Depression is associated with affective and cognitive disorders. The applicant suggest some of these symptoms may be due to loss of hippocampal and cortical morphology (cytoskeletal collapse) induced by loss of serotonin. Loss of serotonin in the adult rat brain produces decreased dendritic length, dendritic spine number and size, synapse number and a reduction in immunoreactivity to antibodies against neuronal (Microtubule Associated Protein-2 and synaptophysin) and glial (S-lOOn) markers. Injection with a 5-HT1A antagonist produces similar loss of synapses and dendritic spines. The loss of neuronal and glial markers is reversed by treatment with 5-HTIA receptor agonists and S-100beta. This renewal application will test the hypothesis that the 5-HT1A receptor stabilize the neuronal cytoskeletal by targeting neurons and glial cells, and may protect neurons from death (apoptosis). The applicant would like to continue and expand our studies on the effects of 5-HT drugs on morphological reversal after 5-HT loss proposed in the onginal grant. In addition, the applicants now propose the 5-HT1A receptor may regulate the cytoskeleton of neurons, by acting both on glial (availability of S100f3) and neurons (receptor-induced changes in phosphorylation pathways (e.g. PKC, PKA and MAPK)). In addition, The applicant would like to test if 5-HT1A receptor stimulation or S lOObeta treatmnent will restore the cytoskeleton after exposure to coichicine. Coichicine promotes microtubule disassembly and promotes apoptosis in culture and in vivo. Rats will be injected with para-chloroamphetamine (PCA) to reduce 5-HT levels The applicant will treat these rats with either a 5-HT1A receptor antagonist, tricyclics, serotonin specific reuptake inhibitors (SSRJ) or MAO-A inhibitor. In addition, the applicants will study possible mechanisms of action after exposure of cultured neurons to 5-HT1A receptor agonist and S-lOObeta. The applicants hope to extend this work to primary hippocampal and cortical neuronal and glial cultures using wild type and knockout (S100beta and the 5-HT1A receptor) mice. Finally, the actions of S-HT1A agonist and S-lOObeta will be studied after microinjections of colchicine into the adult rat hippocampus and cortex. The applicant will focus on dendritic collapse and apoptosis of neurons. This work will continue our long-term research into the interactions between serotonin and adult neumplasticity.
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