candidate's abstract): This application is for a K08. While an M.D.-Ph.D. student in the laboratory of Lewis Seiden, Ph.D., and while a psychiatric resident in the laboratory of George Aghajanian, M.D., I have been impressed by potential clinical applications of understanding the neurobiology of brain 5-HT2A receptors. The 5-HT2A receptor has been implicated in the pathophysiology of schizophrenia, suicide, depression and dementia. Regulation of the 5-HT2A receptor by many antidepressant and atypical antipsychotic drugs may contribute to their therapeutic effects. Recent work in Dr. Aghajanian's laboratory has found that, 5-HT, via a novel mechanisms involving the 5-HT2A receptor, increases the release of glutamate onto atypical but not basilar dendrites of neocortical pyramidal cells. This work demonstrates that the most consistent electrophysiological effect of 5-HT2A receptor activation in the neocortex is an increase in the frequency of excitatory postsynaptic potentials/currents (EPSCs/EPSCs) that is mediated by a presynaptic action of 5-HT2A receptor activation upon glutamatergic terminals. Recent work has also indicated that potent interactions occur between 5-HT2A receptors and brain-derived neurotrophic factor (BDNF): Dr. Ronald Duman's laboratory has found that 5-HT2A agonists increase neocortical BDNF mRNA expression in an apparent activity-dependent manner and previous manner and previous work has shown that BDNF both serves as a growth factor for serotonergic neurons and increases 5-HT turnover. At this time I wish to extend by training under the mentorship of Drs. Duman, to acquire experience in molecular approaches, and Aghajanian, to consolidate my electrophysiological skills, including learning whole cell patch clamp recording. The major aims for the proposed project are: (1) to characterize receptors presynaptic to pyramidal cells that regulate 5-HT2A receptor-induced EPSCs and BDNF mRNA expression in the medial prefrontal cortex; (2) to determine the origin of glutamatergic afferents to the medial prefrontal cortex from which 5-HT2A receptor activation increases EPSCs and BDNF mRNA expression; and (3) to study the regulation of neocortical 5-HT2A receptor-induced EPSCs and BDNF expression by antidepressant and antipsychotic drugs. The overall goal of the present proposed project is to further our understanding of the specific cellular and molecular interactions of 5-HT and neurotrophins in the cortex so that ultimately this knowledge can be translated to the clinical treatment of schizophrenia, mood disorders and dementia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08MH001551-03
Application #
6165121
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Program Officer
Chavez, Mark
Project Start
1998-03-15
Project End
2003-02-28
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
3
Fiscal Year
2000
Total Cost
$125,875
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Marek, Gerard J (2009) Activation of adenosine(1) (A(1)) receptors suppresses head shakes induced by a serotonergic hallucinogen in rats. Neuropharmacology 56:1082-7
Marek, Gerard J (2008) Cortical 5-hydroxytryptamine2A-receptor mediated excitatory synaptic currents in the rat following repeated daily fluoxetine administration. Neurosci Lett 438:312-6
Marek, Gerard J (2008) Regulation of rat cortical 5-hydroxytryptamine2A receptor-mediated electrophysiological responses by repeated daily treatment with electroconvulsive shock or imipramine. Eur Neuropsychopharmacol 18:498-507
Marek, Gerard J; Zhang, Ce (2008) Activation of metabotropic glutamate 5 (mGlu5) receptors induces spontaneous excitatory synaptic currents in layer V pyramidal cells of the rat prefrontal cortex. Neurosci Lett 442:239-43
Zhang, Ce; Marek, Gerard J (2008) AMPA receptor involvement in 5-hydroxytryptamine2A receptor-mediated pre-frontal cortical excitatory synaptic currents and DOI-induced head shakes. Prog Neuropsychopharmacol Biol Psychiatry 32:62-71
Zhang, Ce; Marek, Gerard J (2007) Group III metabotropic glutamate receptor agonists selectively suppress excitatory synaptic currents in the rat prefrontal cortex induced by 5-hydroxytryptamine2A receptor activation. J Pharmacol Exp Ther 320:437-47
Lee, Younglim; Duman, Ronald S; Marek, Gerard J (2006) The mGlu2/3 receptor agonist LY354740 suppresses immobilization stress-induced increase in rat prefrontal cortical BDNF mRNA expression. Neurosci Lett 398:328-32
Marek, Gerard J; Wright, Rebecca A; Schoepp, Darryle D (2006) 5-Hydroxytryptamine2A (5-HT2A) receptor regulation in rat prefrontal cortex: interaction of a phenethylamine hallucinogen and the metabotropic glutamate2/3 receptor agonist LY354740. Neurosci Lett 403:256-60
Marek, Gerard J; Martin-Ruiz, Raul; Abo, Allyson et al. (2005) The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology 30:2205-15
Marek, Gerard J (2003) Behavioral evidence for mu-opioid and 5-HT2A receptor interactions. Eur J Pharmacol 474:77-83

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