The present study was aimed to elucidate the possible mechanism of glucocorticoids on the conditioned fear extinction by using fear-potentiated startle paradigm. We found that (1) Systemic administration of dexamethasone (DEX, 1.0 mg/kg, i.p.) accelerated extinction of conditioned fear. (2) Administration of glutamate NMDA receptor antagonists (±)-HA966 (6.0 mg/kg, i.p.) and intra-amygdala infusion of MK801 (0.5 ng/side, bilaterally) or D,L-2-amino-5- phosphonovaleric acid (AP5, 2.0 ng/side, bilaterally) blocked the DEX facilitation effect. (3) Blockade of corticosteroid synthesis inhibitor metyrapone (25 mg/kg. s.c.) on extinction was removed by co-administration of NMDA receptor agonist D-cycloserine (DCS, 5.0 mg/kg, i.p.). (4) Co-administration of DEX and DCS in a sub-threshold dose provided a synergistic facilitation effect on extinction (0.2 mg/kg and 5 mg/kg, respectively). However, DEX and DCS co-administration did not alter the expression of conditioned fear. (5) The facilitation effect of DEX was blocked by intra-amygdala infusion of mitogen activated protein kinase (MAPKs) inhibitors PD98059 (500 ng/side, bilaterally) or U0-126 (20 μM/side. bilaterally). DEX significantly enhanced the phosphorylation of MAPKs which induced by the extinction training. These results suggested that glutamate NMDA receptors and MAPKs within the amygdala participated in the modulation effect of glucocorticoids on extinction. [J Physiol Sci. 2006;56 Suppl:S87]
