Background: Studies with experimental administration of alcohol offer inconsistent approaches and interpretations in which ways an acute alcohol exposure affects the HPA-system and the cortisol secretion. So far published alcohol experiments differ in alcohol application, the possibility of alcohol self-administration at the subjects own discretion as well as the age of the participants. Question: Is cortisol secretion modified by gender during alcohol infusion? Do men and women show different cortisol levels under alcohol exposure when compared to the baseline? Is there a dose-response relationship between cortisol secretion and acute alcohol exposure? Have family history, smoking habits and alcohol induced side effects like nausea an influence on the cortisol secretion under alcohol exposure? Materials and methods: 48 18 year old subjects participated in two identical sessions in which they were able to regulate their maximum blood alcohol concentration up to a safety limit of 1.2 ‰ (i.e., 0.12%). The experiment was conducted by using a special software for self-infusion of ethanol (CASE) which guided the participants through a two and a half hours long experiment. CASE is founded on a validated physiologically-based pharmacokinetic model and involves calculating the infusion volume needed to increase the blood alcohol concentration in a linear manner. The BAC increases after each alcohol request by 0,075 ‰ (i.e., 0.0075%) within in two and a half minutes. If the subject infuses no alcohol the blood alcohol concentration will decrease by 0.01 ‰ (i.e., 0.001%) per minute. Through the precise calculation of the infusion rate, individual differences can be eliminated. Cortisol levels were measured at five time points: an initial baseline measurement and four measurements at fixed time points during the alcohol self-administration of subjects with two completed alcohol experiments. As an appropriate measure to examine the effect of alcohol self-administration on cortisol secretion, the maximum blood alcohol concentration was determined. In addition the day of experiment, gender and family history were observed as well as exploratory maximum nausea and smoking habits. Results: In conclusion, the results confirmed that women have higher cortisol levels than men at baseline and under alcohol influence. Blood alcohol concentration as examined influencing variable was shown to have different effects on the HPA system on day one and two. On the first day of experimentation there was no effect of blood alcohol concentration on the HPA system. On the second day a dose-response relationship could be identified between cortisol secretion and acute alcohol exposure. Individually higher blood alcohol concentrations attenuated cortisol stronger in comparison to subjects with lower blood alcohol concentrations. Family history, smoking habits and unpleasant side effects (nausea) did not affect the cortisol secretion under alcohol exposure in this series of experiments. Conclusions: Current data suggests that alcohol experiments affect the cortisol secretion in young social drinkers. These findings could be detected for the first time. Up to this point there has not been an experimental study that investigated and evaluated the dose-effect relationship between cortisol secretion and alcohol in a study design which uses intravenous alcohol self-administration. It can be theorized that the first day of experimentation is suitable as a settling-in phase due to unspecific confounding factors, whereas the second day can be considered, in an identical setting, apt for hypothesis testing. The increased cortisol level in women when compared to men is consistent with previous studies and there was no indication that family history, smoking habits and alcohol induced unpleasant side effects have an influence on cortisol secretion.

Background: Studies with experimental administration of alcohol offer inconsistent approaches and interpretations in which ways an acute alcohol exposure affects the HPA-system and the cortisol secretion. So far published alcohol experiments differ in alcohol application, the possibility of alcohol self-administration at the subjects own discretion as well as the age of the participants. Question: Is cortisol secretion modified by gender during alcohol infusion? Do men and women show different cortisol levels under alcohol exposure when compared to the baseline? Is there a dose-response relationship between cortisol secretion and acute alcohol exposure? Have family history, smoking habits and alcohol induced side effects like nausea an influence on the cortisol secretion under alcohol exposure? Materials and methods: 48 18 year old subjects participated in two identical sessions in which they were able to