?????The?neurotransmitter?serotonin?is?thought?to?have?broad?functions?in?the?central? nervous?system,?contributing?to?the?biological?basis?underlying?both?behavior?and? cognition.?This?neurotransmitter?has?also?been?implicated?in?mental?disorders,? especially?anxiety?and?depression,?and?several?pharmacological?agents?used?to?treat? these?diseases?target?serotonergic?systems?in?the?brain.?? ?????Serotonin?acts?through?multiple?serotonin?receptors?to?regulate?neuronal?activity?and? work?during?the?last?decade?has?made?extraordinary?advances?in?our?understanding?of? the?basic?biology?of?these?receptors.?However?our?understanding?of?how?these?receptors? function?within?neurons,?what?they?signal?and?how?they?signal?in?the?central?nervous? system,?is?still?poorly?understood.?This?is?an?important?lacunae,?since?the?biological? basis?of?mental?disorders,?as?well?as?the?development?of?better?treatments,?will?be? grounded?in?the?specific?mechanisms?used?by?these?receptors.? ?????The?long?term?goal?of?the?PI's?research?program?is?to?help?develop?a?mechanistic? understanding,?at?the?molecular?level,?of?serotonin?receptor?function?in?central?nervous? system?neurons.?Specifically?in?this?application?we?propose?to?use?a?synergistic? combination?of?electrophysiological?and?molecular?biological?approaches?to?understand? the?signaling?mechanisms?used?by?5?HT2A?receptors?in?the?cerebral?cortex.?? ???The?application?proposes?three?Specific?Aims.?The?first?of?these?will?elucidate?the? proximal?signaling?mechanism?used?by?5?HT2A?receptors?to?regulate?membrane? excitability?in?pyramidal?cells?of?the?prefrontal?cortex.?The?second?Aim?will?test?the?idea? that?5?HT2A?receptors?inhibit?the?slow?calcium?activated?potassium?current?present?in? pyramidal?cells?by?reducing?the?concentration?of?membrane?PtdIns(4,5)2.?The?third? Specific?Aim?will?determine?how?5?HT2A?receptors?depolarize?and?excite?pyramidal? cells.?? ???The?results?of?this?project?should?contribute?to?our?understanding?of?serotonergic? mechanisms?in?the?brain?and,?as?such,?contribute?to?our?understanding?of?mental? disorders?while?supporting?the?search?for?more?effective?treatments.? The?neurotransmitter?serotonin?has?been?implicated?in?the?genesis?of?anxiety?and? depression?and?in?the?mechanism?of?action?of?several?drugs?effective?in?the?treatment?of? mental?disorders.?The?research?proposed?in?this?application?seeks?to?elucidate?the? molecular?mechanisms?used?by?serotonin?to?regulate?the?function?of?brain?cells?and? brain?circuits.?The?results?of?this?project?should?help?us?better?understand?mental? disorders?and?contribute?to?the?search?of?more?effective?treatments.?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH043985-23
Application #
8267059
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Nadler, Laurie S
Project Start
1988-04-01
Project End
2013-09-24
Budget Start
2012-07-06
Budget End
2013-09-24
Support Year
23
Fiscal Year
2012
Total Cost
$334,986
Indirect Cost
$112,236
Name
Wayne State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
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Yan, Hai-Dun; Villalobos, Claudio; Andrade, Rodrigo (2009) TRPC Channels Mediate a Muscarinic Receptor-Induced Afterdepolarization in Cerebral Cortex. J Neurosci 29:10038-46
Yang, Huibin; Cooley, Desma; Legakis, Julie E et al. (2003) Phosphorylation of the Ras-GRF1 exchange factor at Ser916/898 reveals activation of Ras signaling in the cerebral cortex. J Biol Chem 278:13278-85