The 5-hydroxytryptamine (5-HT, serotonin) neurotransmitter system maintains many homeostatic functions; it has also been implicated in the etiology and treatment of neurological and affective disorders, such as depression, anxiety, obesity, anorexia, and Alzheimer's disease. One of the PI's primary areas of interest is to understand the cellular mechanisms underlying the etiology and treatment of affective disorders. In the past the PI has focused on characterizing normal hippocampal neural activity and the changes in that normal physiology by chronic treatment with antidepressants or the """"""""stress"""""""" hormone corticosterone. The working hypothesis is that the actions of the drugs or mechanism underlying pathological status is due to differential modification of cellular properties or components of the 5-HT neurotransmitter system. In support of this hypothesis chronic treatment with corticosterone or fluoxetine was found to alter hippocampal pyramidal cell neural activity by changing basic cell properties as well as postsynaptic 5-HT receptor mediated responses. As predicted, the nature of the modulatory effects of the chronic treatments are not the same in the CA1 and CA3 subfields. Another likely target for differential modifications in the 5-HT neurotransmitters system is at the level of the 5-HT cell bodies. The median (MR) and dorsal raphe (DR) are the principal sites where 5-HT cell bodies are located. These two nuclei provide the majority of the 5-HT innervation of the forebrain. Even though they share many of the same features, differences between these two nuclei have been identified. The goal of the experiments outlined in this application is to set up a raphe brain slice preparation maintained in vitro to delineate both the common and disparate features of MR and DR cell neural activity. The development of the raphe brain slice will expand the depth of the PIs research focus. The use of the raphe (5-HT cell body) and hippocampal (5-HT fiber projection area) slice preparations in conjunction will provide a mechanism for a more systematic approach to the analysis of the normal physiology and pathophysiological processes of the 5-HT neurotransmitter system.
