Hostname: page-component-cd9895bd7-hc48f Total loading time: 0 Render date: 2024-12-23T07:37:27.042Z Has data issue: false hasContentIssue false
  • English
  • Français

Central D2 receptor blockade and antipsychotic effects of neuroleptics. Preliminary study with positron emission tomography

Published online by Cambridge University Press:  28 April 2020

JL Martinot ,
ML Paillère-Martinot ,
C Loc'h ,
P Péron Magnan ,
B Mazoyer ,
Y Lecrubier ,
P Hardy ,
B Beaufils ,
JF Allilaire  and
B Mazière
...Show all authors
JL Martinot*
Affiliation:
Service Hospitalier Frédéric-Joliot, CEA, Département de Biologie, 91406 Orsay Service de Psychiatrie (A Feline) Hôpital de Bicêtre, 94270, Le Kremlin Bicêtre
ML Paillère-Martinot
Affiliation:
Service de Psychopathologie de l'enfant et de l'adolescent (M Basquin) Hôpital de La Salpétrière, 75013, Paris
C Loc'h
Affiliation:
Service Hospitalier Frédéric-Joliot, CEA, Département de Biologie, 91406 Orsay
P Péron Magnan
Affiliation:
Service Hospitalier Universitaire (H Loo) Hôpital Sainte-Anne, 75014, Paris
B Mazoyer
Affiliation:
Service Hospitalier Frédéric-Joliot, CEA, Département de Biologie, 91406 Orsay
Y Lecrubier
Affiliation:
INSERM U302, Psychopharmacologie et psychopathologie des comportements. Hôpital de La Salpêtrière, 75013, Paris
P Hardy
Affiliation:
Service de Psychiatrie (A Feline) Hôpital de Bicêtre, 94270, Le Kremlin Bicêtre
B Beaufils
Affiliation:
Service de Psychiatrie (A Feline) Hôpital de Bicêtre, 94270, Le Kremlin Bicêtre
JF Allilaire
Affiliation:
Service de Psychiatrie (D Widlocher) Hôpital de La Salpêtrière, 75013, Paris
B Mazière
Affiliation:
Service Hospitalier Frédéric-Joliot, CEA, Département de Biologie, 91406 Orsay
MF Slama
Affiliation:
Service de Psychiatrie (D Ginestet) Hôpital Paul-Brousse, 94800, Villejuif, France
A Syrota
Affiliation:
Service Hospitalier Frédéric-Joliot, CEA, Département de Biologie, 91406 Orsay
*
*Correspondence and reprints. Service de Psychiatrie, Hôpital de Bicêtre, 78, rue du Général-Leclerc, 94270 Le Kremlin-Bicêtre, France
Get access

Summary

The striatal D2 receptor density/affinity index was assessed using positron emission tomography and 76Br-Bromolisuride in 15 schizophrenics, first untreated, and afterwards receiving neuroleptics, and in 14 control subjects. The patients received low or conventional doses of neuroleptics. The schizophrenics receiving low doses (n = 6) had preponderant negative symptoms. Mean D2 receptor occupancy was 24 ± 20%. Despite this weak central D2 receptor blockade, a significant decrease in negative symptoms was observed, a result consistent with the hypothesis of a disinhibitory action of some neuroleptics administered in low doses. The patients treated with conventional doses (n = 9) had mixed positive and negative symptoms, and the mean D2 receptor occupancy was 54 ± 13%. Significant decreases in positive symptoms, but also in negative symptoms, were obtained with this treatment. Before treatment, there was no significant difference in the striatal D2 receptor density/affinity index between: 1) patients and controls, 2) negative and mixed schizophrenics, and 3) the subsequent responder and non-responder patients. In addition, the D2 dopamine receptor occupancy by neuroleptics did not significantly differ in responder or nonresponder patients, suggesting that the central D2 dopamine receptor blockade is a necessary, but insufficient condition to account for the antipsychotic effect of neuroleptics.

