Synthetic glucocorticoids such as dexamethasone are frequently used to enhance pulmonary development in preterm ventilator-dependent infants. In contrast to the short-term benefit on survival and... Show moreSynthetic glucocorticoids such as dexamethasone are frequently used to enhance pulmonary development in preterm ventilator-dependent infants. In contrast to the short-term benefit on survival and lung maturation, early glucocorticoid exposure has been shown to adversely affect neurodevelopmental processes. Both human and animal studies have reported acute and long-lasting impairments, including shortening of the lifespan in rodents. Therefore, the objective of the studies described in this thesis was to investigate, using an animal model: 1) the short- and long-term consequences of neonatal dexamethasone treatment and 2) the possibility to prevent these effects using pharmacological and behavioural intervention strategies. We reported that systemic dexamethasone treatment acutely affects brain development by suppressing cell proliferation and glial activity. These acute effects on the brain can be partially prevented by central glucocorticoid receptor antagonist pre-treatment, which might serve as a protective strategy against the adverse effects of dexamethasone treatment on the developing brain. Although neonatal dexamethasone exposure clearly affects the developmental trajectory, we did not observe the frequently described detrimental long-lasting consequences of this treatment. We showed that daily handling of the neonate, which was an inevitable component of our experimental design and leads to enhanced levels of maternal care towards the offspring, may compensate for some of the adverse effects of dexamethasone treatment. We conclude that the impact of neonatal glucocorticoid exposure highly depends on interactions with other components of the early environment and is therefore susceptible to pharmacological and behavioural intervention strategies. Show less
Pronounced ultradian and circadian rhythms in the hormones of the hypothalamic-pituitary-adrenal (HPA) axis (i.e. glucocorticoids), one of the body__s major neuroendocrine axes, were already... Show morePronounced ultradian and circadian rhythms in the hormones of the hypothalamic-pituitary-adrenal (HPA) axis (i.e. glucocorticoids), one of the body__s major neuroendocrine axes, were already demonstrated several decades ago. Until now, the clinical relevance of the pulsatile nature of glucocorticoids was poorly understood or sometimes even regarded as not important. Its evolutionary conservation across many species however implies biological significance. Indeed, glucocorticoids have been proven to be crucial for a plethora of bodily functions, e.g. emotion, cognition and the central mechanism underlying the adaptation to stress. Furthermore, disturbances in the characteristic temporal pattern of glucocorticoid exposure have often been described in stress-related pathology. However, the significance of glucocorticoids secretory patterns for physiology, stress responsiveness and nuclear receptor signalling is still largely unexplored and is accordingly addressed in this thesis. A new concept in the endocrinology of glucocorticoids has evolved from the data presented here showing that pulsatile release of glucocorticoids is a major determinant in __resilience__ of glucocorticoid signalling in neuronal cells and stress responsiveness. Moreover, we show that particularly the glucocorticoid receptor is affected after disrupting glucocorticoid pulsatility and could thus provide an excellent target for therapy to normalise the downstream effects of disturbances in glucocorticoid rhythms in stress-related disease. Show less
Currently, the raising awareness of the role of glucocorticoids in the onset of numerous (neuro)-pathologies constitutes the increasing necessity of understanding the mechanisms of action of... Show moreCurrently, the raising awareness of the role of glucocorticoids in the onset of numerous (neuro)-pathologies constitutes the increasing necessity of understanding the mechanisms of action of glucocorticoids in bodily processes and brain functioning. Glucocorticoids mediate their effects by binding to intracellular receptors which act as transcription factors. A remarkable and yet unexplained phenomenon described more than two decades ago, is the cell-specific effects glucocorticoids bring about on gene expression in brain. For example, while glucocorticoids suppress corticotrophin-releasing hormone (CRH) synthesis in the hypothalamus, production of CRH in the central nucleus of the amygdala (CeA) is stimulated by increased hormone levels. Inasmuch as the neuroanatomical distribution of the corticosteroid receptors does not satisfactorily explain these effects, it is of interest to decipher the role of recently discovered coregu lator proteins that modulate the direction and the magnitude of steroid receptor-driven transcription. Therefore, in the current thesis the expression and function of central coregulators was studied: the coactivators SRC1a and SRC1e along with the corepressors N-CoR and SMRT were found to be expressed in brain and involved in regulation of CRH gene expression. Finally, a method that allows detection of coregulator recruitment by steroid receptors in brain tissue was developed. Show less
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... 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
