Role of Receptor Coupling to Phosphoinositide Metabolism in the Therapeutic Action of Lithium

  • Robert H. Lenox
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 221)


Lithium is one of the most effective psychopharmacological treatments for affective illness and offers a potential avenue for furthering our understanding of the neurobiological components of this disorder. Among the most specific and potent actions of lithium is its ability to not only treat the acute episode of mania but also reduce the frequency and severity of recurrent episodes of mania and depression in bipolar patients and depression in unipolar patients (Bunney and Garland, 1984). Thus, the unique action of lithium appears to be its long-term ability to dampen pathological neurobiological oscillations in individuals vulnerable to profound cyclic affective disturbances.


Muscarinic Receptor Hippocampal Slice Phorbol Ester Affective Illness Inositol Phospholipid 
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  1. Ahluwalia, P and Singhal, R. L., Monamine uptake into synaptosomes from various regions of rat brain following lithium administration and withdrawal, Neuropharmacology 20: 483–487 (1981).CrossRefGoogle Scholar
  2. Akers, R. F., Lovinger, D. M., Colley, P. A., Linden, D. J. and Routtenberg, A., Translocation of PKC activity may mediate hippocampal long term potentiation. Science 231: 587–589 (1986).CrossRefGoogle Scholar
  3. Allison, J. H., Lithium and brain myo-inositol metabolism, in: Cyclitols and phosphoinositides, pp. 507, Wells, W. W. and Eisenberg, F., Jr. (eds.), Academic Press, New York (1978).Google Scholar
  4. Allison, J. H. and Blisner, M. E., Inhibition of the effect of lithium on brain inositol by atropine and scopolamine, Biochem. Biophys. Res. Commun. 68: 1332–1338 (1976).CrossRefGoogle Scholar
  5. Allison, J. H., Blisner, M. E., Holland, W. H., Hipps, P. P. and Sherman, W. R., Increased brain myo-inositol 1-phosphate in lithium-treated rats, Biochem. Biophys. Res. Commun. 71: 664–670 (1976).CrossRefGoogle Scholar
  6. Allison, J. H. and Stewart, M. A., Reduced brain inositol in lithium-treated rats, Nature (London) New. Biol. 233: 267–268 (1971).CrossRefGoogle Scholar
  7. Berridge, M. J., Phosphatidyinositol hydrolysis: A multifunctional transducing system, Mol. Cell Endocrinol. 24: 115–140 (1981).CrossRefGoogle Scholar
  8. Berridge, M. J., Inositol triphosphate and diacylglycerol as second messengers, Biochem. J. 220: 345–360 (1984).Google Scholar
  9. Berridge, M. J., Downes, C. P. and Hanley, M. R., Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands, Biochem. J. 206: 587–595 (1982).Google Scholar
  10. Berridge, M. J., Rapid accumulation of inositol trisphosphate reveals that agonists hydrolyse polyphosphoinositides instead of phosphatidylinositol, Biochem. J. 212: 849–858 (1983).Google Scholar
  11. Brown, E., Kendall, D. A. and Nahorski, S. R., Inositol phospholipid hydrolysis in rat cerebral coutical slices: I. receptor characterisation, J. Neurochem. 42: 1379–1387.Google Scholar
  12. Bunney, W. E. and Garland, B. L., Lithium and its possible modes of action in: Neurobiology of Mood Disorders, pp. 731–743, Post, R. M. and Ballenger, J. C. (eds.), Williams & Wilkins, Baltimore (1984).Google Scholar
  13. Butcher, L. L. and Woolf, N. J., Cholinergic systems: Synopsis of anatomy and overview of physiology and pathology, in: The Biological Substrates of Alzheimer’s Disease, pp. 73–86, Scheibel, A. B., Wechsler, A. F. and Brazier, M. A. B. (eds.), Academic Press, New York (1986).Google Scholar
  14. Cameron, O. G. and Smith, C. B., Comparison of acute and chronic lithium treatment on [3H]-norepinephrine uptake by rat brain slices, Psychopharmacology 67: 81–85 (1980).CrossRefGoogle Scholar
  15. Colburn, R. W., Goodwin, F. K., Bunney, W. E., Jr. and Davis, J. M., Effect of lithium on the uptake of noradrenaline by synaptosomes, Nature (London) 215: 1395–1397 (1967).CrossRefGoogle Scholar
