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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH055250-01A2
Application #
2034543
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Project Start
1997-04-01
Project End
2000-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
New York University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
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Azmitia, Efrain C; Nixon, Ralph (2008) Dystrophic serotonergic axons in neurodegenerative diseases. Brain Res 1217:185-94
Abbas, Syed Y; Nogueira, Maria I; Azmitia, Efrain C (2007) Antagonist-induced increase in 5-HT1A-receptor expression in adult rat hippocampus and cortex. Synapse 61:531-9
Azmitia, Efrain C (2007) Cajal and brain plasticity: insights relevant to emerging concepts of mind. Brain Res Rev 55:395-405
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de Souza, Sandra Lopes; Nogueira, Maria Ines; de Jesus Deiro, Tereza Cristina Bomfim et al. (2004) Differential effects on somatic and reflex development by chronic clomipramine treatment. Physiol Behav 82:375-9
Azmitia, Efrain C (2004) Serotoninergic chemoreceptive neurons: a search for a shared function. Mol Interv 4:18-21
Brewton, L S; Haddad, L; Azmitia, E C (2001) Colchicine-induced cytoskeletal collapse and apoptosis in N-18 neuroblastoma cultures is rapidly reversed by applied S-100beta. Brain Res 912:9-16
Azmitia, E C (2001) Neuronal instability: implications for Rett's syndrome. Brain Dev 23 Suppl 1:S1-S10
Nishi, M; Kawata, M; Azmitia, E C (2000) Trophic interactions between brain-derived neurotrophic factor and s100beta on cultured serotonergic neurons. Brain Res 868:113-8

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