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A cell membrane correlate of tardive dyskinesia in patients treated with phenothiazines

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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.

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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

    Google Scholar 

  • 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

    Google Scholar 

  • Chen RF, Smith PD, Maly M (1978) The fluorescence of flourescamine amino acids. Arch Biochem Biophys 189:241–250

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • Cohen BM, Zubenko GS (1985a) Aging and the physical properties of cell membranes. Life Sci 37:1403–1409.

    Google Scholar 

  • 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

    Google Scholar 

  • Crews FT, Majchrowicz E, Meeks R (1983) Changes in cortical synaptosomal plasma membrane fluidity and composition in ethanol-dependent rats. Psychopharmacology 81:208–213

    Google Scholar 

  • Csernansky J, Kaplan J, Holman CA, Hollister LE (1983) Serum neuroleptic activity, prolactin, and tardive dyskinesia in schizophrenic outpatients. Psychopharmacology 81:115–118

    Google Scholar 

  • Davis KL, Berger PA, Hollister LE (1976) Tardive dyskinesia and depressive illness. Psychopharmacol Commun 2:125–130

    Google Scholar 

  • Delwaide PJ, Desseilles M (1977) Spontaneous bucco-lingual-facial dyskinesia in the elderly. Acta Neurol Scand 56:256–262

    Google Scholar 

  • Despopoulos A (1970) Antihemolytic actions of tricyclic tranquilizers. Biochem Pharmacol 19:2907–2914

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • Growdon JH, Gelenberg AJ, Dollar JC, Hirsch MJ, Wurtman RJ (1978) Lecithin can suppress tardive dyskinesia. N Engl J Med 298:1029–1030

    Google Scholar 

  • Guy W (1976) ECEDU Assessment Manual for Psychopharmacology, NIMH Psychopharmacology Research Branch, Rockville, MD

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • Harris RA, Schroeder F (1982) Effects of barbiturates and ethanol on the physical properties of brain membranes. J Pharmacol Exp Ther 223:424–431

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • Hirata F, Axelrod J (1978) Enzymatic methylation of phosphatidylethanolamine increases erythrocyte membrane fluidity. Nature 275:219–220

    Google Scholar 

  • Hirata F, Axelrod J (1980) Phospholipid methylation and biological signal transmission. Science 209:1082–1090

    Google Scholar 

  • Insel PA, Nirenberg P, Turnbull J, Shattil SJ (1978) Relationships between membrane cholesterol, alpha-adrenergic receptors, and platelet function. Biochemistry 17:5269–5274

    Google Scholar 

  • Jeste DV, Rosenblatt JE, Wagner RL, Wyatt JR (1979) High serum neuroleptic levels in tardive dyskinesia. New Eng J Med 301:1184

    Google Scholar 

  • 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

    Google Scholar 

  • Jeste DV, Markku L, Wagner RL, Wyatt RJ (1982) Serum neuroleptic concentrations and tardive dyskinesia. Psychopharmacology 76:377–380

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • Lakowicz JR (1983) Principles of Fluorescence Spectroscopy. Plenum Press, New York

    Google Scholar 

  • 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

    Google Scholar 

  • Mavis RD, Vagelos PR (1972) The effect of phospholipid fatty acid composition on membrane enzymes inEscherichia coli. J Biol Chem 247:652–659

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • Podo F, Blasie JD (1977) Nuclear magnetic resonance of lecithin bimolecular leaflets with incorporated fluorescent probes. Proc Natl Acad Sci USA 74:1032–1036

    Google Scholar 

  • 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

    Google Scholar 

  • Radda GD (1971) The design and use of fluorescent probes for membrane studies. Curr Top Bioenerg 4:81–126

    Google Scholar 

  • Radda GD, Vanderkooi J (1972) Can fluorescent probes tell us anything about membranes? Biochim Biophys Acta 265:509–549

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • Rosenbaum AH, Hiven RG, Hanson NP, Swanson DW (1977) Tardive dyskinesia: Relationship with a primary affective disorder. Dis Nerv Syst 38:423–427

    Google Scholar 

  • Schreier S, Polnaszek CF, Smith ICP (1978) Spin labels in membranes: Problems in practice. Biochim Biophys Acta 515:375–436

    Google Scholar 

  • Seeman P (1972) The membrane actions of anesthetics and tranquilizers. Pharmacol Rev 24:583–655

    Google Scholar 

  • Seeman P (1977) Anti-schizophrenic drugs — membrane receptor sites of action. Biochem Pharmacol 26:1741–1748

    Google Scholar 

  • Shinitzky M, Barenholz Y (1974) Dynamics of the hydrocarbon layer in liposomes of lecithin and sphingomyelin containing dicetylphosphate. J Biol Chem 239:2652–2657

    Google Scholar 

  • Shinitzky M, Barenholz Y (1978) Fluidity parameters of lipid regions determined by fluorescence polarization. Biochem Biophys Acta 515:367–394

    Google Scholar 

  • Simpson GM, Varga E, Lee JH, Zoubok B (1978) Tardive dyskinesia and psychotropic drug history. Psychopharmacology 58:117–124

    Google Scholar 

  • 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

    Google Scholar 

  • Smith JM, Oswald WT, Kucharski LT, Waterman LJ (1978) Tardive dyskinesia; Age and sex differences in hospitalized schizophrenics. Psychopharmacology 58:207–211

    Google Scholar 

  • Strittmatter WJ, Hirata F, Axelrod J (1979) Phospholipid methylation unmasks cryptic beta-adrenenergic receptors in rat reticulocytes. Science 204:1205–1207

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • Ueno E, Kuriyama K (1981) Phospholipids and benzodiazepine recognition sites of brain synaptic membranes. Neuropharmacology 20:1169–1176

    Google Scholar 

  • 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

    Google Scholar 

  • Waggoner AS, Stryer L (1970) Fluorescent probes of biological membranes. Proc Natl Acad Sci USA 67:579–589

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • Yassa R, Ghadirian AM, Schwartz G (1983) The prevalence of tardive dyskinesia in affective disease patients. J Clin Psychiatr 44:410–412

    Google Scholar 

  • Yguarabide J, Stryer L (1971) Fluorescent spectroscopy of an oriented model membrane. Proc Natl Acad Sci USA 68:117–1221

    Google Scholar 

  • 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

    Google Scholar 

  • Zubenko G, Cohen BM (1984) In vitro effects of psychotropic agents on the microviscosity of platelet membranes. Psychopharmacology 84:289–292

    Google Scholar 

  • Zubenko GW, Cohen BM (1985a) Effects of phenothiazine treatment on the physical properties of platelet membranes from psychiatric patients. Biol Psychiatry 20:384–396

    Google Scholar 

  • Zubenko GS, Cohen BM (1985b) Effects of psychotropic agents on the physical properties of platelet membranes in vitro. Psychopharmacology 88

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Authors and Affiliations

  1. Western Psychiatric Institute and Clinic, Department of Psychiatry University of Pittsburgh School of Medicine, 3811 O'Hara Street, 15213, Pittsburg, PA, USA

    George S. Zubenko

  2. Department of Biological Sciences, Mellon Institute, Carnegie-Mellon University, 15213, Pittsburgh, PA, USA

    George S. Zubenko

  3. Laboratories for Psychiatric Research Mailman Research Center, McLean Hospital, 115 Mill Street, 02178, Belmont, MA, USA

    Bruce M. Cohen

  4. Harvard Medical School, 02115, Boston, MA, USA

    Bruce M. Cohen

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  1. George S. Zubenko
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  2. Bruce M. Cohen
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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

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  • DOI: https://doi.org/10.1007/BF00652246

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