regulate their maximum blood alcohol concentration up to a safety limit of 1.2 ‰ (i.e., 0.12%). The experiment was conducted by using a special software for self-infusion of ethanol (CASE) which guided the participants through a two and a half hours long experiment. CASE is founded on a validated physiologically-based pharmacokinetic model and involves calculating the infusion volume needed to increase the blood alcohol concentration in a linear manner. The BAC increases after each alcohol request by 0,075 ‰ (i.e., 0.0075%) within in two and a half minutes. If the subject infuses no alcohol the blood alcohol concentration will decrease by 0.01 ‰ (i.e., 0.001%) per minute. Through the precise calculation of the infusion rate, individual differences can be eliminated. Cortisol levels were measured at five time points: an initial baseline measurement and four measurements at fixed time points during the alcohol self-administration of subjects with two completed alcohol experiments. As an appropriate measure to examine the effect of alcohol self-administration on cortisol secretion, the maximum blood alcohol concentration was determined. In addition the day of experiment, gender and family history were observed as well as exploratory maximum nausea and smoking habits. Results: In conclusion, the results confirmed that women have higher cortisol levels than men at baseline and under alcohol influence. Blood alcohol concentration as examined influencing variable was shown to have different effects on the HPA system on day one and two. On the first day of experimentation there was no effect of blood alcohol concentration on the HPA system. On the second day a dose-response relationship could be identified between cortisol secretion and acute alcohol exposure. Individually higher blood alcohol concentrations attenuated cortisol stronger in comparison to subjects with lower blood alcohol concentrations. Family history, smoking habits and unpleasant side effects (nausea) did not affect the cortisol secretion under alcohol exposure in this series of experiments. Conclusions: Current data suggests that alcohol experiments affect the cortisol secretion in young social drinkers. These findings could be detected for the first time. Up to this point there has not been an experimental study that investigated and evaluated the dose-effect relationship between cortisol secretion and alcohol in a study design which uses intravenous alcohol self-administration. It can be theorized that the first day of experimentation is suitable as a settling-in phase due to unspecific confounding factors, whereas the second day can be considered, in an identical setting, apt for hypothesis testing. The increased cortisol level in women when compared to men is consistent with previous studies and there was no indication that family history, smoking habits and alcohol induced unpleasant side effects have an influence on cortisol secretion.:Inhaltsverzeichnis 3 Abbildungsverzeichnis 6 Tabellenverzeichnis 7 Abkürzungsverzeichnis 8 1 Einleitung 10 1.1 Alkohol – eine kurze Einführung 10 1.2 Bedeutung des Zusammenhangs von HPA-System und Alkohol 12 1.2.1 Experimentelle Alkoholselbstverabreichung 12 1.2.2 Neuropharmakologie von Alkohol 13 1.2.3 Geschlechtsunterschiede bei der Cortisolsekretion 14 1.2.4 Übelkeit und die Auswirkungen auf die Cortisolsekretion unter Alkoholexposition 15 1.3 Orale Alkoholverabreichung versus intravenöse Alkoholverabreichung 16 1.4 Zielsetzung 19 2 Material und Methoden 20 2.1 Versuchsteilnehmer 20 2.1.1 Einschlusskriterien 20 2.1.2 Ausschlusskriterien 21 2.1.3 Aufnahmeuntersuchung 22 2.2 Versuchsaufbau und Durchführung 22 2.2.1 Versuchsprinzip 23 2.2.2 Versuchsablauf 24 2.2.3 Verwendete Materialien 27 2.2.4 CASE Software 27 2.2.5 Herstellung der 6%igen Alkohol-Infusionslösung 29 2.2.6 Messung der BAK 30 2.2.7 Verwendete Fragebögen und Selbsteinschätzungstests 30 2.3 Blutverarbeitung 31 2.3.1 Blutbehandlung im Labor (Testkit der Firma IBL International GMBH) 32 2.3.1.1 Testprinzip im Labor 32 2.3.1.2 Testdurchführung bei Serumproben 32 2.3.1.3 Testauswertung 33 2.4 Statistische Auswertung 33 3 Ergebnisse 37 3.1 Versuchsteilnehmer 37 3.2 Konfirmatorische Datenanalyse der Cortisolsekretion 38 3.2.1 CASE Ergebnisvariablen 38 3.2.2 Analyse von Baseline Cortisol Tag eins vs. Tag zwei 39 3.2.3 Einfluss von Familienanamnese, Geschlecht und maximalem Blutalkohol auf die Cortisolsekretion 40 3.2.3.1 Beobachtung beider Experimentaltage zusammen 40 3.2.3.2 Getrennte Beobachtung für den ersten Experimentaltag 44 3.2.3.3 Getrennte Beobachtung für den zweiten Experimentaltag 46 3.2.3.4 Einfluss von max BAK Tag zwei auf den prozentualen Anteil der Nettofläche an der Gesamtfläche Tag zwei 48 Explorative Analyse von potentiellen weiteren Einflussfaktoren 49 3.3.1 Der Effekt von Übelkeit auf die Cortisolsekretion 49 3.3.2 Der Effekt von Rauchen auf die Cortisolsekretion 50 4 Diskussion 52 4.1 Auswahl der CASE Ergebnisvariablen 52 4.2 Unterschiede zwischen dem ersten und zweiten Experimentaltag 53 4.3 Verschiedene Einflüsse auf die Cortisolsekretion 54 4.3.1 Einfluss von Geschlecht 54 4.3.2 Einfluss von max BAK 55 4.3.3 Einfluss von Familienanamnese 55 4.4 Unterschiede zu vorhergehenden Studien 56 4.5 Diskussion der explorativen Datenanalyse 57 4.5.1 Einfluss von Übelkeit auf die Cortisolsekretion 57 4.5.2 Einfluss von Rauchen auf die Cortisolsekretion 58 4.6 Limitation der D-LAYA Studie 59 4.7 Ausblick 60 Zusammenfassung 61

