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SCL E NCE chlorpromazine , on dopamine receptor function , as measured by 13Hlspiroperidol binding in rat striatum. Two series of drug studies were under.reprint Series taken in male Sprague-Dawley rats to I I December 1981. Volume 214 , pp. 1261-1262 examine (i) PLG-haloperidol interaction and (ii) PLG-chlorpromazine interaction. The experimental protocols for the drug treatments of various groups of animals are described in Tables I and 2. The procedure of Creese el ill. (9) was adopted for the 1-phenyl-4-'1-1lspiroperidol (25.64 Ci/nimole: New England Nuclear) binding assay. The specific binding of 13H]spiropcridol was defined as the difference in binding in the presence and absence of 500 Of of unlabeled Neuroleptic Drug - Induced Dopamine Receptor Supersensitivity: spiroperidol. The binding data were analyzed by the Scatchard plot from which Antagonism by L-ProlyI-i.-Leucyl-Glycinanlide the binding parameters, maximal number of binding sites (/1,,,;,x), and dissociation ' the potential evaluate used to u,a.s An animal nrodel of tardive dv.skirtesia Abstract. constant (K,I) were derived by linear antidvskine tie properties o/the ru'uropeptide t.-proh•I-/.-leiii v! irtontide (!'1,G). In regression analysis. The biochemical the nenrolepiir drug haloperidol or sills rats, !'LG administered concurrently data from different groups of animals piropcridol binding in is 'entent of .speri/u ell enlranc ed the chlorpromazine antagoniz were analyzed statistically by one-way the striation that is associated r' it/t long-terni neuroleptic treatment. The results are analysis of variance followed by the discussed in relation to if po.ssible.%unctional ronplin,e of the pn/otit•e PLG receptor Duncan multiple range test. neta'oleptic-dopamine receptor sonrple.r curd clinical intplicationc Jim tardier frith Our results indicate that Scatchard dv.skinesia. plots obtained from normal saline-control rats yielded a single class of noninhavioral responses toward dopamine agAntipsychotics belonging to the chemteracting binding sites with a 11,,, of onists (5). The potential antidyskinetic ical classes of butyrophenone. phenothi317 ± 25 fmole per milligram of protein properties of PLG. a neuropeptide deazine, and thioxanthene are thought to and K5 of 0.52 ± 0.20 nrl1. Protracted rived from the carboxyl terminal of oxyexert their therapeutic eflects by selectreatment with haloperidol and chlorprotocin (6). have not been critically investitively blocking central dopamine recepmazine resulted in significant (I' < .1)5) gated. We found that PLO antagonized tors M. Prolonged neuroleptic therapy elevation of the receptor density of morphine- (7) and haloperidol-induced in the management of psychiatric pa(HJspiroperitlol in rat striatum Cl-able (8) catalepsy and selectively enhanced tients, however, has produced a variety I). compared to that in the saline conthe affinity of the 131-1 Iapomorphine bindof extrapyramidal motor disorders, tartrols. Haloperidol (3 mg/kg. intraperitoing to neuroleptic-dopamitic receptors in dive dyskinesia being the most prevaneally) administered once daily for 21 rat striatum (8). To investigate the possilent. Animal models of tardive dyskinedays caused if mean increase of 58 He desensitizing effect of PLC; on dopasia have been developed in rodents and percent in the 13,,,;,, of 13H ]spi[ Opel idol ntinergic supersensitivity, we studied the nonhuman primates. and such studies binding over the saline controls. wherein chronic effects of PLG. when adminissuggest that supersensitivity of dopaniinchlorpromazine (2(1 mg/kg. iniraperitonelercd concurrently with haloperidol or ergic neuronal systems in the Nasal gan- 3 glia is the primary niechanisni of tardivc dyskinesia (2). Diverse pharmacological approaches have been attempted to reverse or prevent tardive dyskiticsi;i. hill none has yielded a consistent and favorable clinical outcome (?): differential modification of the sensitivity of dopamine receptors remains the preferred theoretical basis for designing therapeutic agents to alleviate tardive dyskmesia. Clinical studies indicated that lithium and t_-prolyl- i--Icticyl-glycinaniide (PLG) transiently but significantly reduced the intensity of dyskinetic symptoms associated with protracted antipsychotic therapy (4). In rats, prolonged lithium treatment in conjunction with neuroleptics abolished both the biochemical and behavioral manifestations of dopantinergic supersensitivity: such treatment enhanced neuroleptic-dopamine receptor binding and augntrnted stereotyped he- Table I. Blockade of haloperidol (IIAL)-induced increase inspector I'Illspiropcridol binding by I -prolyl-l -lcucyl-glycinamide (I'I,(;). Male Sprague-I)awtey rats weighing 2(1(1 it) '50 g were randomly assigned to six groups and received various drug dosages or 21 days according to the living protocol: group I was given isotonic saline 1 I nil/kg. subcutaneous)v(: groups 2 and 3 sere administered ('LG at the respective (loses of Itl and 40 rag/kg. subcutaneously: groups 4 and S cede dosed respectively wills I,I.