  16. Cooper, R. H., Coll, K. E. and Williamson, J. R., Differential effects of phorbol ester on phenylephrine and vasopressin-induced Ca2+ mobilization in isolated hepatocytes, J. Biol. Chem. 260: 3281–3288 (1985).Google Scholar
  17. Corvera, S. and Garcia-Sainz, J. A., Phorbol esters inhibit alpha adrenergic stimulation of glycogenolysis isolated rat hepatocytes, Biochem. Biophys. Res. Comm. 119: 1128–1133 (1984).CrossRefGoogle Scholar
  18. Dilsaver, S. C., Lithium’s effects on muscarinic receptor binding parameters: a relationship to therapeutic efficacy, Biol. Psychiatry 19: 1551–1565 (1984).Google Scholar
  19. Dilsaver, S. C., Konfol, Z., Sackellars, J. C. and Greden, J. F., Antidepressent withdrawal syndromes: evidence supporting the cholinergic overdrive hypothesis, J. Clin. Psychopharm. 3: 157–164 (1983).Google Scholar
  20. Downes, C. P. and Stone, M. A., Lithium-induced reduction in intracellular inositol supply in cholinergically stimulated parotid gland, Biochem. J. 234: 199–204 (1986).Google Scholar
  21. Drummond, A. H. and Raeburn, C. A., The interaction of lithium with thyro-tropin-releasing hormone-stimulated lipid metabolism in GH pituitary tumour cells, Biochem. J. 224: 129–136 (1984).Google Scholar
  22. Ebstein, R. P., Lerer, B., Shlaufman, M. and Belmaker, R. H., ECS and noradrenaline release, in: ECT: Basic mechanisms, pp. 62–66, Lerer, B., Weiner, R. D. and Belmaker, R. H. (eds.), John Libbey and Company Limited, London (1984).Google Scholar
  23. Fisher, S. K., Figueiredo, J. C. and Bartus, R. T., Differential stimulation of inositol phospholipid turnover in brain by analogs of oxotremorine, J. Neurochem. 43: 1171–1179 (1984).CrossRefGoogle Scholar
  24. Gillin, C., Muscarinic supersensitivity in affective illness, Proceedings of the American Psychiatric Association, 138: 124 (1985).Google Scholar
  25. Gispen, W. H., Phosphoprotein B-50 and phosphoinositides in brain synaptic plasma membranes: a possible feedback relationship, Biochem. Soc. Transact. 14: 163 (1986).Google Scholar
  26. Gonzales, R. A. and Crews, F. T., Characterization of the cholinergic stimulation of phosphoinositide hydrolysis in rat brain slices, J. Neurosci., 4: 3120–3127 (1984).Google Scholar
  27. Goodnick, P. and Gershon, S., Lithium, in: Handbook of Neurochemistry, pp. 001.9, Lajtha, A. (ed.), Plenum Press, New York (1983).Google Scholar
  28. Hallcher, L. M. and Sherman, W. R., The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain, J. Biol. Chem. 255: 10896–10901 (1980).Google Scholar
  29. Hermoni, M., Lerer, B., Ebstein, R. P. and Belmaker, R. H., Chronic lithium prevents reserpine-induced supersensitivity of adenylate cyclase, J. Pharm. Pharmacol. 32: 510–511 (1980).CrossRefGoogle Scholar
  30. Ho, A. K. S., Loh, H. H., Graves, F., Hitzemann, R. J. and Gershon, S., The effect of prolonged lithium treatment on the synthesis rate and turnover of monoamines in brain regions of rats, Eur. J. Pharmacol. 10: 72–78 (1970).CrossRefGoogle Scholar
  31. Hobson, J. A., McCartey, R. W. and Wyzinski, P. N., Sleep cycle oscillation: Recipricol discharge by two brain stem neuronal groups, Science 189: 55–58 (1975).CrossRefGoogle Scholar
  32. Hokin, M. R. and Hokin, L. E., Enzyme secretion and the incorporation of 32P into phospholipids of pancreas slices, J. Biol. Chem. 203: 967–977 (1953).Google Scholar
  33. Hokin, M. R. and Hokin, L. E., Effects of acetylcholine on phospholipids in the pancreas, J. Biol. Chem. 209: 549–558 (1954).Google Scholar
  34. Honchar, M. P., Olney, J. W. and Sherman, W. R., Systemic cholinergic agents induce seizures and brain damage in lithium-treated rats, Science 220: 323–325 (1983).CrossRefGoogle Scholar
  35. Janowsky, A., Labarca, R. and Paul, S. M., Characterization of neurotransmitter receptor-mediated phosphotidylinositol hydrolysis in the rat hippocampus, Life Sci. 35: 1953–1961 (1984).CrossRefGoogle Scholar
  36. Janowsky, D. S., El-Yousef, M. K., Davis, J. M. and Sekerke, H. J., A cholinergic-adrenergic hypothesis of mania and depression, Lancet ii: 632–635 (1972).CrossRefGoogle Scholar
