Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory.
Relapse into drug taking among addicts often depends on learned associations between drug-paired cues and the rewarding effects of these drugs, such as cocaine (COC). Memory for drug-paired cues resists extinction and contributes to the high rate of relapse; however, the molecular mechanisms underlying these associations are not understood. We show that COC-conditioned place preference (CPP) activates ERK, CREB, Elk-1, and Fos in the nucleus accumbens core (AcbC) but not shell. Intra-AcbC infusions of U0126, an inhibitor of the ERK kinase MEK, prevent both the activation of ERK, CREB, Elk-1, and Fos and retrieval of COC-CPP. When tested again 24 hr or 14 days after intra-AcbC infusions of U0126 or another MEK inhibitor, PD98059, CPP retrieval and concomitant protein activation were significantly attenuated. Together, these findings indicate the necessity of the AcbC ERK signaling pathway for drug-paired contextual cue memories and suggest that these strong memories can become susceptible to disruption by therapeutic agents.
Miller
Courtney A
CA
Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, California 92627, USA.
Marshall
John F
JF
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D002070:Butadienes / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D003463:Cues; D002373:Cyclic AMP Receptor Protein / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D002070:Butadienes; D002373:Cyclic AMP Receptor Protein; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009570:Nitriles; D016761:Oncogene Proteins v-fos; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases; D003042:Cocaine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one