Skip to main content

Reduction of Hippocampal Na+, K+-ATPase Activity in Rats Subjected to an Experimental Model of Depression


The effect of a model of depression using female rats on Na+, K+-ATPase activity in hippocampal synaptic plasma membranes was studied. In addition, the effect of further chronic treatment with fluoxetine on this enzyme activity was verified. Sweet food consumption was measured to evaluate the efficacy of this model in inducing a state of reduced response to rewarding stimili. After 40 days of mild stress, a reduction in sweet food ingestion was observed. Reduction of hippocampal Na+, K+-ATPase activity was also observed. Treatment with fluoxetine increased this enzyme activity and reversed the effect of stress. Chronic fluoxetine decreased the ingestion of sweet food in both groups. This result is in agreement with suggestions that reduction of Na+, K+-ATPase activity is a caracteristic of depressive disorders. Fluoxetine reversed this effect. Therefore it is possible that altered Na+, K+-ATPase activity may be involved in the pathophysiology of depression in patients.

This is a preview of subscription content, access via your institution.


  1. 1.

    Erecinska, M. and Silver, I. A. 1994. Ions and energy in mammalian brain. Prog. Neurobiol. 43:37-71.

    Google Scholar 

  2. 2.

    Naylor, G. J., Smith, A. H., Dick, E. G., Dick, D. A., McHarg, A. M., and Chambers, C. A. 1980. Erythrocyte membrane cation carrier in manic-depressive psychosis. Psycol. Med. 10:521-525.

    Google Scholar 

  3. 3.

    Hokin-Neaverson, M. and Jefferson, J. W. 1989. Deficient erythrocyte NaK-ATPase activity in different affective states in bipolar affective disorder and normalization by lithium therapy. Neuropsychobiology 22:18-25.

    Google Scholar 

  4. 4.

    Mynett-Johnson, L., Murphy, V., McCormack, J., Shields, D. C., Claffey, E., Manley, P., and McKeon, P. 1998. Evidence for an allelic association between bipolar disorder and a Na+, K+ adenosine triphosphatase alpha subunit gene (ATP1A3). Biol. Psych. 44:47-51.

    Google Scholar 

  5. 5.

    Wood, A. J., Smith, C. E., Clarke, E. E., Cowen, P. J., Aronson, J. K., and Grahame-Smith, D. G. 1991. Altered in vitro adaptive responses of lymphocyte Na,K-ATPase in patients with manic depressive psychosis. J. Affect. Disord. 21:199-206.

    Google Scholar 

  6. 6.

    Pucilowski, O., Overstreet, D. H., Rezvani, A. H., and Janowsky, D. S. 1993. Chronic mild stress-induced anhedonia: Greater effect in a genetic rat model of depression. Physiol. Behav. 54:1215-1220.

    Google Scholar 

  7. 7.

    Katz, R. J., Roth, K. A., and Carroll, B. J. 1981. Acute and chronic stress effects on open field activity in the rat: Implications for a model of depression. Neurosci. Biobehav. Rev. 5:247-251.

    Google Scholar 

  8. 8.

    Willner, P. 1991. Animal models as simulations of depression. TIPS 12:131-136.

    Google Scholar 

  9. 9.

    Kornstein, S. G. 2002. Chronic depression in women. J. Clin. Psychiatry 63:602-609.

    Google Scholar 

  10. 10.

    Bergstrom, R. F., Lemberger, L., Farid, N. A., and Wolen, R. L. 1988. Clinical pharmacology and pharmacokinetics of fluoxetine: A review. Br. J. Psychiatry Suppl., 153:47-50.

    Google Scholar 

  11. 11.

    Van Praag, H. M., Asnis, G. M., Kahn, R. S., Brown, S. L., Korn, M., Friedman, J. M., and Wetzler, S. 1990. Monoamines and abnormal behaviour: A multiaminergic perspective. Br. J. Psychiatry 157:723-734.

    Google Scholar 

  12. 12.

