The 5-hydroxytryptamine (5-HT, serotonin) neruotransmitter system is implicated in the etiology and treatment of psychiatric mood disorders such as anxiety and depression. Drugs used in the treatment of depression and anxiety are known to have effects on the 5-HT system, such as the serotonin selective reuptake inhibitors (SSRIs) and the azipirones, respectively. Also, the recent development of mice in which certain receptors of the 5-HT neurotransmitter system have been genetically eliminated has provided further evidence that the 5-HT system is important in mood disorders. Mice that have the 5-HT1A receptor eliminated by genetic engineering exhibit increased anxiety and antidepressant-like behavior. Selective """"""""rescue"""""""" of forebrain 5-HT1A receptors using gene targeting technology relives the anxiolytic phenotype. The 5-HT system is composed of two primary groups of cell bodies, the dorsal raphe (DR) and median raphe (MR) nuclei. The DR and MR share many features, yet they are distinctive in many ways. Evidence from studies using microdialysis, receptor binding and extracellular recording techniques suggests that there are topographical differences in certain aspects of not only 5-HT synaptic transmission, but also noradrenergic and GABA synaptic transmission in these distinct DR and MR neural circuits. A working hypothesis for the mechanism of action of antidepressants that are serotonin selective reuptake inhibitors (SSRIs) and for the behavioral phenotypes seen in the 5-HT receptor knockout mice is that there is site selective regulation of receptor-mediated responses within the DR and MR circuits. Electrophysiology techniques in brain slice preparations will be used to test this hypothesis in the following Specific Aims.
Aim I will identify differences in 5-HT, alpha1-adrenergic and GABA receptor-mediated responses in 5-HT containing cells of the DR and MR and the frontal cortex (DR projection site) and dorsal hippocampus (MR projection site) of the mouse.
Aim 2 will compare 5-HT, alpha-adrenergic and GABA neurotransmission in the DR and MR circuits in genetically manipulated mice.
Aim 3 will compare 5-HT, alpha-adrenergic and GABA neurotransmission in the DR and MR circuits in mice chronically treated with an SSRI. These experiments will provide important information about the topographical differences in the DR and MR neural circuits and how genetic deletion of 5-HT receptors or antidepressant treatment selectively alters these topographically differences.
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