(i a1 111 and 411 mg/kg. suhcuLmeously. III seconds before administration of haloperidol (3 mg/kg. intraperitoneally). and group 6 received h:dopeodol O mg/kg. inliapcritoneallyl only. The animals were killed 5 days al5er the list drug session and I'Itl.piropelidol binding was citified out on suiala. The striatum holli each rat in the dillclent treatment groups wi', used fin' one Scalchard plot of I'lllspirlperidol binding from which the mean valises and standard errors of H, and K,I were determined. Grou p Treltlnenl N I 2 Saline PLG I'I.G NL(i and IIAI, 8 8 4 4 PL(; and IIAI. IIA1. 4 1 4 5 6 5 B,,,.,, ((mole per milligram of protein) 117 ' 25 44 296 267 29 380 ' 14 384 ' 211 498 22t K,,' Ina/I (0' • (1.20 ((S(1 t 0.11 0.38 :•. 0 07 0. 66 ± 1) 18 0.74 ± 0.25 0 .58 11.'11 •N swlislie;,llp sigililicmlf dillrrencc was found among the six ireatmcml gnwrs isilh resrco lit it,, /., ^;dmis ;u .Ifs IrvcL IsIgnilic:mtly dilfelsnl It ' ' .1151 from treatment gloms t. -. }. a. ;old 5 hs Dune:or s nwhil•lc ..mgr Ir.l IWI tr, `lu'g 1:1 I.`I1 1'1'l^nl 11'11 (oh'lir-hl C 1'IS1 \:\r\S Table 2. Blockade of chlorpromazine (CPZ)-induced increase in specific I'Hlspiroperido) binding by PLG. Four randomly assigned experimental groups of male Sprague-1)uwley rats were subject to the following schedules of drug treatments once daily for 21 days: group I received saline only: group 2 was injected with PLG at II) mg/kg. subcutaneously: group 3 was administered 1 LG (10 mg/kg, subcutaneously) 10 seconds before CPZ (21) mg/kg. intraperitoneally): and group 4 was dosed with CPZ (20 mg/kg, intraperitorieally). I he animals were killed 5 days after the last drug session and striata were assayed for I'Hispiroperidol binding. Group I 2 3 4 Treatment Saline I ' LG PLG and CP Z , CI Z N 8 8 4 4 (tmole per milligram of protein) 117 ' 25 296 44 269 33 529 ± 41 t K,t* (ni11) 1).52 0.20 0.50 ± 0.11 0 . 19. (1 . 07 ().34 ± (1.20 Nn statistically significant ddlerence was round slung the lour ncanncnl group, with respccl to the K, values It 115 level iSigniticantty ddicrent (/1 < .(IS) Item treatment groups I. and 3 by Uuncan's multiple range test. ally) produced a mean increase of 67 spiroperidol toward a normal level in the percent. These observations confirm the striatum. Pert et al. (5) showed that results of other studies (10, 1l) on the lithium cotreatrnent suppressed the (leenhancement of specific binding of 31-1- velopnlent of neuroleptic-induced dopalabeled neuroleptics after prolonged ad- mincrgic supersensitivily and suggested tations of haloperidol-induced supersensitivity of dopamine receptors: it augmented locomotor hyperactivity and hypothermic responses toward apomorphine. Although no attempt was made in our study to correlate the temporal profile of biochemical changes with behavior•il events it rs i I'k t eI y that the pharmacological activity of both PLG and cyclo(Leu-Gly) is produced through interaction with the putative PLG receptor. The distribution of endogenous PLG in mammalian brain is of interest in relation to the possible association of' the putative PLC receptor with the neuroleptic-doparnine receptor-adenylate cyclase complex. Studies by Kastin el a!. (/6) indicate that the pineal constituted one site for the extrahypothalamic distribution of PLG, but detailed topographic mapping of PLG in the brain has not been completed. ministration of the drugs. that the therapeutic action of lithium in Our studies demonstrate the antagoSimultaneous administration of PLG manic depression may be related to its nism of neuroleptic-induced dopamine with haloperidol or chlorpromazine, ability to stabilize the oscillations of doreceptor supersensitivity by the neurohowever, antagonized the elevation in pamine receptor sensitivity. Both the peptide PLG. Hence PLG and its derivas p ecifi c I'H isp i roperidol binding pro- behavioral and biochemical ntanifestatives should be considered as potential duced by long-term administration of lions of neuroleptic-induced dopaminerprophylactic and therapeutic agents in neuroleptics alone. Striata from rats gic supersensitivity have been found to the clinical management of tardive dyskitreated with both haloperidol and PLG be reversed (12) or antagonized (/3) by nesia. (10 