Résumé

Résumé

La densité des récepteurs dopaminergiques D2 striataux a été estimée chez 15 schizophrènes d'abord non traités puis au cours d'un traitement neuroleptique, et chez 14 témoins, en utilisant la tomographie par émission de positons et le 76Br-Bromolisuride. Les patients ont reçu des doses faibles, «désinhibitrices» ou des doses classiques de neuroleptiques. Les schizophrènes ayant reçu de faibles doses avaient une symptomatologie négative prépondérante. Le pourcentage moyen d'occupation des récepteurs D2 était de 24 ± 20%. Malgré ce faible blocage des récepteurs D2, une réduction significative des symptômes négatifs a été observée, un résultat compatible avec l'hypothèse d'un effet désinhibiteur des faibles doses de certains neuroleptiques. Les patients traités par doses classiques avaient une symptomatologie mixte, et le pourcentage d'occupation des récepteurs était de 54 ± 13%. Ce traitement a apporté une réduction significative des symptômes positifs mais aussi négatifs. Avant traitement, l'estimation de la densité des récepteurs D2 striataux ne différait pas entre: 1) les patients et les témoins; 2) les schizophrènes négatifs et les schizophrènes mixtes; et 3) les patients ultérieurement répondeurs ou non répondeurs au traitement. Chez les patients traités, les pourcentages d'occupation des récepteurs D2 des patients répondeurs n'étaient pas significativement différents de ceux des non-répondeurs, suggérant que l'occupation des récepteurs D2 est une condition nécessaire mais sans doute insuffisante pour rendre compte de l'effet antipsychotique des neuroleptiques.

Keywords

schizophreniapositron emission tomographyD2 dopamine receptorsneurolepticsschizophrénietomographie d'émission de positonsrécepteurs dopaminergiques D2neuroleptiques
Type
Original article
Information
Psychiatry and Psychobiology , Volume 5 , Issue 4 , 1990 , pp. 231 - 240
Copyright
Copyright © European Psychiatric Association 1990

