DISSERTATIONES MEDICINAE UNIVERSITATIS TARTUENSIS 18 THE ROLE OF DOPAMINE, 5-HYDROXYTRYPTAMINE, SIGMA AND NMDA RECEPTORS IN THE ACTION OF ANTIPSYCHOTIC DRUGS A A VO LANG TARTU 1995 DISSERTATIONES MEDICINAE UNIVERSITATIS TARTUENSIS 18 DISSERTATIONES MEDICINAE UNIVERSITATIS TARTUENSIS 18 THE ROLE OF DOPAMINE, 5-HYDROXYTRYPT AMINE, SIGMA AND NMDA RECEPTORS IN THE ACTION OF ANTIPSYCHOTIC DRUGS AAVO LANG TAKTO UNTVEMTY PRESS Department of Physiology, University of Tartu, Estonia Dissertation is accepted for the commencement of the degree of Doctor of Medical Sciences on October 4,1995 by the Council of the Faculty of Medicine, University of Tartu, Estonia Opponents: Professor Aleksandr Žarkovski, M.D., Ph.D., University of Tartu Assistant Professor Raimo K. Tuominen, M.D., Ph.D., University of Helsinki Commencement: 20 December 1995 Publication of this dissertation is granted by the Estonian Science Foundation © Aavo Lang, 1995 Tartu Ülikooli Kiijastuse trükikoda Tiigi 78, EE2400 Tartu Tellimus nr. 278 CONTENTS LIST OF ORIGINAL PUBLICATIONS................................................................. 7 ABBREVIATIONS..................................................................................................8 1. INTRODUCTION................................................................................................9 2. REVIEW OF LITERATURE............................................................................. 11 2.1. Properties of typical and atypical antipsychotic drugs............................... 11 2.2. Interactions of antipsychotic drugs with neurotransmitter systems and their receptors............................................................................................13 2.2.1. Dopamine........................................................................................13 2.2.2. 5-Hydroxytryptamine.......................................................................14 2.2.3. Sigma receptors............................................................................... 14 2.2.4. Glutamate and NMDA-gated channels............................................. 15 2.3. Sigma receptor antagonists as potential antipsychotic drugs..................... 16 2.3.1. Biochemical effects..........................................................................16 2.3.2. Behavioural effects.......................................................................... 17 3. AIMS OF THE PRESENT STUDY................................................................... 18 4. MATERIALS AND METHODS........................................................................19 4.1. Animals.................................................................................................... 19 4.2. Drugs........................................................................................................19 4.3. Radioligand binding studies.......................................................................19 4.3 .1. Preparation of brain samples for radioligand binding studies..........20 4.3.2. [3H]-Spiperone binding.................................................................... 20 4.3.3. pH]-Haloperidol binding..................................................................20 4.3.4. [3H]-TCP binding.............................................................................21 4.3.5. [3H]-Ketanserin binding....................................................................21 4.3.6. [3H]-SCH-23390 binding.................................................................21 4.3.7. [3H]-MK-801 binding...................................................................... 21 4.4. Behavioural experiments........................................................................... 22 4.4.1. Apomorphine-induced yawning in rats............................................. 22 4.4.2. Apomorphine-induced climbing in mice........................................... 22 4.4.3. Amphetamine- and dizocilpine-induced motor excitation in mice .... 22 4.4.4. Apomorphine-induced stereotyped behaviour in rats....................... 22 4.4.5. Apomorphine-induced aggressiveness in rats................................... 23 4.4.6. Quipazine-induced head twitches in rats........................................... 23 4.4.7. Behavioural studies after chronic treatment...................................... 23 4.5. Statistical analysis..................................................................................... 24 5. RESULTS...........................................................................................................25 5.1. In vivo receptor binding studies................................................................. 25 5.2. Results of acute behavioural experiments.................................................. 