Hostname: page-component-cd9895bd7-dk4vv Total loading time: 0 Render date: 2024-12-22T16:24:33.177Z Has data issue: false hasContentIssue false

The Significance of Dopamine for the Mode of Action of Neuroleptics and the Pathogenesis of Schizophrenia

Published online by Cambridge University Press:  29 January 2018

H. M. van Praag*
Affiliation:
Department of Biological Psychiatry, Psychiatric University Clinic, State University Groningen, Groningen, The Netherlands

Summary

Animal experiments have demonstrated the likelihood that all known neuroleptics inhibit transmission in central CA-ergic systems, regardless of their chemical structure and via different mechanisms. For clinical psychiatry this fact prompts a number of questions: (1) is this phenomenon also to be found in human individuals; (2) if so, is it of importance for the clinical (side) effects of neuroleptics; (3) do patients with (schizophrenic) psychoses show signs of central CA-ergic hyperactivity ? This article presents a survey of clinical research focused on these questions which, for the sake of brevity, is confined to DA metabolism. The available data indicate the plausibility of a correlation between inhibition of DA-ergic transmission on the one hand, and on the other hand the therapeutic effects of neuroleptics and the occurrence of hypokinetic-rigid symptoms. The hypothesis that DA-ergic hyperactivity is an important pathogenetic mechanism in schizophrenic psychoses can be based only on indirect arguments; direct studies of the DA metabolism have so far failed to reveal supporting evidence. The possible causes of this failure are discussed.