The present thesis examines evidence for the self-relaxation assumption of Personality-Systems-Interactions (PSI) theory, i.e. the involvement of the self-system in the intuitive downregulation of negative affect. Chapter 1 introduces PSI a self-regulation theory that explains personality and behavior according to the dynamic interplay of neuropsychological systems. Chapter 2 provides an evaluation of the Implicit Positive and Negative Affect Test (IPANAT) that indirectly assesses affect via judgments about the phonetic resemblance between artificial pseudo-words and mood adjectives. The test shows remarkable reliability for each scale as well as good factorial, construct and criterion-based validity. Chapter 3 presents an experiment that investigates the extent to which self-activation (experimental presentation of self-referential terms such as my bed, my body, etc.) after stress exposure affects negative and positive affect as measured by both the IPANAT and an explicit affect scale. As compared to neutral terms (the bed, the body, etc.) in the control group, self-referential terms led to a decrease in negative affect and an increase in positive affect according to the IPANAT but not according to the explicit measure. The results are discussed with respect to the intuitive nature of self-relaxation. Chapter 4 includes a study that examines the relationships between inter-individual differences in self-functioning (adult attachment security, self-determination, self-esteem) and the cortisol response to an acute stressor and awakening in the morning. Self-functioning in terms of attachment security was negatively related to the acute stress cortisol response and, along with self-determination and self-esteem, positively related to the awakening cortisol response. A hypothesized link between the hippocampus, which has been shown to be especially important for cortisol regulation and the retrieval of episodic memory, and the self-system is discussed.

Background: Subtle and inconsistent differences in hypothalamic-pituitary-adrenal (HPA) axis activity have been reported for patients with panic disorder. While these patients show little or no alterations in basal ACTH and cortisol levels, it has been hypothesized that HPA hyperresponsivity was a trait in panic patients when exposed to novel and uncontrollable stimulation. Methods: Thirty-four patients (23 females, mean age 35 yrs) diagnosed with panic disorder were compared to 34 healthy controls matched for age, gender, smoking status, and use of oral contraceptives. Both groups were exposed twice to a potent laboratory stress protocol, the Trier Social Stress Test (TSST) on consecutive days. Free salivary cortisol levels and heart rate responses were repeatedly measured before and following the TSST. In addition, the cortisol awakening response (CAR) was assessed to further investigate HPA reactivity in PD patients. Results: While the TSST induced similar heart rate stress responses in both groups, cortisol responses were clearly absent in the panic patients with normal responses in the controls (F(1.96, 66) = 20.16; p < 0.001). No differences in basal cortisol levels were observed in the extended baseline period. The same cortisol stress non-response patterns were observed when patients with/without comorbid depression, or with/without psychotropic medication were compared. In contrast to their non-response to the psychosocial stressor, panic patients showed a significant CAR. Conclusion: These findings provide strong evidence to suggest that PD patients present with a striking lack of cortisol responsivity to acute uncontrollable psychosocial stress under laboratory conditions. This unresponsiveness of the HPA axis appears to be rather specific, since a normal CAR in the morning could be documented in these patients. Thus, the present results do not support the hypothesis that PD patients show a trait HPA hyperresponsiveness to novel and uncontrollable stimulation. In contrast, the data provide support for a hyporesponsive HPA axis under emotional stress in PD patients.

