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.
