Serotonin is a ubiquitous neurotransmitter in the mammalian brain. As such it has been implicated in the control of many behaviors and in the pathophysiology of mental diseases such as depression and obsessive compulsive disorders. It has long been recognized that serotonin acts through a variety of receptor subtypes to exert its effects in the brain. Thus specific serotonin receptor subtypes have long been regarded as promising targets for therapeutic intervention. Efforts to implement such interventions, however, are hampered by our limited understanding of the actions mediated by different serotonin receptor subtypes in the brain. This proposal seeks to address this issue by elucidating the mechanism of actions of two serotonin receptor subtypes that mediate excitatory responses to serotonin in the brain. The effects of serotonin in in vitro rat brain slices will be investigated using whole cell recording electrophysiological techniques. Specifically we will investigate the ability of serotonin to depolarize neurons of the anterior thalamus and prefrontal cortex. We hypothesize that these superficially similar responses involve two different receptors of the 5-HT7 and 5-H2A subtypes respectively. Furthermore we hypothesize that these responses will also be mediated though different cellular and ionic mechanisms. These studies should elucidate the mechanisms by which specific serotonin receptor subtypes regulate membrane excitability in the central nervous system. As such they should contribute to our understanding of the actions of serotonin in the brain. This knowledge should prove helpful in guiding the development of novel therapeutic strategies targeting serotonergic systems in the brain.
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