article

López Ordieres, M.G., Rodríguez de Lores Arnaiz, G. Clozapine Administration Modifies Neurotensin Effect on Synaptosomal Membrane Na+, K+ -ATPase Activity. Neurochem Res 34, 2226–2232 (2009). https://doi.org/10.1007/s11064-009-0018-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-009-0018-5

Keywords

Search

Navigation