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Dissertation Submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-Carola University O

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Dissertation Submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-Carola University O Dissertation submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-Carola University of Heidelberg, Germany for the degree of Doctor of Natural Sciences Presented by Laura Broccoli, MS Pharmaceutical Biotechnologies born in Borgo Maggiore, Republic of San Marino (SMR) Oral-examination: 22.03.2016 CROSS-TALK OF THE CORTICOTROPIN RELEASING HORMONE RECEPTOR SUBTYPE 1 WITH THE DOPAMINE SYSTEM: Functional Evidence on Emotional Responses to Stress and Alcohol Dependence Referees: Prof. Dr. Rainer Spanagel Prof. Dr. Stephan Frings “ I love science, and it pains me to think that so many are terrified of the subject or feel that choosing science means you cannot also choose compassion, or the arts, or be awed by nature. Science is not meant to cure us of mystery, but to reinvent and reinvigorate it. “ Robert M. Sapolski ABSTRACT The concept of “stress” is often associated with unpleasant feelings, even though it is the major trigger of the evolutionary processes. The refined system responsible for the regulation of stress in animals as well as humans controls the release of Corticotropin Releasing Hormone (CRH) in the brain. In the presence of threats, physiological reactions are activated as fast as deactivated once the stressful stimulus has vanished. However, prolonged stimulation of the CRH system leads to the development of anxiety-associated disorders. Increasing evidence indicates that the dopamine (DA) system plays a role in the modulation of emotional responses. The vulnerability to stress is not only a crucial characteristic of anxiety-related diseases, but it is also a major component underlying different stages in the development of addiction. Indeed, alcohol dependence is a chronic-relapsing disease which induces long-term neuroadaptations that recruit a negative emotional state leading to excessive alcohol ingestion motivated by relief of negative emotionality. Thus, this PhD thesis aims to establish the cell-specific involvement of the CRH receptor subtype 1 (CRHR1) in the regulation of emotional responses to stress under healthy conditions and in alcohol dependence. Specifically, Study 1 demonstrates that the amygdala-specific increase in D1 binding sites upon pharmacological activation of CRHR1 is accompanied by an augmented anxiety-like behavior, which is abolished by pretreatment with a D1 antagonist. Further experiments using mice lacking CRHR1 expression in D1-containing neurons revealed that a D1-CRHR1 interaction is due to co- localized receptors, and bioluminescence resonance energy transfer (BRET) assay suggests that D1 and CRHR1 forms heterocomplexes. Together these results demonstrate that amygdala CRHR1 acts via D1 to mediate anxiety-like responses. In alcohol dependence, a maladaptive interaction between the two receptors seems to underlie the increased vulnerability to stress, a hallmark of the post- dependent (PD) phenotype that subsequently triggers stress-induced relapse to alcohol drinking (Study 2). Study 3 reveals that CRHR1 is differentially involved in stress-induced alcohol drinking whether it is expressed in DAT- or D1- neurons. These findings are supported by the anatomical separation within the VTA of D1-containing neurons, expressed in the dorsal portion, and the dopaminergic neuronal population distributed in the ventral part, and both co-localized with CRHR1. The cell-specific impact of CRHR1 in stress-induced alcohol consumption is further investigated in Study 4. Virus-induced αCaMKII-dependent over-expression of the receptor in the central nucleus of the amygdala (CeA) resulted in an increased alcohol-seeking behavior during stress-, but not cue- induced reinstatement in transgenic rats. Finally, an opposite functional impact of D1-CRHR1 and dopaminergic CRHR1 has been established for cue-induced reinstatement of cocaine seeking behavior using two double transgenic mouse lines lacking CRHR1 in D1- and DAT-expressing neurons, demonstrating that the modulation of relapse-like behavior for cocaine is related to the neuron-specific expression of CRHR1 (Study 5). In summary, the results presented in this thesis demonstrate that an interaction of D1 and CRHR1 receptors within the amygdala functions as a novel mechanism involved in the regulation of the emotional responses to stress under healthy condition. However, during alcohol dependence, the maladaptive functionality of the D1-CRHR1 interaction results in a hyper-responsivity to stress, leading to an increase in alcohol consumption as a relief to the negative affective state. Furthermore, our findings reveal the functional impact of dopaminergic and dopaminoceptive CRHR1 on stress-induced