Neurobiology of Learning and Memory 73, 11–20 (2000) doi:10.1006/nlme.1999.3913, available online at http://www.idealibrary.com on Time-Dependent Impairment of Inhibitory Avoidance Retention in Rats by Posttraining Infusion of a Mitogen-Activated Protein Kinase Kinase Inhibitor into Cortical and Limbic Structures Roger Walz,* Rafael Roesler,* Joa ˜o Quevedo,* Ma ´rcia K. Sant’Anna,* Marcelo Madruga,* Cleverson Rodrigues,* Carmen Gottfried,² Jorge H. Medina,‡ and Ivan Izquierdo* *Centro de Memo ´ria, and ² Laborato ´rio de Fosforilac ¸a ˜o de Proteı ´nas Cerebrais, Departamento de Bioquı ´mica, ICBS, UFRGS, Ramiro Barcellos 2600, 90035-003 Porto Alegre, RS, Brazil; and ² Laborato ´rio de Neuroreceptores, Instituto de Biologı ´a Celular, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 3er piso, Buenos Aires, Argentina Mitogen-activated protein kinase (MAPK) is abundantly expressed in postmitotic neurons of the developed nervous system. MAPK is activated and required for induction of long-term potentiation (LTP) in the CA1 area of the hippocampus, which is blocked by the specific inhibitor of the MAPK kinase, PD 098059. Recently it was demonstrated that MAPK is activated in the hippocampus after training and is necessary for contextual fear conditioning learning. The present work tests the role of the MAPK cascade in step-down inhibitory avoidance (IA) retention. PD 098059 (50 M) was bilaterally injected (0.5 l/side) into the CA1 region of the dorsal hippocampus or entorhinal cortex at 0, 90, 180, or 360 min, or into the amygdala or parietal cortex at 0, 180, or 360 min after IA training in rats using a 0.4-mA foot shock. Retention testing was carried out 24 h after training. PD 098059 impaired retention when injected into the dorsal hippocampus at 180 min, but not 0, 90, and 360 min after training. When infused into the entorhinal cortex, PD 098059 was amnestic at 0 and 180 min, but not at 90 and 360 min after training. The MAPKK inhibitor also impairs IA retention when infused into the parietal cortex immediately after training, but not at 180 or 360 min. Infusions performed into amygdala were amnestic at 180 min, but not at 0 and 360 min after training. Our results suggest a time-dependent involvement of the MAPK cascade in the posttraining memory processing of IA; the time dependency is different in the hippocampus, amygdala, entorhinal cortex, or parietal cortex of rats.  2000 Aca- demic Press This work was supported by PRONEX and Fundac ¸a ˙ VITAE, Brazil. Address correspondence and reprint request to Roger Walz, Centro de Memo ´ ria, Departamento de Bioquı ´mica, Instituto de Cie ˆncias Ba ´sicas da Sau ´de, UFRGS, Ramiro Barcelos 2600 (Anexo), 90035-003 Porto Alegre, RS, Brazil. Fax: 55 516 5535. E-mail: rogerwalz@hotmail.com. 11 1074-7427/00 $35.00 Copyright  2000 by Academic Press All rights of reproduction in any form reserved.