The neurobiology of stress-induced hyperthermia

Abstract

Everyone who has been in a stressful situation, whether it is being attacked by a wild animal, the moment right before an important presentation or just finding yourself in an awkward situation, knows the warm and aroused feeling that one can experience at that moment. This change in body temperature in response to stress is referred to as stress-induced hyperthermia (SIH), and is the main subject of the research that has led to this thesis. This response is a consistent phenomenon that occurs in reaction to a stressful experience and is mediated by the autonomic nervous system. It is used throughout this thesis as a quantative read-out parameter for the experience of stress. The principal aim of this thesis is to show diverse applications of the SIH paradigm, and we propose that it constitutes a robust and reproducible across-species phenomenon with translational potential that is very suitable for drug screening. Moreover, this paradigm can be used to investigate the neurobiological mechanisms underlying the stress response as well as to examine the impact (role) of genetic modifications or naturally occurring genetic variation such as strain differences. This thesis consists of six parts. The first part (chapter 1 and 2) describes the background of the SIH paradigm, its neurobiological basis and the putative genetic and pharmacological applications. Specifically, the different drug classes that modify the SIH response are discussed. This introductory part also includes a chapter on the practical requirements to carry out SIH studies in mice. Part two focuses on a variety of pharmacological applications of the SIH response and consists of seven chapters. Chapter 3 describes the contribution of the different GABAA receptor subunits to the benzodiazepine-mediated reduction of the SIH response, whereas chapter 4 examines the role of the serotonergic (5-HT) system in these GABAA receptor mediated actions. Chapter 5 discusses the effects of chronic (subunit-selective) GABAA receptor activation and the consequences for the development of tolerance. The effects of early-life disruption of the serotonergic system on adult benzodiazepine sensitivity and anxiety-related behavior in mice are the main subject of chapter 6. Chapter 7 investigates whether the SIH response should be regarded as a form of fever or not, and chapter 8 studies the effects of injection stress on the SIH-reducing effects of various rapid-acting anxiolytic drugs. The importance of an in-depth pharmaceutical analysis during chronic drug studies is described in chapter 9. Part three of the thesis comprises two studies with a genetic approach. The effects of genetic CRF overactivation on the GABAA and metabotropic glutamate receptor systems are discussed in chapter 10. Chapter 11 investigates the genetic basis of drug sensitivity using chromosome substitution mice. In part four, the involvement of two brain structures in the SIH response is considered. Specifically, chapter 12 discusses the effects of bilateral medial amygdala lesions, whereas in chapter 13, the impact of olfactory bulbectomy on basal and stress-induced autonomic parameters is the central topic. Part five contains a study on the human SIH response in healthy male and female volunteers (chapter 14).The thesis will be concluded with a general discussion which also contains the future directions for SIH research (chapter 15.1). Moreover, three separate reviews discuss the body of SIH literature (also based on the research in this thesis) on the GABAA and GABAB receptor systems (chapter 15.2), the serotonin system (chapter 15.3) and the translational potential of SIH applications (chapter 15.4).