The overall aim is to explore mechanisms by which hallucinogenic drug, actiong through 5-HT2A receptors, enhance glutamatergic synaptic transmission in the prefrontal cortex. The proposed experiments focus upon how 5-HT2A receptor activation induces two distinct types glutamateric excitatory postsynaptic potentials/currents (EPSPs/EPSCs) at apical dendrites of layer V pyramidal cells of medial prefrontal cortex. The first is a 5-HT-induced increase in spontaneous (non-electrically-evoked) EPSCs that directly or indirectly involves thalamocortical terminals in the midline/intralaminar ascending arousal pathway. The second is a late component of corticocortical electrically-evoked EPSCs, a signature effect of both indoleamine (e.g., LSD) and phenethylamine (e.g., mescaline, DOI) psychedelic hallucingenic drugs. The studies will be conducted with a combination of whole cell patch-clamp recording and 2-photon laser scanning to identify events at a single synapse level; this will be done in conjunction with localized molecular manipulations of 5-HT2 receptor expression.
Specific aims are: 1) To determine how 5-HT-induced spontaneous EPSCs (spEPSCs) are generated in layer V pyramidal cells of medial prefrontal cortex and 2) To determine the mechanisms underlying hallucinogen-induced late electrically-evoked EPSCs (evEPSCs) in mPFC layer V pyramidal cells and its modulation by non-5-HT2A and NMDA receptors. Significance: Hyperglutamatergic states have been suggested to underlie both drug-induced psychoses and prodromal stages of naturally occurring psychoses as schizophrenia. The concept that a downstream dysfunction of glutamatergic transmission could be involved in the early pathogenesis of schizophrenia prompts a search for novel therapies that are prophylactic rather than symptomatic as are the traditional monoamine receptor-targeted typical or atypical antipsychotic drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH017871-35
Application #
6925794
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Asanuma, Chiiko
Project Start
1975-04-01
Project End
2009-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
35
Fiscal Year
2005
Total Cost
$232,800
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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