Familial risk and environmental stress promote the development of alcohol dependence. We investigated whether a positive family history of alcoholism affects the neuroendocrine response to a standardized laboratory stress test in healthy subjects without alcohol use disorders. Twenty-four high-risk subjects with a paternal history of alcoholism (PHA) and 16 family history negative (FHN) controls were evaluated. Psychosocial stress was induced by having subjects deliver a 5-min speech and mental arithmetics in front of an audience on separate days, after drinking either placebo or ethanol (0.6 g/kg) in a randomized sequence. Adrenocorticotropin (ACTH) was measured in 10 plasma samples covering up to 75 min after the stress test. Plasma arginine vasopressin (AVP) was determined before the stressor, at the time of maximum ACTH secretion, and at 75 min after stress onset. The stress test induced a phasic increase in ACTH secretion. At the time of maximum ACTH, AVP was significantly increased in relation to baseline. Compared to placebo, alcohol administration significantly attenuated maximum ACTH concentration in PHA but not FHN subjects, and decreased AVP measured in the same samples in PHA but not FHN subjects. We conclude that activation of the hypothalamic–pituitary–adrenal system by psychosocial stress is accompanied by an increase in peripheral plasma AVP levels. Secretion of both ACTH and AVP suggest that alcohol attenuates the stress response selectively in PHA but not FHN subjects. This might imply some short-term positive alcohol effect in sons of alcoholics, but also constitute a mechanism by which their risk to develop alcohol use disorders is increased.

Background: Subtle and inconsistent differences in hypothalamic-pituitary-adrenal (HPA) axis activity have been reported for patients with panic disorder. While these patients show little or no alterations in basal ACTH and cortisol levels, it has been hypothesized that HPA hyperresponsivity was a trait in panic patients when exposed to novel and uncontrollable stimulation. Methods: Thirty-four patients (23 females, mean age 35 yrs) diagnosed with panic disorder were compared to 34 healthy controls matched for age, gender, smoking status, and use of oral contraceptives. Both groups were exposed twice to a potent laboratory stress protocol, the Trier Social Stress Test (TSST) on consecutive days. Free salivary cortisol levels and heart rate responses were repeatedly measured before and following the TSST. In addition, the cortisol awakening response (CAR) was assessed to further investigate HPA reactivity in PD patients. Results: While the TSST induced similar heart rate stress responses in both groups, cortisol responses were clearly absent in the panic patients with normal responses in the controls (F(1.96, 66) = 20.16; p < 0.001). No differences in basal cortisol levels were observed in the extended baseline period. The same cortisol stress non-response patterns were observed when patients with/without comorbid depression, or with/without psychotropic medication were compared. In contrast to their non-response to the psychosocial stressor, panic patients showed a significant CAR. Conclusion: These findings provide strong evidence to suggest that PD patients present with a striking lack of cortisol responsivity to acute uncontrollable psychosocial stress under laboratory conditions. This unresponsiveness of the HPA axis appears to be rather specific, since a normal CAR in the morning could be documented in these patients. Thus, the present results do not support the hypothesis that PD patients show a trait HPA hyperresponsiveness to novel and uncontrollable stimulation. In contrast, the data provide support for a hyporesponsive HPA axis under emotional stress in PD patients.

Familial risk and environmental stress promote the development of alcohol dependence. We investigated whether a positive family history of alcoholism affects the neuroendocrine response to a standardized laboratory stress test in healthy subjects without alcohol use disorders. Twenty-four high-risk subjects with a paternal history of alcoholism (PHA) and 16 family history negative (FHN) controls were evaluated. Psychosocial stress was induced by having subjects deliver a 5-min speech and mental arithmetics in front of an audience on separate days, after drinking either placebo or ethanol (0.6 g/kg) in a randomized sequence. Adrenocorticotropin (ACTH) was measured in 10 plasma samples covering up to 75 min after the stress test. Plasma arginine vasopressin (AVP) was determined before the stressor, at the time of maximum ACTH secretion, and at 75 min after stress onset. The stress test induced a phasic increase in ACTH secretion. At the time of maximum ACTH, AVP was significantly increased in relation to baseline. Compared to placebo, alcohol administration significantly attenuated maximum ACTH concentration in PHA but not FHN subjects, and decreased AVP measured in the same samples in PHA but not FHN subjects. We conclude that activation of the hypothalamic–pituitary–adrenal system by psychosocial stress is accompanied by an increase in peripheral plasma AVP levels. Secretion of both ACTH and AVP suggest that alcohol attenuates the stress response selectively in PHA but not FHN subjects. This might imply some short-term positive alcohol effect in sons of alcoholics, but also constitute a mechanism by which their risk to develop alcohol use disorders is increased.