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Alfredsson, G, Harnry, D, Wiesel, FA (1985) Effects of sulpiride and chlorpromazine on autistic and positive psychotic symptoms in schizophrenic patients. Relationship to drug concentration.. Psychopharmacology 85, 8–13CrossRefGoogle Scholar
Andreasen, NC (1987) L'utilisation de la SANS et de la SAPS. Psychiatry Psychobiol 2, 412Google Scholar
Baldessarini, RJ, Cohen, B, Teicher, MH (1988) Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses. Arch Gen Psychiatry 45, 79–91CrossRefGoogle ScholarPubMed
Baron, JC, Martinot, JL, Cambon, H, Boulenger, JP, Poirier, MF, Caillard, V, Blin, J, Huret, JD, Loc'h, C, Mazière, B (1989) Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacology 99, 463–472CrossRefGoogle ScholarPubMed
Baron, JC, Mazière, B, Loc'h, C, Cambon, H, Sgouropoulos, P, Bonnet, AM, Agid, Y (1986) Loss of striatal76Br-Bromospiperone binding sites demonstrated by positron tomography in progressive supranuclear palsy. J Cereb Blood Flow Metab 6, 131–136CrossRefGoogle ScholarPubMed
Benkert, O, Holsboer, F (1984) Effect of sulpiride in endogenous depression. Acta Psychiat Scand 69 (suppl 311), 42–48CrossRefGoogle Scholar
Boyer, P (1986) Etude de l'efficacité de faibles doses de neuroleptiques atypiques dans les états déficitaires. Ann Med Psychol 6, 593–599Google Scholar
Boyer, P, Puech, AJ (1987a) Determinants for clinical activity of neuroleptic drugs: Chemical substance, doses, assessment tools. Psychiatry Psychobiol 2, 296–305Google Scholar
Boyer, P, Lecrubier, Y (1987b) Fiche descriptive et traduction française de la SAPS. Psychiatry Psychobiol 2, 425–437Google Scholar
Boyson, SJ, McGonigle, P, Luthin, GR, Wolfe, BB, Molinoff, PB (1988) Effects of chronic administration of neuroleptics and anticholinergic agents on densities of D2 dopamine and muscarinic cholinergic receptors in rat striatum. J Pharmacol Exp Ther 244, 987–993Google ScholarPubMed
Breier, A, Wolkowitz, OM, Doran, ARet al (1987) Neuroleptic responsivity of negative and positive symptoms in schizophrenia. Am J Psychiatry 144, 1549–1555Google Scholar
Carlsson, A, Lindqvist, M (1963) Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 20, 140–144CrossRefGoogle ScholarPubMed
Carnoy, P, Ravard, S, Wemerman, B, Soubrie, P, Simon, P (1986) Behavioral deficit induced by low doses of apomorphine in rats; evidence for a motivational and cognitive dysfunction which discriminates among neuroleptics. Pharmacol Biochem Behav 25, 503–509CrossRefGoogle Scholar
Creese, I, Burt, DR, Snyder, SH (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenics drugs. Science 192, 481–483CrossRefGoogle Scholar
Crow, TJ (1980) Molecular pathology of schizophrenia: more than one disease process. Br Med J 280, 66–68CrossRefGoogle ScholarPubMed
Deniker, P, Ginestet, D (1973) Neuroleptiques. Encycl Med Chir Psychiatrie 37860 B 20, Doin, ParisGoogle Scholar
Farde, L, Wiesel, FA, Hall, H, Haldin, C, Stone-Elander, S, Sedvall, G (1987) No D2 receptor increase in PET study of schizophrenia. Arch Gen Psychiatry 44, 671–672CrossRefGoogle ScholarPubMed
Farde, L, Wiesel, FA, Halldin, C, Sedvall, G (1988) Central D2 Dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45, 71–76CrossRefGoogle ScholarPubMed
Giros, B, Sokoloff, P, Martres, MP, Riou, JF, Emorine, LJ, Schwartz, JC (1989) Alternative splicing directs the expression of two D2 dopamine receptor isoforms. Nature 342, 923–926CrossRefGoogle ScholarPubMed
Golberg, SC (1985) Negative and deficit symptoms in schizophrenia do respond to neuroleptics. Schizophr Bull 11, 453–456CrossRefGoogle Scholar
Haas, S, Beckmann, H (1982) Pimozide versus haloperidol in acute schizophrenia. A double-blind controlled study. Pharmacopsychiatry 15, 70–74CrossRefGoogle ScholarPubMed
Keller, HH, Schaffner, R, Haeffely, W (1976) Interaction of benzodiazepines with neuroleptics at central dopamine neurons. Nauyn Schmiedeberg's Arch Pharmacol 294, 1–7CrossRefGoogle ScholarPubMed
Kolakowska, T, Williams, AO, Ardern, M, Revely, MA, Jambor, K, Gelder, MG, Mandelbrote, BM (1985) Schizophrenia with good and poor outcome. I : early clinical features, response to neuroleptics and signs of organic dysfunction. Br J Psychiatry 146, 229–246CrossRefGoogle ScholarPubMed
Kolivakis, T, Azian, H, Kingstone, E (1974) A double-blind comparison of pimozide and chlorpromazine in the maintenance of chronic schizophrenic patients. Curr Ther Res 16, 998–1004Google Scholar
Kornhuber, J, Riederer, P, Reynolds, GP, Beckmann, H, Jellinger, R, Gabriel, E (1989) 3H-Spiperone binding sites in post-mortem brains from schizophrenic patients: relationships to neuroleptic drug treatment, abnormal movements, and positive symptoms. J Neural Transm 75, 1–10CrossRefGoogle Scholar
Lapierre, YD, Lavallee, J (1975) Pimozide and the social behavior of schizophrenics. Curr Ther Res 18, 181–188Google ScholarPubMed
Lecrubier, Y, Boyer, P (1987) Fiche descriptive et traduction française de la SANS. Psychiatry Psychobiol 2, 414–420Google Scholar
