PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/147779 Please be advised that this information was generated on 2021-10-04 and may be subject to change. The influence of psychoactive drugs on brain self-stimulation behaviour A. Wauquier The influence of psychoactive drugs on brain self-stimulation behaviour A. Wauquier D/1976/1060/65 Promotores: Prof. Dr. J.M.H. VOSSEN Prof. Dr. J.M. VAN ROSSUM The influence of psychoactive drugs on brain self-stimulation behaviour Proefschrift ter verkrijging van de graad van doctor in de Sociale Wetenschappen aan de Katholieke Universiteit te Nijmegen, op gezag van de Rector Magnificus prof. dr. A.J.H. Vendrik volgens besluit van het College van Decanen in het openbaar te verdedigen op vrijdag 8 oktober 1976 des namiddags te 4.00 uur door ALBERT WAUQUIER geboren te Menen Drukkerij Daneels, Beerse, Belgium 1976 3 Aan Annie 4 Acknowledgements The author would like to thank all those who have contributed to the realization of this study whether or not they are explicitly mentioned here. The assistance of Dr. P.A.J. Janssen in providing the opportunity to perform the experiments in optimal conditions in his laboratory is grate­ fully acknowledged. His interest and suggestions have stimulated much of the present work. Dr. C.J .E. Niemegeers's constructive criticism of many of the experiments has been much appreciated. It is to him that I owe my education in the field of pharmacology. Many thanks are due to my co-workers Messrs. J. Fransen, W. Melis and W. Van den Broeck, without whose excellent technical assistance these experiments could not have been carried out. Calculations and statistical evaluations were carried out in an expert fashion by Mr. G. Claessen and co-workers Miss M. Mertens, Mrs. M.J. Princen and Mr. R. Van Beek. I am also indebted to Mr. L Desmedí for his help with the more sophisticated statistical analysis. I would further like to acknowledge the valuable discussions with my colleague Mr. F.C. Colpaert and the suggestions by Prof. Dr. W. Soudijn and Dr. van Wijngaarden. The technical and electronic equipment was manufactured in the Janssen Scientific Instruments Division under the skillful guidance of Ing. H. Geivers, Ing. R. Nuyens and Mr. L. de Proost. I am very grateful to them and those who built the apparatus. Preparing the manuscript of this study also involved the assistance of many people. I would like to thank, firstly, Mrs. A. Nuyts who carried out the secreterial burden with friendly patience and Messrs. H. Vermeer and J. Van Mierlo for their skillful preparation of the graphs and figures. My sincere thanks are also due to Mrs. V. van Kesteren and Mr. H. Vanhove for their help in correcting the manuscript and Mr. A. Op de Beeck and his department, for their professional realization of the design and final printing. 5 Contents Chapter I: Introduction 10 Chapter II: Aims of the study 14 Chapter III: The influence of psychoactive drugs on brain self- stimulation: a literature survey 16 1. Material collection 1.1. Classification i.2. Key to the tables 1.3. Tables 2. Discussion 2.1. Methodology 2.2. Drug-analysis 2.3. Theoretical aspects Chapter IV: General methods 80 1. Subjects 2. Surgery 3. Materials 3.1. Cage 3.2. Electrode 3.2.1. Metal 3.2.2. Monopolar vs. bipolar stimulation 3.3. Stimulator and electrical parameters 3.3.1. Considerations on wave-form and current character­ istics 3.3.2. Stimulator and recording 4. Establishment of self-stimulation Chapter V: The influence of various stimulus parameter com­ binations 87 1. Excitability of neuronal tissue with respect to self-stimulation 2. Experimental study 2.1. Experimental procedures 2.2. Results 2.3. Discussion Chapter VI: The influence of various psychoactive drugs on brain self-stimulation behaviour: an experimental study 106 1. Test procedures 7 2. Control results: analysis of variance 2.1. Definition of variables 2.2. Design 2.3. Some remarks concerning the fundamental assumptions in the analysis of variance. 2.4. Results 2.5. Discussion 3. Drug effects 3.1. Introduction 3.2. CNS-stimulants 3.2.1. Cocaine 3.2.2. Amphetamine 3.2.3. Apomorphine 3.2.4. Conclusion 3.2.5. Discussion 3.3. Cholinergics and anticholinergics 3.3.1. Cholinergics 3.3.2. Anticholinergics 3.3.2.1. Dexetimide 3.3.2.2. Benztropine 3.3.2.3. Scopolamine 3.3.3. Conclusion 3.3.4. Discussion 3.4. Minor tranquillizers 3.4.1. Chlordiazepoxide 3.4.2. Diazepam 3.4.3. Nitrazepam 3.4.4. Conclusion 3.4.5. Discussion 3.5. Narcotic analgesics 3.5.1. Morphine 3.5.2. Fentanyl 3.5.3. Piritramide 3.5.4. Conclusion 3.5.5. Discussion 3.6. Antidepressants 3.6.1. Desipramine 3.6.2. Amitriptyline 3.6.3. Dexamisole 3.6.4. Conclusion 3.6.5. Discussion 3.7. Hypnosedatives 3.7.1. Etomidate 3.7.2. Methohexital 3.7.3. Pentobarbital 3.7.4. Conclusion 3.7.5. Discussion 3.8. General discussion 8 Chapter VII: Neuroleptics and brain self-stimulation 114 1. Introduction 2. The involvement of dopamine in brain self-stimulation. 