Type
Research Article
Copyright
Copyright © Royal College of Psychiatrists, 1977 

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

Andén, N. E., Butcher, S. G., Corrodi, H., Fuxe, K. & Ungerstedt, U. (1970) Receptor activity and turnover of dopamine and noradrenaline after neuroleptics. Journal of Pharmacology, 11, 303–14.Google ScholarPubMed
Atsmon, A., Blum, I., Maoz, B., Steiner, M., Ziegelman, G. & Wijsenbeek, H. (1971) The short-term effects of adrenergic blocking agents in a small group of psychotic patients: preliminary clinical observations. Psychiatria Neurologia Neurochirurgia, 74, 251–8.Google Scholar
Atsmon, A., Blum, I., Steiner, M., Latz, A. & Wijsenbeek, H. (1972) Further studies with propranolol in psychotic patients. Psychopharmacologia, 27, 249–54.Google Scholar
Bowers, M. B. Jr (1972a) Acute psychosis induced by psychomimetic drug abuse. II. Neurochemical findings. Archives of General Psychiatry, 27, 440–2.Google Scholar
Bowers, M. B. Jr (1972b) Clinical measurements of central dopamine and 5-hydroxytryptamine metabolism: reliability and interpretation of cerebrospinal fluid acid monoamine metabolite measures. Neuropharmacology, 11, 101–11.Google Scholar
Bowers, M. B. Jr (1973) 5-Hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) following probenecid in acute psychotic patients treated with phenothiazines. Psychopharmacologia, 28, 309–18.Google Scholar
Bowers, M. B. Jr (1974) Central dopamine turnover in schizophrenic syndromes. Archives of General Psychiatry, 31, 50–4.CrossRefGoogle ScholarPubMed
Carlsson, A., Persson, T., Roos, B.-E. & Wálinder, J. (1972) Potentiation of phenothiazines by α-methyl-tyrosine in treatment of chronic schizophrenia. Journal of Neural Transmission, 33, 8390.CrossRefGoogle Scholar
Carlsson, A., Roos, B.-E., Wálinder, J. & Skott, A. (1973) Further studies on the mechanism of antipsychotic action: potentiation by α-methyl-tyrosine of thioridazine effects in chronic schizophrenia. Journal of Neural Transmission, 34, 125–32.CrossRefGoogle Scholar
Chase, T. N. (1972) Drug-induced extrapyramidal disorders. In Neurotransmitters (ed. Kopin, I. J.), pp 488–71. Baltimore: Williams and Wilkins.Google Scholar
Goodwin, F. K., Post, R. M., Dunner, D. L. & Gordon, E. K. (1973) Cerebrospinal fluid amine metabolism in affective illness: the probenecid technique. American Journal of Psychiatry, 130, 73–9.Google Scholar
Hassler, R., Bak, I.J. & Kim, J. S. (1970) Unterschiedliche Entleerung der Speicherorte für Noradrenaline, Dopamin und Serotonin als Wirkungsprinzip des Oxypertins. Nervenartzt, 41, 105–18.Google Scholar
Iversen, L. L. (1975) Dopamine receptors in the brain. Science, 188, 1084–9.CrossRefGoogle ScholarPubMed
Kirkstein, A. & Bowers, M. (1976) CSF amine metabolites, clinical symptoms and body movement in psychiatric patients. Biological Psychiatry. Google Scholar
Korf, J. & Praag, H. M. van (1971) Amine metabolism in human brain: further evaluation of the probenecid test. Brain Research, 35, 221–30.Google Scholar
Korf, J., Schutte, H. H. & Venema, K. (1973) A semiautomated fluorometric determination of 5-hydroxyindoles in the nanogram range. Analytical Biochemistry, 53, 146–53.Google Scholar
Matthijsse, S. (1973) Antipsychotic drug actions: a clue to the neuropathology of schizophrenia? Federation Proceedings, 32, 200–5.Google Scholar
Meltzer, H., Sachar, E. J. & Frantz, A. G. (1975) Serum prolactin levels in unmedicated schizophrenic patients. Archives of General Psychiatry, 31, 564–9.Google Scholar
Munkvad, I., Fog, R. & Randrup, A. (1975) Amphetamine psychosis: A useful model of schizophrenia? In On the Origin of Schizophrenic Psychoses (ed. van Praag, H. M.). Amsterdam: De Erven Bohn, B.V.Google Scholar
Nybäck, H. & Sedvall, G. (1970) Further studies on the accumulation and disappearance of catecholamines formed from — 14C in mouse brain. Effect of some phenothiazine analogues. European Journal of Pharmacology, 10, 193205.CrossRefGoogle ScholarPubMed
O'Keefe, R., Sharman, D. F. & Vogt, M. (1970) Effect of drugs used in psychoses on cerebral dopamine metabolism. British Journal of Pharmacology, 38, 287304.Google Scholar
Post, R. M., Fink, E., Carpenter, W. T. & Goodwin, F. K. (1975a) Cerebrospinal fluid amine metabolites in acute schizophrenia. Archives of General Psychiatry, 32, 1063–9.CrossRefGoogle ScholarPubMed
Post, R. M. & Goodwin, F. K. (1975b) Time-dependent effects of phenothiazines on dopamine turnover in psychiatric patients. Science, 190, 488–9.CrossRefGoogle ScholarPubMed
Praag, H. M. van (1967) The possible significance of cerebral dopamine for neurology and psychiatry. Psychiatria Neurologia Neurochirurgia, 70, 361–79.Google Scholar
Praag, H. M. van, Korf, J. & Schut, T. (1973) Cerebral monoa and depression. An investigation into their corrtion with the aid of the probenecid technique. Archives of General Psychiatry, 28, 827–31.Google Scholar
Praag, H. M. van (1975) Neuroleptics as a guideline to biological research in psychotic disorders. Comprehensive Psychiatry, 16, 722.CrossRefGoogle ScholarPubMed
Praag, H. M. van & Korf, J. (1975a) Neuroleptics, catecholamines and psychotic disorders. A study of their interrelation. American Journal of Psychiatry, 132, 593–7.Google Scholar
Praag, H. M. van (1975b) The importance in the pathogenesis of psychosis and the actions of antipsychotic (neuroleptic) drugs. Proceedings of the Sixth International Congress of Pharmacology. Helsinki. In press.Google Scholar
Praag, H. M. van, Dols, L. C. W. & Schut, T. (1975c) Biochemical versus psychopathological action profile of neuroleptics: A comparative study of chlorpromazine and oxypertine in acute psychotic disorders. Comprehensive Psychiatry, 16, 255–63.Google Scholar
Praag, H. M. van, Korf, J., Lakke, J. P. W. F. & Schut, T. (1975d) Dopamine metabolism in depressions, psychoses and parkinson's disease: the problem of the specificity of biological variables in behavior disorders. Psychological Medicine, 5, 138–46.Google Scholar
Praag, H. M. van (1976a) Depression and Schizophrenia: A contribution on their Chemical Pathology. New York: Spectrum Publications.Google Scholar
Praag, H. M. van (1976b) About the impossible concept of schizophrenia. Comprehensive Psychiatry, 17, 481.Google Scholar
Praag, H. M. van (1976) Importance of the dopamine metabolism for the clinical effects and side effects of neuroleptics. American Journal of Psychiatry. In press.CrossRefGoogle Scholar
Praag, H. M. van & Dols, L. C. W. (1976) Clozapine versus perphenazine or the value of the biochemical mode of action of neuroleptics in predicting their therapeutic activity. British Journal of Psychiatry, 129, 547–55.Google Scholar
Randrup, A. & Munkvad, I. (1970) Biochemical anatomical and psychological investigations of stereotyped behavior induced by amphetamines. In Amphetamines and Related Compounds (eds. Costa, E. and Garattini, S.), pp 695713. New York: Raven Press.Google Scholar
Randrup, A. & Munkvad, I. (1972) Evidence indicating an association between schizophrenia and dopaminergic hyperactivity in the brain. Orthomolecular Psychiatry, 1, 227.Google Scholar
Seeman, P. & Lee, T. (1975) Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science, 188, 121, 7–9.CrossRefGoogle ScholarPubMed
Sjöström, R. & Roos, B.-E. (1972) 5-Hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluid in manic-depressive psychosis. European Journal of Pharmacology, 4, 170–6.Google ScholarPubMed
Snyder, S. H. (1973) Amphetamine psychosis: a ‘model’ schizophrenia mediated by catecholamines. American Journal of Psychiatry, 130, 61–6.CrossRefGoogle Scholar
Snyder, S. H., Banerjee, S. P., Yamamura, H. I. & Greenberg, D. (1974) Drugs, neurotransmitters and schizophrenia. Science, 184, 1243–53.Google Scholar
Steiner, M., Latz, A., Blum, I., Atsmon, A. & Wijsenbeek, H. (1973) Propranolol versus chlorpromazine in the treatment of psychoses associated with child-bearing. Psychiatria Neurologia Neurochirurgia, 421–6.Google Scholar
Westerink, B. H. C. & Korf, J. (1975a) Influence of drugs on striatal and limbic homovanillic acid concentration in the rat brain. European Journal of Pharmacology, 33, 3140.Google Scholar
Westerink, B. H. C. & Korf, J. (1975b) Determination of nanogram amounts of homovanillic acid in the central nervous system with a rapid semiautomated fluorometric method. Biochemical Medicine, 12, 106–14.Google Scholar
Wiesel, F. A. & Sedvall, G. (1975) Effect of antipsychotic drugs on homovanillic acid levels in striatum and olfactory tubercle of the rat. European Journal of Pharmacology, 30, 364–7.CrossRefGoogle ScholarPubMed
Yorkston, N. J., Zaki, S. A., Malik, M. K. U., Morrison, R. C. & Havard, C. W. H. (1974) Propranolol in the control of schizophrenic symptoms. British Medical Journal, iv, 633–5.Google Scholar
Submit a response

eLetters

No eLetters have been published for this article.