There are several reports showing evidence for the existence of high levels of prolactin (PRL) in chronic alcoholic men and women. The study conducted by us during the past funded period provided data that suggest that chronic ethanol administration not only elevates plasma levels of PRL but also increases proliferation of pituitary lactotropes. We also found that ethanol affects the expression of estrogen-responsive hormones and polypeptides that promote growth and transformation of lactotropes. Hence, we hypothesized that, like estrogen, chronic ethanol might promote tumor development in lactotropes.The present proposal will address this issue by studying ethanol's in vivo and in vitro effects on lactotropic cell secretion, growth and transformation using the rat as an animal model. The proposed research will test the hypothesis that ethanol may cross-talk with estrogen receptors, an estrogen-responsive signaling cascade or estrogen-regulated cell-cell communication to control prolactin secretion and lactotropic cell proliferation. Specific proposal objectives are: (1) to evaluate the mechanisms of ethanol action on PRL gene transcription by determining the role of G protein-coupled D2 receptors and cAMP-PKA-CREB signaling, and the role of TGF-beta, estrogen receptors and p42/p44 MAP kinase; and (2) to determine the cellular action of ethanol on lactotrope proliferation by testing the role of estrogen receptors, G proteins, cAMP, PKA, PKC and MAPK in the ethanol actions. To study the mechanisms of ethanol action on lactotropes, we will pharmacologically and genetically manipulate the signal transduction systems, and measure the intracellular level of these signal transducers by histological, biochemical and molecular techniques.These studies have the potential to elucidate important cellular mechanisms underlying the ethanol effect on prolactinomas. Such knowledge will improve the understanding and management of hyperprolactinemia in alcoholic patients.