京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第21027号 / 医科博第88号 / 新制||医科||6(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 杉田 昌彦, 教授 濵﨑 洋子, 教授 河本 宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The Hypothalamus-Pituitary-Adrenal axis (HPA-axis) with its end product cortisol mediates the physiological response to stress thereby promoting mobilization of energy. The cortisol levels follow a diurnal rhythm with a distinct awakening response. Regulation of the HPA-axis differs among persons with certain psychiatric disorders when compared with controls. Some reports concern Attention-Deficit/Hyperactivity Disorder (ADHD) but findings are inconclusive. The main aim of the present thesis was to investigate diurnal levels of saliva cortisol in school aged children with ADHD and age matched non-affected comparisons, also taking early adversity, perceived stress and ADHD-medication into consideration. Children with ADHD had lower cortisol levels at awakening, 30 minutes later and before going to bed than comparisons. When the study group was split into three different age groups similar results were found only for children above 10 years of age. Within the ADHD group, subtype of ADHD or co-occurring symptoms did not affect the cortisol levels. Furthermore, children in the ADHD group had to a higher degree been exposed to foetal and childhood psychosocial adversity than comparisons. Since exposure to early adversity has been associated with both ADHD and HPA-axis functioning, such exposures could theoretically explain the low cortisol levels in ADHD via early programming of the HPA-axis. However, no relation was found between exposures to psychosocial adversity and diurnal cortisol levels. Neither did continuous medication with stimulants or atomoxetine explain the low cortisol levels. Possibly, medication may rather increase the levels. Finally, children with ADHD scored higher on perceived stress, measured by the Pressure-Activation-Stress (PAS) scale, than the comparison group. Female sex was also associated with higher stress in both groups, as well as increasing age in the comparison group. As with psychosocial adversity, no association was found between the higher PAS-scores and the lower cortisol levels, indicating the complexity of the stress regulating system. The results indicate a down-regulated or displaced HPA-axis with lower cortisol levels in children with ADHD. Stress related fragility – with more exposure to early stressors, higher perceived stress and lower diurnal cortisol levels – seem to accompany ADHD during childhood.

Abstract available through the Infant Behavior & Development: Special ICIS Issue.

No description available.

Background Obesity is currently one of the major causes of ill health and it is clear that overeatingis the cause of obesity. However, the actions of many endogenous factors that contribute to overeating are still not well understood. Gamma-aminobutyric acid (GABA)-ergic transmission has been shown to be of great importance for food intake regulation. The progesterone metabolite allopregnanolone is a potent positive GABAA receptor modulating steroid (GAMS) and in humans, elevated allopregnanolone levels have been suggested to be involved in increased food intake, and also with overweight and obesity. GABAA receptors that express the α2 and α3 subunits are proposed to be the main subtypes involved in food intake regulation. Therefore, the aims of the work in this thesis were to further investigate the effect of allopregnanolone on food intake, feeding behaviour, possible effects on weight gain and also to characterize a possible antagonist at α2β3γ2and α3β3γ2 GABAA receptors. Methods Allopregnanolone effects on food intake of different food items were recorded in male Wistar rats. Feeding patterns were analyzed. Food preference tests were also conducted and rats were repeatedly exposed to allopregnanolone under different feeding conditions to elucidate possible effects on body weight gain. To deeper investigate GABAA receptor subtypes suggested to be involved in food intake regulation, electrophysiological whole-cell patch-clamp recordings were performed to identify the specificity of the GAMS antagonist UC1020, at human α2β3γ2 and α3β3γ2 GABAA receptors expressed in HEK293-cells. Results Allopregnanolone increased the intake of standard chow, cookies and a high fat diet in male Wistar rats. Preferentially, allopregnanolone increased the rats´intake of the more calorie dense food type. Allopregnanolone reduced feeding latency and prolonged feeding duration. The increased chow intake induced by allopregnanolone was more pronounced at the beginning of the rats´ active period compared to the inactive. Repeated allopregnanolone administration during 5 consecutive days led to an increased body weight gain, more evident in schedule fed rats on a high fat diet. Both obesity prone and obesity resistant rats gained significantly more weight with repeated allopregnanolone exposure and the increased body weight gain correlated with increased food intake. The compound UC1020 was a potent antagonist of GAMS-enhanced GABA evoked currents at human α3β3γ2 GABAA receptors, whereas it had no effect at α2β3γ2 GABAA receptors. Conclusions Our findings indicate that allopregnanolone induced hyperphagia may be one of the endogenous factors involved in weight gain, especially when the diet is energy-rich. The compound UC1020 may prove useful for investigating the involvement of the α2 and α3 GABAA receptor subtypes in GAMS-induced hyperphagia.

No description available.