The overall aim of this proposal is to explore mechanisms by which serotonin (5-HT) and hallucinogenic drugs (acting via 5-HT2A receptors) enhance glutamatergic EPSPs/EPSCs (excitatory postsynaptic potentials/currents) in apical dendrites of layer V pyramidal cells of prefrontal cortex.
Specific aims are (1) to map and characterize in rat brain slices, hot spots along the apical dendrite at which 5-HT2A receptor activation elicits an increase in EPSCs (e.g., using infrared/differential interference contrast videornicroscopy, whole cell patch-clamp recording, focal puff application of 5-HT, and close-in electrical stimulation) and (2) To explore preversus postsynaptic mechanisms underlying the 5-HT2A receptor mediated enhancement of EPSCs in layer V pyramidal cells (e.g., the role postsynaptic G protein activation and pre- and postsynaptic Ca2+ and K+ channel mechanisms). Previously, we have shown that activation of 5-HT2A receptors by 5-HT or hallucinogens increase the frequency of spontaneous EPSCs and a late component of electrically-evoked EPSCs. Our preliminary results indicate that these effects are likely to be mediated through activation of the two major 5-HT2A receptor signal transduction pathways: suppression of K+ currents and a release of intracellular Ca2+ via the PLC/PI/IP3 pathway. Based on our preliminary findings, it is suggested that the effects of psychedelic hallucinogens (in common with that reported for psychotomimetic NMDA antagonist drugs) are mediated by a hyperglutamatergic mechanism downstream from the initial receptor. If hypergiutamatergic states play a role in naturally occurring psychoses (e.g., schizophrenia), as they do in the psychotomimetic drug models, then treatments that normalize glutamate release (e.g., inhibitory presynaptic metabotropic autoreceptor agonists) may be therapeutic or prophylactic in these conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH017871-31A1
Application #
6325081
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Asanuma, Chiiko
Project Start
1975-04-01
Project End
2005-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
31
Fiscal Year
2001
Total Cost
$241,675
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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