alcohol-seeking and cocaine-mediated behavior. In addition, this thesis gives support for the functional relevance of receptor-receptor interaction in stress and addiction- related processes, and thus the promise of the development of pharmacological compounds acting on these receptor-heterocomplexes as medication therapies. I ZUSAMMENFASSUNG Der Begriff „Stress“ wird oft mit unangenehmen Gefühlen in Verbindung gebracht, obwohl es sich um den wichtigsten Auslöser der Evolution handelt. Das ausgeklügelte System, welches für die Regulierung von Stress in Tieren und Menschen verantwortlich ist, kontrolliert die Ausschüttung des Corticotropin-releasing Hormone (CRH) im Gehirn. Bei Gefahr werden physiologische Reaktionen aktiviert, und ebenso schnell auch wieder deaktiviert, sobald der Stress-verursachende Reiz verschwunden ist. Jedoch führt die anhaltende Anregung des CHR Systems zur Entwicklung von Angststörungen. Zunehmende Indizien deuten darauf hin, dass das Dopamin (DA)-System eine Rolle bei der Regulierung der emotionalen Reaktionen spielt. Die Anfälligkeit für Stress ist nicht nur eine wesentliche Eigenschaft der Angststörungen, sie ist auch ein wichtiger Bestandteil verschiedener Stadien in der Entwicklung von Sucht. Tatsächlich ist Alkoholabhängigkeit eine chronische, rezidivierende Krankheit, welche langfristige Veränderungen im Gehirn verursacht. Diese Veränderungen sorgen für ein negatives Gefühlserleben, was wiederum zu erhöhtem Alkoholkonsum sorgt, welcher diesem negativen Befinden entgegenwirken soll. In dieser Doktorarbeit soll die zellspezifische Beteiligung des CRH Rezeptor Subtyp 1 (CRHR1) an der Regulierung der emotionalen Reaktionen auf Stress, sowohl unter normalen Bedingungen als auch in Alkoholabhängigkeit, ermittelt werden. In Studie 1 wird gezeigt, dass die Amygdala-spezifische Zunahme an D1 Rezeptorbindungen durch pharmakologische Aktivierung des CRHR1 von verstärktem Angstverhalten begleitet wird, welches durch Vorbehandlung mit einem D1 Antagonisten verhindert wird. Weitere Experimente an Mäusen, die in D1-beinhaltenden Neuronen keinen CRHR1 exprimieren, zeigten, dass die Interaktion zwischen D1 und CRHR1 auf der Kolokalisierung der Rezeptoren basiert. Der Biolumineszenz-Resonanzenergietransfer (BRET)-Test deutet außerdem darauf hin, dass D1 und CRHR1 Heterokomplexe bilden. Zusammengenommen zeigen diese Ergebnisse, dass Amygdala- lokalisierte CRHR1 das Angstverhalten mithilfe von D1 vermitteln. In der Alkoholabhängigkeit scheint die verstärkte Stressanfälligkeit einer maladaptiven Interaktion der beiden Rezeptoren zu unterliegen, was charakteristisch für den „post-dependent“ (PD) Phänotyp ist. Dadurch lösen D1- CRHR1 vermutlich den stressinduzierten Rückfall in den Alkoholkonsum aus (Studie 2). Studie 3 deckt auf, dass CRHR1 unterschiedliche Aufgaben beim stressinduzierten Alkoholkonsum übernimmt, je nachdem ob es in Neuronen mit Dopamintransporter (DAT) oder D1 exprimiert wird. Diese Ergebnisse werden durch die anatomische Trennung von D1 Neuronen im dorsalen Teil des ventralen tegmentalen Areals (VTA) und dopaminergen Neuronenpopulationen im ventralen Teil der VTA unterstützt, welche beide jeweils mit CRHR1 kolokalisiert sind. Die zellspezifischen Effekte von CRHR1 im stressinduzierten Alkoholkonsum werden in Studie 4 weiter untersucht. Durch eine Virus-induzierte, αCAMKII abhängige Überexpression des Rezeptors im zentralen Kern der Amygdala (CeA) kommt es zu einem erhöhten Alkoholsuchverhalten bei stressinduziertem, aber nicht reizinduziertem Rückfall in transgenen Ratten. Letztlich wird eine gegensätzliche Funktion von CRHR1 auf D1-Neuronen und CRHR1 auf dopaminergen Neuronen gezeigt. Hierzu werden zwei doppelt transgene Mauslinien verwendet, welche kein CRHR1 in entweder D1- oder DAT-Neuronen exprimieren. Der reizinduzierte Rückfall in Kokainsuchverhalten zeigt, dass II dopaminerge und dopaminozeptive CRHR1 die Regulierung von Rückfall-ähnlichem Verhalten modulieren (Studie 5). Zusammenfassend zeigen die Ergebnisse dieser Studien eine Interaktion von D1 und CRHR1 Rezeptoren innerhalb der Amygdala als einen neuen Mechanismus, durch den emotionale Stressreaktionen unter normalen Bedingungen reguliert werden. In Alkoholabhängigkeit führt eine fehlerhafte Interaktion von D1 und CRHR1 zu einer verstärkten Stressreaktion, welches wiederum zu erhöhtem Alkoholkonsum führt, durch den negative affektive Zustände gelindert werden sollen. Des Weiteren zeigen unsere Ergebnisse die funktionellen Auswirkungen von dopaminergen und dopaminozeptiven CRHR1 auf stressinduziertes Alkoholsuchverhalten und durch Kokain ausgelöstes Verhalten. Zusätzlich unterstützt diese Doktorarbeit die funktionelle Bedeutung der Rezeptor-Rezeptor-Interaktionen bei Stress und suchtbedingten Prozessen, und unterstreicht damit die Wichtigkeit der Entwicklung von pharmakologischen Präparaten mit Auswirkungen auf diese
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