Leptin: a potential anxiolytic by facilitation of fear extinction.

AIMS: Anxiety disorders are characterized by a deficient extinction of fear memory. Evidence is growing that leptin influences numerous neuronal functions. The aims of this study were to investigate the effects and the mechanism of leptin on fear extinction.

METHODS AND RESULTS: Leptin (1 mg/kg, i.p) was applied to evaluate the anxiolytic effect in rat behavioral tests. Field potentials recording were used to investigate the changes in synaptic transmission in the thalamic-lateral amygadala (LA) pathway of rat. We found that leptin produced strong anxiolytic effects under basal condition and after acute stress. Systemic administration and intra-LA infusions of leptin facilitated extinction of conditioned fear responses. The antagonist of NMDA receptor, MK-801, blocked the effect of leptin on fear extinction completely. Furthermore, these effects of leptin on fear extinction were accompanied by a reversal of conditioning-induced synaptic potentiation in the LA. Leptin facilitated NMDA receptor-mediated synaptic transmission, and reversed amygdala long-term potentiation (LTP) in a dose-dependent manner in vitro, and this LTP depotentiation effect was mediated by NMDA receptor and MAPK signaling pathway.

CONCLUSIONS: These results identify a key role of leptin in dampening fear conditioning-induced synaptic potentiation in the LA through NMDA receptor and indicate a new strategy for treating anxiety disorders.