The role of the M-current in the anorectic effects of estrogen and serotonin.

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DESCRIPTION (provided by applicant): The long range goal of the proposed research is to understand how estrogen affects energy homeostasis either through controlling potassium channel gene expression in hypothalamic neurons or by synergistically altering neuronal excitability with other neurotransmitters such as serotonin. Estrogens are anorectic leading to decreased food intake and body weight and are known to potentiate the anorectic effects of serotonergic drugs. One potential mechanism for the anorectic effects of estrogen and serotonin is inhibition of the M- current in POMC neurons. In order to determine if the M-current plays a role in these effects, changes in expression of KCNQ subunits (2, 3, & 5), which form the heteromultimeric channels responsible for the M- current in the brain, and their signaling modulators will be determined following estrogen treatment in the arcuate nucleus using qRT-PCR. Single cell RT-PCR will be used to determine the distribution pattern of KCNQ subunits and co-localization with cell type markers (POMC, NPY). The effects of estrogen pre- treatment on the electrophysiological properties of the M-current in arcuate neurons will be examined using whole cell patch recordings of POMC and NPY neurons from oil and estrogen-treated animals. Recordings will also determine any direct modulation of the M-current via a rapid response to estrogen through the putative estrogen membrane receptor using the M-current attenuation by a muscarinic receptor agonist and a selective 5HT2C receptor agonist. The inhibition of food intake by serotonin may involve modulation of the M-current through 5HT2C receptors. Agonist of the 5HT2C receptor will injected (icv) into ovariectomized mice treated with oil or estrogen. Weight and food intake will be measured for 48 hr after injection of a selective 5HT2CR agonist with or without pharmacological modulators of the M-current. If the modulation of the M current is important for the regulation of food intake by either serotonin or estrogen, the M-current activator should partially or completely attenuate the anorectic effects of 5HT and/or estrogen. Obesity is one of the major health issues facing the adolescents and adults in the developed world with few safe therapeutic drugs available to assist the population in maintaining a healthy weight. The mechanism through which peripheral and central signals control food intake must be examined to develop new strategies and therapies for one of the most serious health issues facing us today.