Abstract
Phenothiazine administration to psychiatric patients is associated with an increase in the “structural order” of platelet membranes as determined by steady-state fluorescence polarization measurements with 1,6-diphenyl-1,3,5-hexatriene (DPH), a fluorescent probe that localizes preferentially in the hydrocarbon region of cell membranes (Zubenko and Cohen 1984, 1985a, b). In this study, platelet membranes prepared from a group of psychiatric patients who developed tardive dyskinesia following chronic treatment with phenothiazines exhibited a significant elevation in DPH fluorescence polarization when compared to similar preparations from an otherwise matched group of patients who had no symptoms or history of tardive dyskinesia. The distribution of polarization values obtained for the tardive dyskinesia group displayed minimal overlap with that of an unmedicated, psychiatrically-healthy control group matched for age and gender. The fluorescence polarization of DPH-labelled platelet membranes was not significantly correlated with phenothiazine daily dose or serum cholesterol concentration in the phenothiazine-treated patient groups, or with dyskinesia severity (AIMS rating) in the tardive dyskinesia group. Patient gender and the presence of an affective disorder did not significantly correlate with DPH fluorescence polarization. The potential physiological and clinical significance of these findings is discussed.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
APA Task Force Report (1980) Tardive Dyskinesia, Baldessarini RJ (chairperson), American Psychiatric Association, Washington, D.C.
Alivisatos SGS, Papastavrou C, Dourka-Liapati E, Molyvdas AP, Mikitopoulou G (1977) Enzymatic and electrophysiological changes in the function of membrane proteins by cholesterol. Biochem Biophys Res Commun 79:677–683
Boudet G, Levy-Toledano S, Maclouf J, Rendu F, Salesse R (1985) Change in the physical state of platelet plasma membranes upon ionophore A23187 activation. A fluorescence polarization study. Biochem Biophys Acta 812:243–248
Chen RF, Smith PD, Maly M (1978) The fluorescence of flourescamine amino acids. Arch Biochem Biophys 189:241–250
Chin JH, Goldstein DB (1977) Effects of low concentrations of ethanol on the fluidity of spin-labelled erythrocyte and brain membranes. Mol Pharmacol 13:435–441
Cohen BM (1983) The clinical utility of plasma neuroleptic levels. In: Stancer HC (ed) Guidelines for the use of psychotropic drugs. Spectrum Publications Inc, Jamaica, NY
Cohen BM, Zubenko GS (1985a) Aging and the physical properties of cell membranes. Life Sci 37:1403–1409.
Cohen BM, Zubenko GS (1985b) In vivo effects of psychotropic agents on the physical properties of cell membranes in the rat brain. Psychopharmacology (in press)
Crews FT (1982) Effects of membrane fluidity on secretion and receptor stimulation. Psychopharmacol Bull 18:135–143
Crews FT, Majchrowicz E, Meeks R (1983) Changes in cortical synaptosomal plasma membrane fluidity and composition in ethanol-dependent rats. Psychopharmacology 81:208–213
Csernansky J, Kaplan J, Holman CA, Hollister LE (1983) Serum neuroleptic activity, prolactin, and tardive dyskinesia in schizophrenic outpatients. Psychopharmacology 81:115–118
Davis KL, Berger PA, Hollister LE (1976) Tardive dyskinesia and depressive illness. Psychopharmacol Commun 2:125–130
Delwaide PJ, Desseilles M (1977) Spontaneous bucco-lingual-facial dyskinesia in the elderly. Acta Neurol Scand 56:256–262
Despopoulos A (1970) Antihemolytic actions of tricyclic tranquilizers. Biochem Pharmacol 19:2907–2914
Farias RN, Bloj B, Morero RD, Sineriz F, Trucco RD (1975) Regulation of allosteric membrane-bound enzymes through changes in membrane lipid composition. Biochim Biophys Acta 414:213–251
Frenzel J, Arnold K, Nuhn P (1978) Calorimetric,13C NMR, and31P NMR studies of the interaction of some phenothiazine derivatives with dipalmitoyl phosphatidylcholine model membranes. Biochim Biophys Acta 507:185–197
Gelenberg AJ, Wojcik JD, Growdon JH (1979) Lecithin for the treatment of tardive dyskinesia. In: Barbeau A, Growdon JH, Wurtman RJ (eds) Nutrition and the brain. Raven Press, New York
Growdon JH, Gelenberg AJ, Dollar JC, Hirsch MJ, Wurtman RJ (1978) Lecithin can suppress tardive dyskinesia. N Engl J Med 298:1029–1030
Guy W (1976) ECEDU Assessment Manual for Psychopharmacology, NIMH Psychopharmacology Research Branch, Rockville, MD