mg/kg, subcutaneously) exhibited a administering dopamine agonists like SIMON CHIU receptor density for specific I3Hjspiro- bromocriptine. In view of the multiple C. S. PAULOSE peridol binding that was not significantly complex interactions of dopamine with RArrt K. MISHRA different from that found in saline con- other putative neurotransmitters in the Departments of'Psychiairy and trols or PLG controls (Table 1). Rats basal ganglia, the ability of an agent to Neuroscienc'es, McMaster University, concu rrent l y treated with both PLG (10 exhibit direct agonist activity at the doHamilton, Ontario, Canada L8N 3Z5 mg/kg) and chlorpromazine (20 mg/kg) pamine receptor site is not a prerequisite failed to demonstrate the increase in for the desensitizing process. Reference s and Notes specific I'Hlspiroperidol binding associ- It is conceivable that there is a pharI. Y. C. Clement-Cormier, J. W. Kebabian, G. L. Petzold, 1'. Greengard. Pro(. Nall. Acad. Sci. ated with treatment with chlorpromazind macolbgically distinct receptor for PLG U.S.A. 71, 1 113 (1974). 2. P. Muller and P. Seeman. l'sychophor,nucoloalone (Table 2). Administration of PLG that is functionally coupled to the neurogicc (41. I (1978). alone at the dose of 40 mg/kg for 3 weeks leptic-doparnine receptor-adenyl to cy3. R. J. Haldessarini and D. Tarsy. inc. Re%. Nearoblo/. 21. 1) 1979): 1). V. Jesse and J. R. Wyatt, produced a slight decrease in specific close complex and that activation of the .Schizoplrr. Bull. 5. 251 (1979). 13111spiroperidol binding (Table I): the putative I'LG receptor is responsible for 4. K. H. Fhrensing. Lancer 11-1974, 1459 11974): difference. however, was not statistically the observed desensitizing effects of A. J. Kastin, P. F. Larson, G. A. Bishop. Disord. Nerr. Sysc. significant (at U.S 38. 103 (1977). ,level) compared with PLG on doparnine receptors. We have 5. A. Pert, J. F. Rosenblatt, C. Sivit, C. It. Pert, W. E. Bonney, Jr., Science 201, 171 (1978). that for the saline-Ireated groups. already shown (8) that PLG selectively 6. M. F. Celis. S. Tallisnick. R. Walters. Pro,. Natl. Arad.Sci. U.S.A. 68, 1428 (1971). In all the drug treatment groups, no increases the affinity of the specific bind7. S. Chiu and R. K. Mishra. Eur. J. Pharnuccol. statistically significant difference was ing of the dopamine agonist I'Illaponror53, 119 (1979). found in the Ktr of 13HIspiroperidol bind- phine to the neuroleptic-doparnine re8. S. Chin. C. S. Pauluse, R. K. Mishra, Peptides 2. 105 (1981). ing sites in the striatum. Hence the after- ceplor in vitro without affecting specific 9. I. esc 78,)'t. Prosser, S. H. Snyder, Lii u• Sri. 23, 495Cre ations in the sensitivity of neurolc c119 . Pu 1311 lspiioperidol binding. We also identi10. A. St. Marshall and R. K. Mishra, Adv. Biodopantine receptors in the striatum, ficd, by a radioligand-hinding technique. chcvu. P.nrhaphurma,ul. 24, 153 (1980). 11. I'. Muller and 1'. Seeman, Life Sci. 21. 1751 caused by prolonged neuroleplic admin- high-affinity PLG binding sites that cx(1977): D. R. Burt, I. Creese, S. H. Snyder. Scictrce 196, 326 (1977). isiration, and reversal of the changes by hibited saturahility, reversibility, and 12. C. Ezrin-Waters and P. Seeman, Life Sri. 22. cotreatrnent with I'LG are reflected pri- pharmacological and regional specificity 1027 (1978): S. List and P. Seeman, ibid. 24. 1447 (1979). rnaril}' in the relative density of 1'HI- in rat and human brain (/4). It is relevant 13. A. J. Friedhoff, K. Bonner, H. kosengarten. spiropcridol binding sites rather than in to note that cyclo(Leu-Gly), a diketopiRes. Comm. Checn. Pathul. Pharmacol. 16, 411 (1977). the affinity of the binding ligand. perazine derivative of PLG, competed 14. S. Chiu, Y. W. Wong, R. K. Mishra, Fed. /'roc. The results demonstrate that PLG, for specific PLG binding as actively as /:'ed. Am. Sac. Evp. Viol. 64. 625 (1980): S. Chiu, Y. W. Wong. Y. Wan, R. K. Mishra, in when administered concurrently with a it (foes in vivo, whereas inactive monopreparation. prolotypal dopamine receptor antagonist and dipeptides like L.eu-Gly and prolinc 15, H. N. Bhargava and R. F. Ritzrn:mn, l'lmrma(ologist 22. 548 (1980). (chlorpromazine or haloperidol), efl'ec- failed to affect I'LL binding. Bhargava lively antagonizes the development of and Rilzmann (/5) found that c,r/o(L.eudopanline receptor supersensitivily by Gly) when aulnlinici .r • I k .f I l 16. A. J. Kastin. S. I'. Lawrence. 1). H. Coy. flocrawcol. l(ioclrrnr. Behar. 13. 9)11 (1980). 17. This Study "as supported by ?be Ontario Mental h ealth I ound: rliun. rrsturing the specific binding of I'11I- idol. suppressed the hchavior'tl r11L'Ilufcs 10 April 1981: rc,ised 14 ),,1, 1'+8)