NPY controls fear conditioning and fear extinction by combined action on Y(1) and Y(2) receptors

BACKGROUND AND PURPOSE: Neuropeptide Y (NPY) and its receptors have been implicated in the control of emotional-affective processing, but the mechanism is unclear. While it is increasingly evident that stimulation of Y(1) and inhibition of Y(2) receptors produce prominent anxiolytic and antidepressant effects, the contribution of the individual NPY receptor subtypes in the acquisition and extinction of learned fear are unknown. EXPERIMENTAL APPROACH: Here we performed Pavlovian fear conditioning and extinction in NPY knockout (KO) and in NPY receptor KO mice. KEY RESULTS: NPY KO mice display a dramatically accelerated acquisition of conditioned fear. Deletion of Y(1) receptors revealed only a moderately accelerated acquisition of conditioned fear, while lack of Y(2) receptors was without any effect on fear learning. However, the strong phenotype seen in NPY KO mice was reproduced in mice lacking both Y(1) and Y(2) receptors. In addition, NPY KO mice showed excessive recall of conditioned fear and impaired fear extinction. This behaviour was replicated only after deletion of both Y(1) and Y(2) receptors. In Y(1) receptor single KO mice, fear extinction was delayed and was unchanged in Y(2) receptor KO mice. Deletion of NPY and particularly Y(2) receptors resulted in a generalization of conditioned fear. CONCLUSIONS AND IMPLICATIONS: Our data demonstrate that NPY delays the acquisition, reduces the expression of conditioned fear while promoting fear extinction. Although these effects appear to be primarily mediated by Y(1) receptors, the pronounced phenotype of Y(1)Y(2) receptor double KO mice suggests a synergistic role of Y(2) receptors in fear acquisition and in fear extinction.