Leptin Action on Dopamine Neurons: Biochemical and Behavioral Analysis

It has been demonstrated that there are brain regions commonly activated by hedonic foods and drugs of abuse, and therefore, potentially common mechanisms underlying behaviors associated with them. Additionally, the metabolic state of an animal can affect drug seeking behavior. The discovery that leptin receptor (Lepr) is expressed on dopamine neurons in the ventral tegmental area (VTA) provides a link between metabolic state and rewarding behavior. By using a multitude of techniques, the functional roles for Lepr signaling on dopamine neurons have been assessed. By activating Lepr in the VTA via direct infusion of leptin, or conversely reducing Lepr signaling in the VTA with viral-mediated shRNAi, a role for VTA leptin signaling in feeding behavior was demonstrated. Lepr activation in the VTA leads to intracellular signaling pathways similar to that observed in the hypothalamus. These studies also identify differences in signaling between these two brain regions, specifically the phosphorylation of AMP-activated protein kinase (AMPK), which is opposite to what is observed in the hypothalamus. Interestingly, food restriction was found to differentially affect the signaling pathways in the VTA. Preliminary evidence also suggests a role for Lepr in saccharin and cocaine seeking behaviors. Rats with attenuated Lepr signaling in the VTA demonstrate persistent saccharin and cocaine seeking. Conversely, leptin infusions reduced lever pressing during drug withdrawal. These results are indicative of a potential role for leptin in drug and food seeking behavior. In sum, these results suggest a neuronal mechanism by which this key metabolic signal can modify both food and drug intake.