    Lesch, K. P., Aulakh, S. C., Wolozin, B. L., Tolliver, T. J., Hill, J. L., and Murphy, D. L. 1993. Regional brain expression of serotonin transporter mRNA and its regulation by reuptake inhibiting antidepressants. Mol. Brain. Res. 17:31-35.

    Google Scholar 

  13. 13.

    Worrall, D. M. and Willians, D. C. 1994. Sodium ion-dependent transporters for neurotransmitter: A review of recent developments. Biochem. J. 297:425-436.

    Google Scholar 

  14. 14.

    Zanatta, L. M., Nascimento, F. C., Barros, S. V., Silva, G. R., Zugno, A. I., Netto, C. A., and Wyse, A. T. S. 2001. In vivo and in vitro effect of imipramine and fluoxetine on Na+, K+-ATPase activity in synaptic plasma membranes from the cerebral cortex of rats. Braz. J. Med. Biol. Res. 34:1265-1269.

    Google Scholar 

  15. 15.

    Willner, P., Towell, A., Sampson, D., Sophokleus, S., and Muscat, R. 1987. Reduction of sucrose preference by chronic unpredictable mild stress and its restoration by tricyclic antidepressant. Psycopharmacology (Berl.) 93:358-364.

    Google Scholar 

  16. 16.

    Konarska, M., Stewart, R. E., and McCarty, R. 1990. Predictability of chronic intermittent stress: Effects on sympathetic-adrenal medullary responses of laboratory rats. Behav. Neural Biol. 53:231-243.

    Google Scholar 

  17. 17.

    Murua, V. S. and Molina, V. A. 1992. Effects of chronic variable stress and antidepressant drugs on behavioral inactivity during an uncontrollable stress: Interaction between both treatments. Behav. Neural Biol. 57:87-89.

    Google Scholar 

  18. 18.

    Ely, D. R., Dapper, V., Marasca, J., Corrêa, J. B., Gamaro, G. D., Xavier, M. H., Michalowski, M. B., Catelli, D., Rosat, R., Ferreira, M. B. C., and Dalmaz, C. 1997. Effect of restraint stress on feeding behavior of rats. Physiol. Behav. 61:395-398.

    Google Scholar 

  19. 19.

    Beaufour, C. C., Ballon, N., Le Bihan, C., Hamon, M., and Thiebot, M. H. 1999. Effects of chronic antidepressants in an operant conflict procedure of anxiety in the rat. Pharmacol. Biochem. Behav. 62:591-599.

    Google Scholar 

  20. 20.

    Jones, D. H. and Matus, A. I. 1974. Isolation of synaptic plasma membrane from brain by combination flotation-sedimentation density gradient centrifugation. Biochim. Biophys. Acta 356:276-287.

    Google Scholar 

  21. 21.

    Wyse, A. T. S., Streck, E. L., Worm, P., Wajner, A., Ritter, F., and Netto, C. A. 2000. Preconditioning prevents the inhibition of Na+, K+-ATPase activity after brain ischemia. Neurochem. Res. 25:971-975.

    Google Scholar 

  22. 22.

    Tsakiris, S. and Deliconstantinos, G. 1984. Influence of phosphatidylserine on (Na+ + K+)-stimulated ATPase and acetylcholinesterase activities of dog brain synaptosomal plasma membranes. Biochem. J. 220:301-307.

    Google Scholar 

  23. 23.

    Chan, K. M., Delfert, D., and Junger, K. D. 1986. A direct colorimetric assay for Ca2+-stimulated ATPase activity. Anal. Biochem. 157:375-380.

    Google Scholar 

  24. 24.

    Bradford, M. M. 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-die-binding. Anal. Biochem. 72:248-254.

    Google Scholar 

  25. 25.

    Basso, A. M., Depiante-Depaoli, M., Cancela, L., and Molina, V. 1993. Seven-day variable-stress regime alters cortical beta-adrenoceptor binding and immunologic responses: Reversal by imipramine. Pharmacol. Biochem. Behav. 45:665-672.

