Neuropathological mechanisms and role of second messenger cascades in mood disorders
10 / 1998 - 12 / 2003
Depression, anxiety and panic disorders are common and serious psychiatric disorders. They can be triggered by abrupt hormonal changes, life events, or a genetic predisposition. They cause enormous disability and significant mortality, and cost many hundreds of millions of dollars every year. Moreover, it seems that mood disorders are prevalently female diseases, since women experience depression, anxiety and panic twice as often as men. Despite several decades of research, the pathophysiology of mood disorders is poorly understood. Several neurotransmitters (GABA, dopamine, serotonin are only few examples), hormones and neuropeptides seem to be involved in these pathologies. In the last decade the interest has been concentrated on the study of serotonergic system for trying to clarify its role in the mood disorder pathophysiology. Phylogenetically, the serotonergic system is one of the oldest transmitter systems in the brain. Combining a complex and widespread innervation of most cortical and subcortical structures, with over a dozen receptor subtypes, there is a diversity of signaling opportunities and functional roles that explain the association of serotonin with many different types of psychopathological conditions. Dysfunctions of the serotonergic system have been implicated in a number of psychiatric disorders including depression, anxiety and panic disorders. Effects on the serotonergic system underlie the antidepressant action of many types of medications and must be integrated into a neurobiological model of mood disorders. The influence of serotonin, as well as other neurotransmitters, hormones and neuropeptides on neuronal function are mediated by regulation of receptor-coupled intracellular signal transduction pathways, and the therapeutic action of 5-HT selective reuptake inhibitors (SSRIs), as well as other types of antidepressants, most likely involves regulation of these intracellular pathways, including, among others, the cyclic adenosine monophosphate (cAMP) second messenger system, phosphatidyl inositol (PI) signaling pathway, and mitogen activated protein kinase (MAPK) cascades. The focus of this project is the investigation, by the use of animal models and immunohistological tools, the intracellular events that follow the interactions between neurotransmitters and their receptors, the administration of antidepressant drugs, and the analysis of the brain circuitry involved in mood and physiological and pathological emotions.