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Jong, I.E.M. de (2007)

Vulnerability to cocaine: role of stress hormones

Doctoral Thesis
Not everyone who experiments with cocaine acquires compulsive drug use. The mechanism underlying this individual difference in susceptibility to addiction is poorly understood. Recent studies have identified genes and adverse 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 adaptations underlying 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 (__adrenalectomy__) prevented cocaine sensitisation in DBA/2, but not C57BL/6 mice. The impact of genetic background was further emphasised by strain...Show moreNot everyone who experiments with cocaine acquires compulsive drug use. The mechanism underlying this individual difference in susceptibility to addiction is poorly understood. Recent studies have identified genes and adverse 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 adaptations underlying 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 (__adrenalectomy__) prevented cocaine sensitisation in DBA/2, but not C57BL/6 mice. The impact of genetic background was further emphasised by strain-specific changes in the midbrain dopamine system that mediates the rewarding effects of drugs. 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 pharmacological intervention in stress hormone action has therapeutic potential in drug addiction.Show less
Brain
Cocaine
Dopamine
Epinephrine
genes
Glucocorticoids
HPA-axis
Stress
Sympathetic nervous system
All authors
Jong, I.E.M. de
Supervisor
Kloet, E.R. de; Oitzl, M.S.
Qualification
Doctor (dr.)
Awarding Institution
Leiden University Medical Center (LUMC), Leiden University
Date
2007-10-17
Publisher
Division of Medical Pharmacology of the Leiden/Amsterdam Center for Drug Research (LACDR) and Leiden University Medical Center (LUMC), Leiden University
ISBN (print)
9789085591474

Funding

Sponsorship
The research was financially supported by The Dutch Organisation for Scientific Research (NWO/ZonMW) and the Royal Dutch Academy of Sciences (KNAW). Financial support for the printing of the thesis was kindly provided by: -Leiden/Amsterdam Center for Drug Research (LACDR) -Noldus Information Technology B.V. -J.E. Jurriaanse Stichting