    Google Scholar 

  26. 26.

    Papp, M., Willner, P., and Muscat, R. 1991. An animal model of anhedonia: Attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress. Psychopharmacology (Berl.) 104:255-259.

    Google Scholar 

  27. 27.

    Nielsen, C. K., Arnt, J., and Sánchez, C. 2000. Intracranial self-stimulation and sucrose intake differ as hedonic measures following chronic mild stress: Interstrain and interindividual differences. Behav. Brain Res. 107:21-33.

    Google Scholar 

  28. 28.

    Papp, M., Willner, P., and Muscat, R. 1993. Behavioural sensitization to a dopamine agonist is associated with reversal of stress-induced anhedonia. Psychopharmacology (Berl.) 110:159-164.

    Google Scholar 

  29. 29.

    Matthews, K., Forbes, N., and Reid, I. C. 1995. Sucrose consumption as an hedonic measure following chronic unpredictable mild stress. Physiol. Behav. 57:241-248.

    Google Scholar 

  30. 30.

    Echandia, E. L. R., Gonzalez, A. S., Cabrera, R., and Fracchia, L. N. 1988. A further analysis of behavioral and endocrine effects of unpredictable chronic stress. Physiol. Behav. 43:789-795.

    Google Scholar 

  31. 31.

    Muscat, R., Papp, M., and Willner, P. 1992. Reversal of stress-induced anhedonia by the atypical antidepressants, fluoxetine and maprotiline. Psychopharmacology (Berl.) 109:433-438.

    Google Scholar 

  32. 32.

    Silveira, P. P., Xavier, M. H., Souza, F. H., Manoli, L. P., Rosat, R. M., Ferreira, M. B., and Dalmaz, C. 2000. Interation between repeated restraint stress and concomitant midazolam administration on sweet food ingestion in rats. Braz. J. Med. Biol. Res. 33:1343-1350.

    Google Scholar 

  33. 33.

    Simansky, K. J. 1996. Serotonergic control of the organization of feeding and satiety. Behav. Brain Res. 73:37-42.

    Google Scholar 

  34. 34.

    Leibowitz, S. F. and Alexander, J. T. 1998. Hypothalamic serotonin in control of eating behavior, meal size, and body weight. Biol. Psychiatry 44:851-864.

    Google Scholar 

  35. 35.

    Wong, D. T., Reid, L. R., and Threlkeld, P. G. 1988. Suppression of food intake in rats by fluoxetine: Comparison of enantiomers and effects of serotonin antagonists: Pharmacol. Biochem. Behav. 31:475-479.

    Google Scholar 

  36. 36.

    Halford, J. C. and Blundell, J. E. 1996. Metergoline antagonizes fluoxetine-induced suppression of food intake but not changes in the behavioural satiety sequence. Pharmacol. Biochem. Behav. 54:745-751.

    Google Scholar 

  37. 37.

    Weiss, G. F., Rogacki, N., Fueg, A., Buchen, D., Suh, J. S., Wong, D. T., and Leibowitz, S. F. 1991. Effect of hypothalamic and peripheral fluoxetine injection on natural patterns of macronutrient intake in the rat. Psychopharmacology (Berl.) 105:467-476.

    Google Scholar 

  38. 38.

    Wurtman, R. J. and Wurtman, J. J. 1995. Brain serotonin, carbohydrate-craving, obesity and depression. Obes. Res. Suppl. 4:477S-480S.

    Google Scholar 

  39. 39.

    EI-Mallakh, R. S. and Wyatt, R. J. 1995. The Na, K-ATPase hypothesis for bipolar illness. Biol. Psychiatry 37:235-244.

    Google Scholar 

  40. 40.

    EI-Mallakh, R. S. and Li, R. 1993. Is the Na+-K+-ATPase the link between phosphoinositide metabolism and bipolar disorder? J. Neuropsychiatry 5:361-368.

