ELECTROPHYSIOLOGICAL TESTING OF DRUG COMBINATIONS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity and "overweightness" are significant medical problems and the prevalence of the disease is increasing, especially in young people. Pharmacotherapy remains the best option for the population if effective drugs can be developed. Studies on the locus and mechanism of action of several satiety factors have identified a neural circuit that is responsive to many signals of energy state. Signals of energy stores are sensed by proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons in the arcuate nucleus of the hypothalamus. Clinical literature and our mechanistic studies have identified potential drug combinations that may be effective therapies for obesity. Part of validating these new drug combinations is to test if they act upon this arcuate circuitry. Selective serotonin reuptake inhibitors (SSRIs) increase the concentration of serotonin in the brain; we have previously shown that serotonin activates POMC neurons. Mu opioid receptor (MOP-R) antagonists inhibit the activation of MOP-R; we have previously shown that MOP-R acts to inhibit the activity of POMC neurons, thus we can reasonably postulate that MOP-R antagonism will allow activators of POMC neurons to exert more potent effects on POMC neurons. The first combination, SSRI and MOP-R agonist have been shown to act separately upon the "satiety circuitry"; other combinations have not been tested, but are indicated as effective weight loss agents. We propose to test the effects of the SSRI/MOP-R antagonist combination upon the activity of POMC and NPY neurons in the arcuate nucleus, and the weight loss efficacy of this drug combination, in mice.