Hanski E, Levitzki A (1978) The absence of desensitization in the adrenergic receptors of turkey reticulocytes and erythrocyters and its possible origin. Life Sci 22:53–60
Harris RA, Baxter DM, Mitchell MA, Hitzemann RJ (1984) Physical properties and lipid composition of brain membranes from ethanol tolerant-dependent mice. Mol Pharmacol 25:401–409
Harris RA, Schroeder F (1982) Effects of barbiturates and ethanol on the physical properties of brain membranes. J Pharmacol Exp Ther 223:424–431
Hawkes SP, Meeham TD, Bissell MJ (1976) The use of fluorescamine as a probe for labelling the outer surface of the plasma membrane. Biochem Biophys Res Commun 68:1226–1233
Heron DS, Hershkowitz M, Shinitzky M, Samuel D (1980a) The lipid fluidity of synaptic membranes and the binding of serotonin and opiate ligands. In: Ertlane UZ, Duai Y, Silman S, Teichberg VI, Vogel Z (eds) Neurotransmitters and their receptors. John Wiley and Sons, New York
Heron DS, Shinitzky M, Hershowitz M, Samuel D (1980b) Lipid fluidity markedly modules the binding of serotonin to mouse brain membranes. Proc Natl Acad Sci USA 77:7463–7467
Hirata F, Axelrod J (1978) Enzymatic methylation of phosphatidylethanolamine increases erythrocyte membrane fluidity. Nature 275:219–220
Hirata F, Axelrod J (1980) Phospholipid methylation and biological signal transmission. Science 209:1082–1090
Insel PA, Nirenberg P, Turnbull J, Shattil SJ (1978) Relationships between membrane cholesterol, alpha-adrenergic receptors, and platelet function. Biochemistry 17:5269–5274
Jeste DV, Rosenblatt JE, Wagner RL, Wyatt JR (1979) High serum neuroleptic levels in tardive dyskinesia. New Eng J Med 301:1184
Jeste DV, DeLisi LE, Zalcman S, Wise CD, Phelps BH, Rosenblatt JE, Potkin SG, Bridge TP, Wyatt RJ (1981) A biochemical study of tardive dyskinesia in young male patients. Psychiatr Res 4:327–331
Jeste DV, Markku L, Wagner RL, Wyatt RJ (1982) Serum neuroleptic concentrations and tardive dyskinesia. Psychopharmacology 76:377–380
Johnson DA, Lee NM, Cooke R, Loh HH (1980) Adaptation to ethanol-induced fluidization of brain lipid bilayer: cross tolerance and reversibility. Mol Pharmacol 17:52–55
Kawato S, Kinosita K Jr, Ikegami A (1977) Dynamic structure of biological membranes as probed by 1,6-diphenyl 1,3,5-hexatriene: A nanosecond fluorescence polarization study. Biochemistry 20:4270–4277
Kimelberg HK (1975) Alterations in phospholipid-dependent (Na+-K+) ATPase activity due to lipid fluidity effects of cholesterol and Mg2+. Biochim Biophys Acta 413:143–156
Klein I, Moore L, Pastan I (1978) Effect of liposomes containing cholesterol on adenylate cyclase activity of cultured mammalian fibroblasts. Biochim Biophys Acta 506:42–53
Lakowicz JR, Prendergast FG, Hogen D (1979) Differential polarized phase fluorometric investigations of diphenylhexatriene in lipid bilayers. Quantitation of hindered depolarization rotations. Biochemistry 18:508–519
Lakowicz JR (1983) Principles of Fluorescence Spectroscopy. Plenum Press, New York
Loh H, Hitzemann RJ (1981) Synaptic membrane structure as a determinant of CNS drug actions and interactions. Rev Drug Metab Drug Interact 3:155–194
Mavis RD, Vagelos PR (1972) The effect of phospholipid fatty acid composition on membrane enzymes inEscherichia coli. J Biol Chem 247:652–659
Ogiso T, Iwaki M, Mori K (1981) Fluidity of human erythorocyte membrane and effect of chlorpromazine on fluidity and phase separation of membrane. Biochim Biophys Acta 649:547–552
Pang K-Y, Chang T-L, Miller KW (1979) On the coupling between anesthetic induced membrane fluidization and cation permeability in lipid vesicles. Mol Pharmacol 15:129–138
Perlman BJ, Goldstein DB (1984) Genetic influences on the central nervous system depressant and membrane-disordering actions of ethanol and sodium valproate. Mol Pharmacol 26:547–552
Podo F, Blasie JD (1977) Nuclear magnetic resonance of lecithin bimolecular leaflets with incorporated fluorescent probes. Proc Natl Acad Sci USA 74:1032–1036
Pottell H, Van der Meer W, Herreman W (1983) Correlation between the order parameter and the steady-state fluorescence anisotropy of 1,6-diphenyl 1,3,5-hexatriene and an evaluation of membrane fluidity. Biochim Biophys Acta 730:181–186
Radda GD (1971) The design and use of fluorescent probes for membrane studies. Curr Top Bioenerg 4:81–126