  37. Janowsky, D. S., Abrams, A. A., Groom, G. P., Judd, L. L. and Cloptin, P., Lithium antagonizes cholinergic behavioral effects in rodents, Psychopharmacology, 63: 147–150 (1979).CrossRefGoogle Scholar
  38. Janowsky, D. S., Risch, S. C., Judd, L. L., Huey, L. Y. and Parker, D. C., Brain cholinergic system and the pathogenesis of affective disorders, in: Central Cholinergic Mechanisms and Adaptive Dysfunctions, pp. 309–333, Singh, M. D., Warburton, D. M., Lal, H. and Mason, B. (eds.), Plenum Press, New York (1985).CrossRefGoogle Scholar
  39. Jolles, J., Zwiers, H., Van Dongen, C. J., Schotman, P., Wirtz, K. W. A. and Gispen, W. H., Modulation of brain polyphosphoinositide metabolism by ACTH sensitive protein phosphorylation, Nature 286: 623 (1980).CrossRefGoogle Scholar
  40. Jope, R. S., Effects of lithium treatment in vitro and in vivo on acetylcholine metabolism in rat brain, J. Neurochem. 33: 487–495 (1979).CrossRefGoogle Scholar
  41. Kafka, M. S., Wirz-Justice, A., Naber, D., Marangos, P. J., O’Donohue, T. L. and Wehr, T. A., The effect of lithium on circadian neurotransmitter receptor rhythms, Neuropsychobiology 8: 41–50 (1982).CrossRefGoogle Scholar
  42. Kuriyama, K. and Speken, R., Effect of lithium on content and uptake of norepinephrine and 5-hydroxytryptamine in mouse brain synaptosomes and mitochondria, Life Sci. 9: 1213–1220 (1970).CrossRefGoogle Scholar
  43. Labarca, R., Janowsky, A., Patel, J. and Paul, S. M., Phorbol esters inhibit agonist-induced [3H] inositol-1-phosphate accumulation in rat hippocampal slices, Biochem. Biophys. Res. Comm., 123: 703–709 (1984).CrossRefGoogle Scholar
  44. Lenox, R. H., Hendley, D. D. and Ellis, J., Receptor coupled hydrolysis of phosphoinositides in hippocampal slices: Muscarinic vs adrenergic, New York Acad. Sci. 736 (19871987).Google Scholar
  45. Lenox, R. H., Meyers, S., Hendley, D., Ellis, J. and Ehrlich, Y. H., Effects of chronic lithium on protein kinase C activity in rat brain, Society for Neuroscience Abstracts, 12: 566 (1986).Google Scholar
  46. Lerer, B., Studies on the role of brain cholinergic systems in the therapeutic mechanisms and adverse effects of ECT and lithium, Biol. Psychiat. 20: 20–40 (1985).CrossRefGoogle Scholar
  47. Lerer, B. and Stanley, M., Effect of chronic lithium on cholinergically mediated responses and [3H]QNB binding in rat brain, Brain Res. 334: 211–219 (1985).CrossRefGoogle Scholar
  48. Levy, A., Zohar, J. and Belmaker, R. H., The effect of chronic lithium pretreatment on rat brain muscarinic receptor regulation, Neuropharmacology 21: 1199–1201 (1982).CrossRefGoogle Scholar
  49. Maggi, A. and Enna, S. J., Regional alterations in rat brain neurotransmitter systems following chronic lithium treatment, J. Neurochem 34: 888–889 (1980).CrossRefGoogle Scholar
  50. Mash, D. C., Flynn, D. D. and Potter, L. T., Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer’s disease and experimental cholinergic denervation, Science 228: 1115–1117 (1985).CrossRefGoogle Scholar
  51. Micheli, R. H., Inositol phospholipids and cell surface receptor function, Biochem. Biophys. Acta. 415: 81–147 (1975).CrossRefGoogle Scholar
  52. Miyauchi, T., Oikawa, S. and Kitada, Y., Effects of lithium chloride on the cholinergic system in different brain regions in mice, Biochem. Pharmacol. 29: 654–657 (1980).CrossRefGoogle Scholar
  53. Nishizuka, Y., The role of protein kinase C in cell surface signal transduction and tumour promotion, Nature 308: 693–698 (1984a).CrossRefGoogle Scholar
  54. Nishizuka, Y., Turnover of inositol phospholipids and signal transduction, Science 225: 1365–1370 (1984b).CrossRefGoogle Scholar
  55. Nishizuka, Y., Studies and perspectives of protein kinase C., Science 233: 305–312 (1986).CrossRefGoogle Scholar
  56. Oppenheim, G., Ebstein, R. P. and Belmaker, R., Effect of lithium on the physostigmine-induced behavioral syndrome and plasma cyclic GMP, J. Psychiat. Res. 15: 133–138 (1979).CrossRefGoogle Scholar
  57. Poitou, P. and Bohuon, C., Catecholamine metabolism in the rat brain after short and long term lithium administration, J. Neurochem. 25: 535–537 (1975).CrossRefGoogle Scholar