26 5.2.1. Antipsychotic drugs..........................................................................26 5.2.2. Sigma receptor antagonists...............................................................28 5.2.3. Correlations between radioligand binding and behavioural effects ... 28 5.3. Subchronic administration of antipsychotic drugs and sigma antagonists . 29 5.3.1. Results of radioligand binding..........................................................29 5.3.2. Results of behavioural experiments.................................................. 30 5.4. Apomorphine-induced aggressiveness....................................................... 31 6. DISCUSSION............................................................ ........................................33 6.1. Profile of tested compounds in radioligand binding studies...................... 33 6.2. Comparison of typical and atypical antipsychotic drugs in acute and subchronic studies..................................................................................... 33 6.3. Comparison of antipsychotic drugs and sigma antagonists....................... 36 6.4. Apomorphine-induced aggressiveness: a model to reveal and study new antipsychotic drugs....................................................................................38 7. CONCLUSIONS................................................................................................41 8. REFERENCES...................................................................................................43 SUMMARY IN ESTONIAN................................................................................. 54 ACKNOWLEDGEMENTS................................................................................... 57 PUBLICATIONS...................................................................................................59 CURRICULUM VITAE........................................................................................ 89 LIST OF ORIGINAL PUBLICATIONS The present study is based on the following original publications, which are referred to in the text by Roman numerals (I-III): I Lang A., Vasar E., Soosaar A. and Harro J. The involvement of sigma and phencyclidine receptors in the action of antipsychotic drugs. Pharmacology & Toxicology 1992,71: 132-138. II Lang A., Soosaar A., Kõks S., Volke V., Bourin М., Bradwejn J. and Vasar E. Pharmacological comparison of antipsychotic drugs and о-antagonists in rodents. Pharmacology & Toxicology 1994,75: 222-221. III Lang A., Harro J., Soosaar A., Kõks S., Volke V., Oreland L., Bourin М., Vasar E., Bradwejn and Männistö P. T. Role of N-methyl-D-aspartic acid and cholecystokinin receptors in apomorphine-induced aggressive behaviour in rats. Naunyn-Schmiedeberg's Archive o f Pharmacology 1995,351: 363-370. Articles are reprinted with permission of copyright owners. 7 4 ABBREVIATIONS ^MAX apparent number of binding sites DTG 1,3-di(2-tolyl)guanidine ED50 effective dose50, the dose which causes the desired effect in 50% compared to drug-induced effect in control animals EPS extrapyramidal side effects 5-HT 5 -hydroxytryptamine IC50 50% inhibitory concentration i. p. intraperitoneal(ly) KD dissociation constant NMDA N-methyl-D-aspartic acid PCP phencyclidine 3-PPP 3 -(3 -hydroxypheny 1)-N-n-propyl-piperidine s. c. subcutaneous(ly) (±)-SKF 10,047 (±)N-allyl-normetazocine TCP 1 - [ 1 -(2-thienyl)cyclohexyl]piperidine 8 1. INTRODUCTION Compounds having antipsychotic activity belong to a chemically heterogenous group of drugs. The blockade of dopamine D2 receptors is a common feature of these drugs and a necessary requisite to treat positive symptoms of schizophrenia (Seeman, 1980; Richelson, 1984). Long-term administration of antipsychotic drugs such as chlorpromazine and haloperidol is accompanied with the development of extrapyramidal side effects (EPS) ranging from acute dystonia and drug-induced parkinsonism to tardive dyskinesia. Therefore, a substantial effort has been directed to develop new antipsychotic drugs lacking EPS. Recently Seeman and Van Tol (1994) have proposed the hypothesis that effective antipsychotic medication without disabling EPS requires blockade of more than one receptor in the brain. Indeed, risperidone and clozapine, blocking dopamine D2, 5-hydroxytryptamine 5-HT2A, and 5-HT2C receptors do not cause significant EPS but potently ameliorate positive and negative symptoms of schizophrenia (Leysen et al., 1993). In 1976, Martin developed a new functional classification of opioid receptors according to action of various drugs in spinal dogs (Martin et al., 1976). Psychotomimetic action of SKF 10,047 in dogs was attributed to sigma opioid receptors (Martin et al, 1976). However, the subsequent studies did not confirm belonging of these receptors to