Radda GD, Vanderkooi J (1972) Can fluorescent probes tell us anything about membranes? Biochim Biophys Acta 265:509–549
Raisman R, Sechter E, Briley MS, Zarifian E, Langer SZ (1981) High affinity3H-imipramine binding in platelets from untreated depressed patients compared to healthy volunteers. Psychopharmacology 77:332–335
Rivnay B, Bergman S, Shinitzky M, Gloverson A (1980) Correlations between membrane viscosity, serum cholesterol, lymphocyte activation, and aging in man. Mech Ageing Dev 12:119–126
Rosenbaum AH, Hiven RG, Hanson NP, Swanson DW (1977) Tardive dyskinesia: Relationship with a primary affective disorder. Dis Nerv Syst 38:423–427
Schreier S, Polnaszek CF, Smith ICP (1978) Spin labels in membranes: Problems in practice. Biochim Biophys Acta 515:375–436
Seeman P (1972) The membrane actions of anesthetics and tranquilizers. Pharmacol Rev 24:583–655
Seeman P (1977) Anti-schizophrenic drugs — membrane receptor sites of action. Biochem Pharmacol 26:1741–1748
Shinitzky M, Barenholz Y (1974) Dynamics of the hydrocarbon layer in liposomes of lecithin and sphingomyelin containing dicetylphosphate. J Biol Chem 239:2652–2657
Shinitzky M, Barenholz Y (1978) Fluidity parameters of lipid regions determined by fluorescence polarization. Biochem Biophys Acta 515:367–394
Simpson GM, Varga E, Lee JH, Zoubok B (1978) Tardive dyskinesia and psychotropic drug history. Psychopharmacology 58:117–124
Sinensky M (1974) Homeoviscous adaption: A homeostatic process that regulates the viscosity of membrane lipids inEscherichia coli. Proc Natl Acad Sci USA 71:522–525
Smith JM, Oswald WT, Kucharski LT, Waterman LJ (1978) Tardive dyskinesia; Age and sex differences in hospitalized schizophrenics. Psychopharmacology 58:207–211
Strittmatter WJ, Hirata F, Axelrod J (1979) Phospholipid methylation unmasks cryptic beta-adrenenergic receptors in rat reticulocytes. Science 204:1205–1207
Thulborn KR, Sawyer WH (1978) Properties and the locations of a set of fluorescent probes sensitive to the fluidity gradient of the lipid bilayer. Biochim Biophys Acta 511:125–140
Thulborn KR, Trelor FE, Sawyer WH (1978) A microviscosity barrier in the lipid bilayer due to the presence of phospholipids containing unsaturated acyl chains. Biochem Biophys Res Commun 81:42–49
Ueno E, Kuriyama K (1981) Phospholipids and benzodiazepine recognition sites of brain synaptic membranes. Neuropharmacology 20:1169–1176
Van Blitterswijk WJ, Van Hoeven RP, Van der Meer BW (1981) Lipid structural order parameters (reciprocal of fluidity) in biomembranes derived from steady-state fluorescence polarization measurements. Biochim Biophys Acta 644:323–332
Waggoner AS, Stryer L (1970) Fluorescent probes of biological membranes. Proc Natl Acad Sci USA 67:579–589
Whitkin JC, Gordon RK, Corwin LM, Simons ER (1982) The effect of vitamin E deficiency on some platelet membrane properties. J Lipid Res 23:276–282
Widerlöv E, Häggström Kilts CD, Andersson U, Breese GR, Mailman RB (1982) Serum concentrations of thioridazine, its major metabolites and serum neuroleptic-like activities in schizophrenics with and without tardive dyskinesia. Acta Psychiatr Scand 66:294–305
Yassa R, Ghadirian AM, Schwartz G (1983) The prevalence of tardive dyskinesia in affective disease patients. J Clin Psychiatr 44:410–412
Yguarabide J, Stryer L (1971) Fluorescent spectroscopy of an oriented model membrane. Proc Natl Acad Sci USA 68:117–1221
Zimmer G (1984) Fluidity of cell membranes in the presence of some drugs and inhibitors. In: Kates M, Manson LA (eds) Biomembranes, Volume 12. Plenum Press, New York, pp 169–203
Zubenko G, Cohen BM (1984) In vitro effects of psychotropic agents on the microviscosity of platelet membranes. Psychopharmacology 84:289–292
Zubenko GW, Cohen BM (1985a) Effects of phenothiazine treatment on the physical properties of platelet membranes from psychiatric patients. Biol Psychiatry 20:384–396
Zubenko GS, Cohen BM (1985b) Effects of psychotropic agents on the physical properties of platelet membranes in vitro. Psychopharmacology 88
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Zubenko, G.S., Cohen, B.M. A cell membrane correlate of tardive dyskinesia in patients treated with phenothiazines. Psychopharmacologia 88, 230–236 (1986). https://doi.org/10.1007/BF00652246
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00652246