The serotonin system is known to be decreased in some depressed patients. Depression, in addition to its affective component, produces deficits in learning and memory which are normally associated with hippocampal synaptic function. These cognitive deficits are responsive to treatment with drugs that increase 5-HT. A loss of 5-HT in rats produces a decrease in synaptophysin, MAP-2 immunoreactivity and non-monoaminergic synapses in cortex and hippocampus. While these neuronal markers are decreased, we found an increase of trophic responses and of antipeptide labeling of the 5-HT-1A receptor protein. Likewise, in depressed humans, a fall of 5-HT in cortex is associated with an increase in 5-HT-1A receptor binding. In animals, activation of this receptor with a 5-HT-1A agonist rapidly reverses the changes induced by 5-HT loss. The long-term aim of this application is to test the hypothesis that the 5-HT-1A receptor regulates the fluctuation of adult hippocampal neurons between mature and immature states. Specifically, we propose that loss of 5-HT will induce a retraction of neuronal dendrites and an increase in 5-HT-1A receptor protein and gene expression. We predict 5-HT-1A receptor stimulation will restore the mature neuronal phenotype more effectively than either tricyclic antidepressants or specific serotonin reuptake inhibitors. 5-HT will be reduced by para-chlorophenylalanine (PCPA), para-chloroamphetamine (PCA) or 5,7-dihydroxytryptamine (5,7-DHT) and measured by HPLC or paroxetine binding. The neuronal morphology will be studied and compared to animals treated with a 5-HT-1A receptor antagonist. 5-HT-1A receptors labeled with our antipeptide antibodies will be studied morphometrically in vivo by immunocytochemistry and quantified in vitro by slot blots and immunoblots. Finally we will examine the 5-HT1A receptor mRNA using in situ hybridization. These results may help understand the etiology of depression and related disorders and provide insights for effective and novel treatments.

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National Institute of Mental Health (NIMH)
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New York University
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