The general purpose of this project continues to be the investigation of the electrophysiological actions of the indoleamine/phenethethylamine class of psychedelic hallucinogens on identified neurons of the rat brain.
Specific aims are: 1. To investigate the pathways by which hallucinogenic drugs alter the activity and reactivity of locus coeruleus neurons in vivo: The role of major afferent inputs will be examined since the effect of psychedelic hallucinogens on locus coeruleus neurons does not appear to be due to a direct action on these cells. 2. To analyze cellular subtypes and membrane mechanisms underlying 5-HT2- receptor-mediated excitatory actions of serotonin and hallucinogenic drugs on identified neurons in brain slices. The membrane mechanisms underlying the excitatory/facilitatory effects of serotonin and hallucinogenic drugs will be studied on identified neurons in brain slices from facial nucleus and cerebral cortex. 3. To evaluate the role of G proteins and protein kinase C in modulating neuronal responses to serotonin and hallucinogenic drugs. The involvement of G proteins and protein kinase C in the mediation of 5-HT2 responses will be examined in brain slices from cerebral cortex and facial nucleus. 4. To study the cellular mechanisms of tolerance and sensitization to hallucinogenic drugs. Chronic studies will be conducted in terms of known changes in receptor and effector mechanisms (e.g., 5-HT2 receptor downregulation by hallucinogenic drugs). The value of the proposed research would be to advance knowledge about the mechanism of action of a major class of drugs, the psychedelic hallucinogens. In addition to any implications for the treatment of drug overdose (or other untoward reactions), this information could aid the rational development of more efficacious antipsychotic drugs, which, for example, might act upon convergent effector mechanisms and second messenger systems rather than the initial receptor site as is the case with currently available treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH017871-23
Application #
2243435
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1975-04-01
Project End
1995-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
23
Fiscal Year
1992
Total Cost
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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