3. The influence of neuroleptics on self-stimulation. 3.1. Methods 3.2. Results 3.2.1. General description 3.2.2. Dose-effect relationship 3.2.3. Potency 3.2.4. Control base-line 3.2.5. Discussion 4. Lick-experiment 4.1. Methods 4.2. Results 4.3. Discussion 5. Implantation site and species differences 5.1. Implantation site 5.2. Species 5.2.1. Introduction 5.2.2. Methods 5.2.3. Results 5.2.4. Conclusion 6. Self-stimulation and psychotropic assays. 6.1. Classification of neuroleptics 6.1.1. Classification based on potency ratios 6.1.2. Spectral map analysis 6.2. Positioning of psychotropic assays. 7. Studies on drug-interaction 7.1. Literature on neuroleptic-anticholinergic interaction 7.2. Reversal of the specific inhibition obtained with anticholin­ ergics. 7.2.1. Differentiation from narcotic analgesics 7.2.2. Dose-related antagonism 7.2.3. Antiparkinsonian drugs 7.3. Differential antagonisms 7.3.1. Differential antagonism between the neuroleptics 7.3.2. Specificity of the antagonists 7.4. General discussion 8. Conclusions 8.1. Impairment of self-stimulation 8.2. Clinical implications References 208 Summary 247 Samenvatting 250 Curriculum vitae 254 9 I. Introduction The present study deals with the influence of psychoactive drugs on self- stimulation behaviour in the rat. The term «self-stimulation» denotes the particular behaviour performed by the rat, in order to obtain electrical stimulation through chronically implanted electrodes in the brain. The discovery of self-stimulation by Olds and Milner (1954) occurred accidentally, but it was the start of numerous studies (see survey in: Brain stimulation reward; Wauquier and Rolls, 1976). In 1953, Jim Olds worked as a postdoctoral fellow together with the graduate student Peter Milner, who was experienced in surgical and electronic techniques, at McGill University in Canada. Olds was interested in the neurophysiology of learning. For this purpose, he used the rather new and still crude technique of chronically indwelling brain electrodes. These electrodes were aimed at the reticular formation, which was stimulated during learning at chosen points in a simple maze. During one of these experiments Olds observed that a rat did not run into an arm of the maze, but, rather, returned to the place where it had previously received brain stimulation. In the light of the experiments of Delgado et al. (1954), who showed the brain stimulation could elicit eversive reactions, it occurred to Olds that the rat apparently «liked» the stimulation. The behaviour could be evoked repeatedly and Olds together with Milner aimed to quantify this behaviour. For this purpose, the rat was placed into a Skinner box equipped with a lever, on which pressing evoked brain stimulation. To their surprise, the rat rapidly started to press the lever. Moreover, the rat continued for many hours and Olds, being afraid that this would not be repeatable, collected many meters of paper with cumulative recordings of the rat's activity. Although not certain, because histology could not been studied, it is likely that the electrode they had implanted went deeper than originally planned and arrived in the hypothalamic region. During subsequent weeks, many rats were implanted and it was confirmed that rats could be trained to press a lever for direct brain stimulation in septal and other regions. Olds and Milner reported their original findings in 1954, and papers attractively entitled «Pleasure centres in the brain?» reached the public press. The phenomenon self-stimulation (term introduced by Brady, 1955) gained a world-wide popularity. The experiments of Delgado et al. (1954) on the one hand, and Olds and Milner (1954) on the other hand, suggested that «hell and heaven» were detected in brain. During the years following the discovery, self-stimulation was shown in many species throughout the whole phylogenic scale, including Man. 10 Sem-Jacobsen and Torkildsen (1960) and Heath and Mickle (1960) (see survey by Sem-Jacobsen, 1976) demonstrated during stereotaxic surgery that electrical stimulation of particular brain areas in Man was experienced as pleasant. It is not without significance that a symposium dedicated to electrical brain-stimulation was entitled «The role of pleasure in behaviour» (Heath, 1964). This reflected the belief that pleasure could be caused directly in the brain by electrical current. Feibleman wrote: «The best interpretation seems to indicate that the stimulated animals are experiencing pleasure» (Feibleman, 1964).