  58. Raiteri, M., Leardi, R. and Marchi, M., Heterogeneity of presynaptic muscarinic receptors regulating neurotransmitter release in the rat brain, J. Pharmacol. and Exp. Ther. 228: 209–214 (1984).Google Scholar
  59. Risch, S. G. and Janowsky, D. S., Cholinergic-adrenergic balance in affective illness, in: Neurobiology of Mood Disorders pp. 652–663, Post R. M. and Ballenger, J. C. (eds.), Williams and Wilkins, Baltimore (1984).Google Scholar
  60. Robinson, S. E., Cholinergic pathways in the brain, in: Central Cholinergic Mechanisms and Adaptive Dysfunctions, pp. 37–61, Singh, M. M., Warburton, D. M., Lal, H., Mason, B. (eds.), Plenum Press, New York (1985).CrossRefGoogle Scholar
  61. Robinson, S. E., Cheney, D. L. and Costa, E., Effect of nomifensine and other antidepressant drugs on acetylcholine turnover in various regions of rat brain, Naunyn. Schmeid. Arch. Pharmacol. 304: 263–269 (1978).CrossRefGoogle Scholar
  62. Rosenblatt, J. E., Pert, C. B., Tallman, J. F., Pert, A. and Bunney, W. E., Jr., The effect of imipramine and lithium on alpha and beta receptor binding in rat brain, Brain Res. 160: 186–191 (1979).CrossRefGoogle Scholar
  63. Samples, J., Janowsky, D. S., Pechnick, R. and Judd, L. L., Lethal effects of physostigmine plus lithium in rats, Psychopharmacology 52: 307–309 (1977).CrossRefGoogle Scholar
  64. Schildkraut, J. J., Logue, M. A. and Dodge, G. A., The effect of lithium salts on the turnover and metabolism of norepinephrine in rat brain, Psychopharmacology 14: 135–141 (1969).CrossRefGoogle Scholar
  65. Schrama, L. H., De Graan, P. N. E., Eichberg, J. and Gispen, W. H., Feedback control of inositol phospholipid response in rat brain is sensitive to ACTH, Eur. J. Pharmacol. 121: 403 (1986).CrossRefGoogle Scholar
  66. Schubert, J., Effect of chronic lithium treatment on monoamine metabolism in the rat brain, Psychopharmacology 32: 301–311 (1973).CrossRefGoogle Scholar
  67. Sherman, W. R., Leavitt, A. L., Honchar, M. P., Hallcher, L. M. and Phillips, B. E., Evidence that lithium alters phosphoinositide metabolism: chronic administration elevates primarily d-myo-inositol-1-phosphate in cerebral cortex of the rat, J. Neurochem. 36: 1947–1951 (1981).CrossRefGoogle Scholar
  68. Sherman, W. R., Munsell, L. Y., Gish, B. G. and Honchar, M. P., Effects of systemically administered lithium on phosphoinositide metabolism in rat brain, kidney, and testis, J. Neurochem. 44: 798–807 (1985).CrossRefGoogle Scholar
  69. Sitaram, N., Gillin, J. C. and Bunney, W. E., Cholinergic and catecholaminergic receptor sensitivity in affective illness: Strategy and theory, in: Neurobiology of Mood Disorders, pp. 629–651, Post, R. M. and Ballenger, J. C. (ed.), Williams and Wilkins, Baltimore (1984).Google Scholar
  70. Treiser, S. and Kellar, K. J., Lithium effects on adrenergic receptor supersensitivity in rat brain, Eur. J. Pharmacol. 58: 85–86 (1979).CrossRefGoogle Scholar
  71. Van Rooijen, L. A. A., Rossowska, M. and Bazan, N. G., Inhibition of phosphatidylinositol-4-phosphate kinase by its product phosphatidylinositol-4,5-bisphosphate, Biochem. Biophys. Res. Commun. 126: 150 (1985).CrossRefGoogle Scholar
  72. Williamson, J. R., Role of inositol lipid breakdown in the generation of intracellular signals, Hypertension 8: 140–156 (1986).Google Scholar
  73. Wolf, M., Levine, H. III, May, S. W., Cuatrecasas, P. and Sahyoun, J., A model for intracellular translocation of protein kinase C involving synergism between Ca++ and phorbol esters, Nature 317: 546–549 (1985).CrossRefGoogle Scholar
  74. Worley, P. F., Baraban, J. M. and Snyder, S. H., Heterogeneous localization of protein kinase C in rat brain: Autoradiographic analysis of phorbol ester receptor binding, J. Neurosci. 6(1): 199–207 (1986).Google Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Robert H. Lenox
    • 1
  1. 1.Neuroscience Research Unit, Department of Psychiatry College of MedicineUniversity of VermontBurlingtonUSA

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