Vulnerability to cocaine: role of stress hormones
Jong, I.E.M. de
Citation
Jong, I. E. M. de. (2007, October 17). Vulnerability to cocaine: role of stress hormones.
Division of Medical Pharmacology of the Leiden/Amsterdam Center for Drug Research
(LACDR) and Leiden University Medical Center (LUMC), Leiden University. Retrieved from
https://hdl.handle.net/1887/12382
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the
Institutional Repository of the University of Leiden
Downloaded from: https://hdl.handle.net/1887/12382
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Vulnerability to cocaine:
role of stress hormones
Inge E.M. de Jong
Vulnerability to cocaine: role of stress hormones Inge Elisabeth Maria de Jong
Thesis, Leiden University October 2007
ISBN: 978-90-8559-147-4
Cover: Inge de Jong
Printing: Optima Grafische Communicatie B.V., Rotterdam, The Netherlands
© 2007, I.E.M. de Jong except:
Chapter 2: Elsevier B.V., 2007
No part of this thesis may be reproduced or transmitted in any form or by any means without written permission of the author.
Vulnerability to cocaine:
role of stress hormones
Proefschrift ter verkrijging van
de graad van Doctor aan de Universiteit Leiden, op gezag van Rector Magnificus prof. mr. P.F. van der Heijden,
volgens besluit van het College voor Promoties te verdedigen op woensdag 17 oktober 2007
klokke 15:00 uur
door
Inge Elisabeth Maria de Jong geboren te Leidschendam
in 1978
PROMOTIECOMMISSIE:
Promotores: Prof. Dr. E.R. de Kloet Prof. Dr. M.S. Oitzl
Referent: Dr. L.J.M.J. Vanderschuren (Rudolf Magnus Instituut, Utrecht) Overige leden: Prof. Dr. F.G. Zitman
Prof. Dr. J.M.A. van Gerven Prof. Dr. M. Danhof Prof. Dr. G.J. Mulder Dr. A.M. Pereira Arias Dr. O.C. Meijer
The studies described in this thesis have been performed at the division of Medi- cal Pharmacology of the Leiden/Amsterdam Center for Drug Research (LACDR) and Leiden University Medical Center (LUMC), The Netherlands. This research was financially supported by The Dutch Organisation for Scientific Research (NWO/
ZonMW) and the Royal Dutch Academy of Sciences (KNAW) and was part of a col- laboration with Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux, France.
Financial support for the printing of this thesis was kindly provided by:
- Leiden/Amsterdam Center for Drug Research (LACDR) - Noldus Information Technology B.V.
- J.E. Jurriaanse Stichting
Science may set limits to knowledge, but should not set limits to imagination.
Bertrand Russel (1872-1970)
Voor mijn vader
7
Table of contents
Preface 9
Chapter 1: General introduction 11
Chapter 2: Adrenalectomy prevents behavioural sensitisation of mice to cocaine in a genotype-dependent manner
51
Chapter 3: Strain differences in the effects of adrenalectomy on the midbrain dopamine system: implication for behavioural sensitisation to cocaine
75
Chapter 4: Critical time-window for the actions of adrenal glucocorticoids in behavioural sensitisation to cocaine
93
Chapter 5: Behavioural sensitisation to cocaine: cooperation between glucocorticoids and epinephrine
113
Chapter 6: General discussion 133
Chapter 7: Summary 163
Chapter 8: Samenvatting (Dutch) 169
Chapter 9: References 177
List of abbreviations 229
Curriculum Vitae 231
Publications 233
9
Preface
Not every individual who experiments with cocaine will acquire compulsive drug use. The mechanism underlying this individual difference in susceptibility to drug addiction is still poorly understood. Recent studies have identified genes and ad- verse life events (stress) as risk factors. The objective of this thesis is to investigate the contribution of the adrenal stress hormones glucocorticoids and epinephrine to the psychostimulant effects of cocaine in the inbred DBA/2 and C57BL/6 mouse strains. Behavioural sensitisation, measured as an enhanced locomotor response to repeated cocaine exposure, was used as a model for the long-term neural adapta- tions underlying certain aspects of drug addiction.
The results demonstrate that adrenal hormones play a critical role in cocaine sensitivity, which depends on genetic background because surgical removal of the adrenals or ‘adrenalectomy’ fully prevented cocaine sensitisation in the DBA/2, but not the C57BL/6 strain. The impact of genetic background was further empha- sised by strain-specific changes in the midbrain dopamine system that mediates the rewarding effects of drugs of abuse. The effects of adrenalectomy could only be fully reversed by co-administration of glucocorticoids and epinephrine. These findings show that, depending on genetic background, adrenal stress hormones are important risk factors for vulnerability to cocaine, suggesting that pharmacologi- cal intervention in stress hormone action may have therapeutic potential in drug addiction.
