SEROTONIN RECEPTOR SUBTYPES--REGULATION AND INTERACTION

  • Hensler, Julie G (PI)

Project: Research project

Project Details

Description

The regulation of receptors in brain is important in explaining certain
effects of psychotherapeutic drugs. Historically, studies of receptor
regulation have focused on the effect of chronic under- or over-exposure
of a receptor to its neurotransmitter. The regulation of receptors and
responses may also occur through interactions between receptor subtypes
for a particular neurotransmitter. The overall objective of this
proposal is to investigate whether interactions between the 5-HT1A and
5-HT2 receptors are involved in their regulation. Treatments that result
in a desensitization of 5-HT1A receptor-mediated responses also regulate
5-HT2 receptor number and/or the sensitivity of 5-HT2 receptor-mediated
responses. The studies proposed in the first specific aim are designed
to explore, using cells maintained in culture, whether interactions
between the second messenger systems linked to each subtype occur and
contribute to regulatory phenomena. Activation of protein kinase C, an
integral part of the second messenger system to which the 5-HT2 receptor
is coupled, leads to the desensitization of the 5-HT1A receptor. Thus,
5-HT2 receptor activation may play a role in the desensitization of the
5-HT1A receptor. P11 cells, which express 5-HT2 receptors coupled to
phosphoinositide (PI) hydrolysis, will be transfected with the 5-HT1A
receptor in order to study the interactions between these serotonin
receptor subtypes and their respective second messenger systems on the
same cell. Whether activation of 5-HT2 receptors causes desensitization
of 5-HT1A receptor-mediated inhibition of forskolin-stimulated adenylyl
cyclase and/or changes in 5-HT1A receptor binding will be determined.
The effect of activation of the adenylyl cyclase cascade on 5-HT2
receptor stimulated PI hydrolysis and 5-HT2 receptor binding will also
be investigated. The regulation of 5-HT1A receptors in P11 cells
expressing both serotonin receptor subtypes will be compared to its
regulation in Chinese Hamster Ovary (CHO) cells, transfected to express
only the 5-HT1A receptor. In the second specific aim, studies are
proposed to test in vivo whether the regulation of 5-HT1A receptors
occurs as a result of activation of 5-HT2 receptors, or as a result of
the desensitization or down regulation of 5-HT2 receptors and whether
intact serotonergic neurons are required for this to occur. Rats will
receive a single injection of the 5-HT2 receptor agonist DOI, or single
injection of the antagonist mianserin, or chronic treatment with the 5-
HT2 receptor antagonist ketanserin. Treatment with DOI causes activation
of 5-HT2 receptors but no down regulation of 5-HT2 receptors at the time
when measurements will be done. By contrast, these treatments with
antagonists have been shown to down regulate 5-HT2 receptors. The
sensitivity and function of both serotonin receptor subtypes will be
assessed in the same animal and in the same brain region, specifically
5-HT1A receptor-mediated inhibition of adenylyl cyclase in cortical
homogenates and 5-HT2 receptor stimulated PI hydrolysis in cortical
slices. This combined approach should provide important information that
will contribute to our understanding not only of the interactions between
serotonin receptor subtypes and their respective second messenger systems
but also of the regulation of the 5-HT1A receptor in vivo.
StatusFinished
Effective start/end date9/1/934/30/10

Funding

  • National Institutes of Health: $134,886.00
  • National Institutes of Health: $295,650.00
  • National Institutes of Health: $288,702.00
  • National Institutes of Health: $101,500.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $249,183.00
  • National Institutes of Health: $249,183.00
  • National Institutes of Health: $252,875.00
  • National Institutes of Health: $101,500.00
  • National Institutes of Health: $295,650.00
  • National Institutes of Health
  • National Institutes of Health: $216,750.00
  • National Institutes of Health: $252,875.00

ASJC

  • Medicine(all)

Fingerprint Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.