Lecrubier, Y, Puech, AJ, Aubin, F, Boyer, P, Deyrieux, B (1988) Improvement by amisulpride of the negative syndrome in non-psychotic subjects: a preliminary study. Psychiatry Psychobiol 3, 329–334Google Scholar
Lecrubier, Y, Puech, AJ, Simon, P, Widlocher, D (1980) Schizophrénie: hyper ou hypofonctionnement du système dopaminergique? une hypothèse bipolaire. Psychol Med 12, 2431–2441Google Scholar
Mackay, AVP, Crow, TJ (1980) Discussion: positive and negative schizophrenic symptoms and the role of dopamine. Br J Psychiatry 137, 379–386CrossRefGoogle Scholar
Martinot, JL, Peron-Magnan, P, Huret, JD, Mazoyer, B, Baron, JC, Boulenger, JP, Loc'h, C, Mazière, B, Caillard, V, Loo, H, Syrota, A (1990) Striatal D2 Dopaminergic receptors assessed by positron emission tomography and 76 Br-Bromospiperone in untreated schizophrenics. Am J Psychiatry 147, 44–50Google Scholar
Mazière, B, Loc'h, C, Stulzaft, O, Hantraye, P, Ottaviani, M, Cornard, D, Mazière, M (1986) (76 Br)Bromolisuride: a new tool for quantitative in vivo imaging of D2 Dopamine receptors. Eur J Pharmacol 127, 239–247CrossRefGoogle Scholar
Mazière, B, Loc'h, C, Baron, JC, Sgouropoulos, P, Duquesnoy, N, D'Antona, R, Cambon, H (1985) In vivo quantitative imaging of dopamine receptors in human brain using positron emission tomography and 76 Br-Bromospiperone. Eur J Pharmacol 114, 267–272CrossRefGoogle Scholar
Mazière, B, Loc'h, C, Stulzaft, O, Martinot, JL, Syrota, A, Mazière, M (1990) PET imaging of D2 receptors in the living baboon and human brain in normal and pathological conditions using 76Br-Bromolisuride. In: Neuropsychopharmacology (Bunney, WE, Hippius, H, Laakmann, G, Schmauss, M, eds) Springer-Verlag, Heidelberg, 409-417Google Scholar
Meltzer, HY, Sommers, AA, Luchins, JD (1986) The effect of neuroleptics and other psychotropic drugs on the negative symptoms in schizophrenia. J Clin Psychopharmacol 6, 329–338CrossRefGoogle Scholar
Moscarelli, M, Maffei, C, Cesana, BMet al (1987) An international perspective on assessment of negative and positive symptoms in schizophrenia. Am J Psychiatry 144, 1595–1598Google Scholar
Petit, M, Zann, M, Lesieur, P, Colonna, L (1987) The effect of sulpiride on negative symptoms of schizophrenia. Br J Psychiatry 150, 270–271CrossRefGoogle ScholarPubMed
Pickar, D, Breier, A, Wolkowitz, OM, Pato, C (1987) Profiles of the pharmacologic response of positive and negative symptoms in schizophrenia. Psychiatry Psychobiol 2, 277–287Google Scholar
Poirier-Littre, MF, Galinowski, A, Peron-Magnan, P, Vanelle, JM, Raffaitin, F, Piron, JJ, Piketti, M, Loo, H (1989) Bipolar effect of pipotiazine according to dosage in negative and positive forms of schizophrenia. In: Psychiatry Today, Accomplishment and Promises, VIII world congress of psychiatry abstracts (Stefanis, CN, Soldatos, CR, Rabavilas, AD, eds) Excerpta Medica, International congress series 899, p 661Google Scholar
Puech, AJ, Simon, P, Boissier, JR (1978) Benzamides and classical neuroleptics: comparison of their actions using 6 apomorphine-induced effects. Eur J Pharmacol 50, 291–300CrossRefGoogle ScholarPubMed
Seeman, P (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1, 133–152CrossRefGoogle ScholarPubMed
Sokoloff, P, Martres, MP, Redouane, K, Schwartz, JC, Protais, P, Vasse, M, Dubuc, I, Costentin, J, Hamdi, P, Mann, A, Wermuth, CG (1987) Behavioral and neurochemical profiles of discriminant benzamides derivatives. Psychiatry Psychobiol 2, 253–264Google Scholar
Soussaline, F, Campagnolo, R, Verrey, B, Bendriem, B, Bouvier, A, Lecomte, JL, Comard, D (1984) Physical characterisation of a time of flight positron emission tomography System for whole body quantitative studies. J Nucl Med 25, 46Google Scholar
Wiesel, FA, Farde, L (1989) Plasma level relationship of oral benzamides and phenothiazines. In: Psychiatry Today, Accomplishments and Promises, VIII world congress of psychiatry abstracts (Stéfanis, CN, Soldatos, CR, Rabavillas, AD, eds) Excerpta Medica, International congress series 899, p 621Google Scholar
Wolkin, A, Barouche, F, Wolf, AP, Rotrosen, J, Fowler, JS, Shive, CY, Cooper, TB, Brodie, JD (1989) Dopamine blockade and clinical response: evidence for two biological subgroups of schizophrenia. Am J Psychiatry 146, 905–908Google ScholarPubMed
Wong, DF, Wagner, HN, Tune, LE, Dannals, RF, Pearlson, GD, Links, JM, Tamminga, CA, Broussolle, EP, Ravert, HT, Wilson, AA, Toung, JKT, Malat, J, Williams, JA, O'Tuama, LA, Snyder, SH, Kumar, MJ, Gjedde, A (1986) Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science 234, 1558–1563CrossRefGoogle ScholarPubMed
Wong, DF, Pearlson, GD, Young, LT, Singer, H, Villemagne, V, Tune, L, Ross, C, Dannal, RF, Links, JM, Chan, B, Wilson, AA, Ravert, HT, Wagner, HN, Gjedde, A (1989) D2 dopamine receptors are elevated in neuropsychiatric disorders other than schizophrenia. J Cereb Blood Flow Metab 9 (suppl 1), S593Google Scholar
Submit a response

Comments

No Comments have been published for this article.