Project: Research project

Project Details


The broad, long-term objectives of this proposal are to characterize
the effects of the sex steroids on neurotransmission at a cellular
level and to determine the underlying mechanisms of their actions.
The immediate goal is to integrate electrophysiological
(intracellular and field potential recordings), biochemical,
pharmacological and endocrinological methods to delineate the effects
of estrogen treatment (in vivo and in vitro), and their modulation by
progesterone, on signal transduction mechanisms coupled to
postsynaptic serotonergic receptors in the rat hippocampus.
Alterations of serotonergic neurotransmission and fluctuations in the
levels of estrogen have been implicated in the etiology of affective
disorders and depressive illness. The 5-HT system is also involved
in other estrogen dependent functions, such as sexual behavior and
gonadotropin secretion. But, little is known of the cellular
mechanisms by which estrogen alters 5-HT neurotransmission. The
hippocampus is an ideal locus to study 5-HT neurotransmission and is
ideal for electrophysiological and pharmacological investigations.
The Specific Aims are: 1) To characterize the estrogen-induced
increase in responsiveness of the 5-HT1A full and partial agonists in
hippocampal slices from OVX rats treated chronically with estrogen
and estrogen plus progesterone. Estrogen antagonists will be used to
demonstrate that estrogen's actions are receptor mediated. Estrogen
treatment in vivo need not act directly at the hippocampus to alter
5-HT1A responsiveness. The hypothesis that estrogen acts directly at
the hippocampus will be tested by administering estrogen to the
hippocampus of ovariectomized rats in vitro and in vivo. The
influence of progesterone on estrogen's effect will also be examined.
2) To elucidate the mechanisms by which estrogen enhances 5-HT1A
responsiveness. Estrogen-induced changes in agonist affinity and
density of 5-HT1A receptors will be assessed with quantitative
autoradiography. The effects of estrogen treatment on the signal
transduction and effector mechanisms linked to the 5-HT1A receptor
will be examined by studying estrogen's effects on G-proteins and on
responses that share different components of the signal transduction
pathway involved in the inhibition of pyramidal cells (e.g. responses
to activation of adenosine A1 and GABAB receptors). 3) Changes in 5-
HT1A responsiveness will be studied during the estrous cycle and
pregnancy. 4) The effect of estrogen treatment on non-5-HT1A
responses in hippocampus, including blockade of the post-spike after-
hyperpolarization, slow depolarization of pyramidal cells, increase
in population spike amplitude, will be investigated. These
experiments will elucidate the mechanism(s) that govern estrogen
enhancement of serotonergic function in hippocampus and provide
additional insight into the mechanisms of serotonergic and estrogen
actions in the CNS. An understanding of the effects and the
mechanisms of estrogen's action on the 5-HT system may provide useful
information for the treatment of affective illness.
Effective start/end date3/1/922/28/98


  • National Institutes of Health: $92,529.00


  • Medicine(all)


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