Facilitation of conditioned fear extinction by d-cycloserine is mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase cascades and requires de novo protein synthesis in basolateral nucleus of amygdala.
Recent results showed that either systemic or intra-amygdala administration of d-cycloserine, a partial agonist at the glycine modulatory site on the glutamate N-methyl-d-aspartate receptor facilitates the extinction of conditioned fear. Here we evaluated the role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase in the basolateral nucleus of amygdala on the effect of d-cycloserine. The facilitation effect of d-cycloserine on fear extinction and mitogen-activated protein kinase activation was completely blocked by intra-amygdala administration of mitogen-activated protein kinase inhibitor PD98059 (500 ng/side, bilaterally) or U0-126 (20 microM/side, bilaterally). Furthermore, phosphatidylinositol 3-kinase inhibitor (wortmannin, 5.0 microg/side, bilaterally) infused into the basolateral nucleus of amygdala significantly reduced both facilitation effect of d-cycloserine and phosphatidylinositol 3-kinase activation. Intra-amygdala administration of a transcription inhibitor (actinomycin D, 10 microg dissolved in 1.6 microl vehicle; 0.8 microl per side) and a translation inhibitor (anisomycin, 125 microg dissolved in 1.6 microl vehicle; 0.8 microl per side) completely blocked the facilitation effect of d-cycloserine. Control experiments indicated the blockage by actinomycin D or anisomycin were not due to lasting damage to the basolateral nucleus of amygdala or state dependency. In addition, none of the active drugs used here altered the expression of conditioned fear. These results suggested that phosphatidylinositol 3-kinase and mitogen-activated protein kinase-dependent signaling cascades and new protein synthesis within the basolateral nucleus of amygdala played important roles in the d-cycloserine facilitation of the extinction of conditioned fear.
Yang
Y L
YL
Institute of Biotechnology, Department of Molecular Biology and Biochemistry, National Chia-Yi University, 300 University Road, Chia-Yi, Taiwan.
Lu
K T
KT
D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D003213:Conditioning, Psychological / Q000187:drug effects*; D003523:Cycloserine / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects*; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects; D013997:Time Factors
D003523:Cycloserine; D004791:Enzyme Inhibitors; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases