| Melanin Concentrating Hormone (MCH) is a hypothalamic peptide originally isolated from fish to induce paling of the skin by causing the aggregation of melanin granules. In 1999, by our group, it was found that MCH acts through G protein coupled receptor. Within the last decade, multiple biological functions for MCH have been discovered. This dissertation focuses on studying its central and peripheral roles, in particular, the role of the MCH system in cocaine reward and energy homeostasis.;Chapter 1 describes briefly about GPCR systems in general and a brief overview of the MCH system. To fully understand MCH function, acute blockade of the MCH is necessary. We present here in Chapter 2, the isolation and the characterization of a MCH1R antagonist from mixture-based combinatorial libraries. This antagonist, TPI 1361-17 was identified through the screening of multiple non-peptide positional scanning synthetic combinatorial libraries (PS-SCL) totaling more than eight million compounds. TPI 1361-17 is a novel and selective MCH1R antagonist with high affinity.;Chapter 3 describes the role of MCH system in energy homeostasis. A MCH1R antagonist, TPI 1361-17 decreases potently food intake. We further show that this effect is parallel by an increase in lipid utilization. Consistent with these effects, chronic blockade of the MCH system by TPI 1361-17 in mice fed high fat diet exhibit a reduction in body weight, in body fat composition and a return to normal in serum parameters such as glucose and triglycerides.;Chapter 4 describes the role of the MCH system in reward. Mice lacking MCH1R exhibit decreased cocaine-induced conditioned place preference and cocaine sensitization. In addition, acute blockade of the MCH system by using a specific MCH1R antagonist not only reduces cocaine self-administration but also attenuates cue- and cocaine-induced reinstatement. Finally, we determine that, in the NAcSh, the MCH1R is co-expressed with dopamine receptors (D1R and D2R) and that MCH increases D1R- and D2R-induced electrophysiological and biochemical responses. Thus, the MCH system displays an important modulatory role in cocaine reward and reinforcement.;In conclusion, MCH is a hypothalamic neuropeptide which regulates diverse physiological functions. Here, I showed that MCH system plays an important role in energy homeostasis and reward by using a specific pharmacological tool as well as a genetic model. |
