Effects of 2‐Chloroethyl Ethyl Sulfide (CEES), a Mustard Gas Analog, on Serotonin/Dopamine Signaling in Guinea Pig Brain

We reported earlier that exposure of guinea pigs to CEES, a mustard gas analog, resulted in body weight gain associated with a down‐regulation of the pro‐opiomelanocortin (POMC) gene. However, its mechanism is not clear. It is known that d‐fenfluramine, a serotonin (5‐HT) 2C receptor agonist and an appetite suppressant, causes activation of c‐fos of POMC neurons in the arcuate nucleus of the hypothalamus. POMC neurons in this area express 5‐HT 2C receptor mRNA, suggesting that the 5‐HT 2C receptor mediates fenfluramine's actions in this area. Serotonin has also been shown to regulate dopamine neurotransmission. Dopamine directs energy balance by exerting effects on food intake through the mesolimbic, meso‐hypothalamic, and nigro‐striatal brain circuitry. HPLC analysis showed a 50% reduction in the levels of serotonin and a small increase in the levels of dopamine in the midbrain due to CEES exposure. Western blot analysis indicated that CEES exposure had no effect on the protein levels of either D1 or D2 dopamine receptors in the frontal and midbrain area. However, the protein levels of D1 receptors were increased and protein levels of D2 receptors were decreased in the lateral brain. These results indicate that down‐regulation of POMC gene by CEES exposure may be mediated by its effect on serotonin/dopaminergic signaling. This project was supported by DOD grant W81XWH‐06‐2‐0044 and NIH grant 5T32HL007735‐12.