    Google Scholar 

  41. 41.

    Farman, N., Bonvalet, J. P., and Seckl, J. R. 1994. Aldosterone selectively increases Na(+)-K(+)-ATPase alpha 3-subunit mRNA expression in rat hippocampus. Am. J. Physiol. 266(2 Pt 1):C423-428.

    Google Scholar 

  42. 42.

    Awaiss, D., Shao, Y., and Isamil-Beigi, F. 2000. Thyroid hormone regulation of myocardial Na/K-ATPase gene expression. J. Mol. Cell. Cardiology 32:1969-1980.

    Google Scholar 

  43. 43.

    Hernandez, R. J. 1992. Na+/K+-ATPase regulation by neurotransmitters. Neurochem. Int. 20:1-10.

    Google Scholar 

  44. 44.

    Swann, A. C. 1983. Stimulation of brain Na+, K+-ATPase by norepinephrine in vivo: Prevention by receptor antagonists and enhancement by repeated stimulation. Brain. Res. 260:338-341.

    Google Scholar 

  45. 45.

    Peña-Rangel, M. T., Rosalio Mercado, C., and Hernandez-Rodriguez, J. 1999. Regulation of glial Na+/K+ ATPase by serotonin: identification of participating receptors. Neurochem. Res. 24:643-649.

    Google Scholar 

  46. 46.

    Valentino, R. J. and Van Bockstaele, E. 2001. Opposing regulation of the locus coeruleus by corticotropin-releasing factor and opioids: Potential for reciprocal interactions between stress and opioid sensitivity. Psychopharmacology (Berl.) 158:331-342.

    Google Scholar 

  47. 47.

    Chaouloff, F. 1993. Physiopharmacological interactions between stress hormones and central serotonergic systems. Brain. Res. Rev. 18:1-32.

    Google Scholar 

  48. 48.

    Malyszko, J., Urano, T., Takada, Y., and Takada, A. 1994. Serotonergic systems in brain and blood under stress and tranylcypromine treatment in rats. Brain Res. Bull. 35:9-13.

    Google Scholar 

  49. 49.

    Ewart, H. S. and Klip, A. 1995. Hormonal regulation of the Na(+)-K(+)-ATPase: Mechanisms underlying rapid and sustained changes in pump activity. Am. J. Physiol. 269(2 Pt 1):C295-311.

    Google Scholar 

  50. 50.

    McEwen, B. S. 2001. Plasticity of the hippocampus: Adaptation to chronic stress and allostatic load. Ann. N. Y. Acad. Sci. 933:265-277.

    Google Scholar 

  51. 51.

    McEwen, B., Magarinos, A., and Reagan, L. 2002. Studies of hormone action in the hippocampal formation: Possible relevance to depression and diabetes: J. Psychosom. Res. 53:883.

    Google Scholar 

  52. 52.

    Duman, R. S., Heninger, G. R., and Nestler, E. J. 1997. A molecular and cellular theory of depression. Arch. Gen. Psychiatry 54:597-606.

    Google Scholar 

  53. 53.

    Hernandez, J. and Condes-Lara, M. 1989. Serotonin-dependent (Na+, K+)ATPase in kindled rats: A study in various brain regions. Brain. Res. 480:403-406.

    Google Scholar 

  54. 54.

    Reddy, P. L, Khanna, S., Subhash, M. N., Channabasavanna, S. M., and Rao, B. S. 1992. Erythrocyte membrane sodium-potassium adenosine triphosphatase activity in affective disorders. J. Neural. Transm. Gen. Sect. 89:209-218.

    Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Carla Dalmaz.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gamaro, G.D., Streck, E.L., Matté, C. et al. Reduction of Hippocampal Na+, K+-ATPase Activity in Rats Subjected to an Experimental Model of Depression. Neurochem Res 28, 1339–1344 (2003).

Download citation

  • Na+, K+-ATPase
  • fluoxetine
  • chronic mild stress
  • hippocampus
  • depression