title: Contribution of an SFK-Mediated Signaling Pathway in the Dorsal Hippocampus to Cocaine-Memory Reconsolidation in Rats.
abstract: Environmentally induced relapse to cocaine seeking requires the retrieval of context-response-cocaine associative memories. These memories become labile when retrieved and must undergo reconsolidation into long-term memory storage to be maintained. Identification of the molecular underpinnings of cocaine-memory reconsolidation will likely facilitate the development of treatments that mitigate the impact of cocaine memories on relapse vulnerability. Here, we used the rat extinction-reinstatement procedure to test the hypothesis that the Src family of tyrosine kinases (SFK) in the dorsal hippocampus (DH) critically controls contextual cocaine-memory reconsolidation. To this end, we evaluated the effects of bilateral intra-DH microinfusions of the SFK inhibitor, PP2 (62.5 ng per 0.5 μl per hemisphere), following re-exposure to a cocaine-associated (cocaine-memory reactivation) or an unpaired context (no memory reactivation) on subsequent drug context-induced instrumental cocaine-seeking behavior. We also assessed alterations in the phosphorylation state of SFK targets, including GluN2A and GluN2B N-methyl-D-aspartate (NMDA) and GluA2 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits at the putative time of memory restabilization and following PP2 treatment. Finally, we evaluated the effects of intra-DH PEAQX (2.5 μg per 0.5 μl per hemisphere), a GluN2A-subunit-selective NMDAR antagonist, following, or in the absence of, cocaine-memory reactivation on subsequent drug context-induced cocaine-seeking behavior. GluN2A phosphorylation increased in the DH during putative memory restabilization, and intra-DH PP2 treatment inhibited this effect. Furthermore, PP2-as well as PEAQX-attenuated subsequent drug context-induced cocaine-seeking behavior, in a memory reactivation-dependent manner, relative to VEH. These findings suggest that hippocampal SFKs contribute to the long-term stability of cocaine-related memories that underlie contextual stimulus control over cocaine-seeking behavior.
authors.affiliation: Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, CA, USA.
authors.forename: Audrey M
authors.initials: AM
authors.lastname: Wells
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC, USA.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, WA, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Higginbotham
authors.affiliation: Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, WA, USA.
authors.forename: Amy A
authors.initials: AA
authors.lastname: Arguello
authors.affiliation: Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Kati L
authors.initials: KL
authors.lastname: Healey
authors.affiliation: Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Blanton
authors.affiliation: Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, WA, USA.
authors.forename: Rita A
authors.initials: RA
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D000069077:Memory Consolidation / Q000187:drug effects* / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012646:Self Administration; D015398:Signal Transduction / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D011743:Pyrimidines; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D019061:src-Family Kinases; C498554:5-(alpha-methyl-4-bromobenzylamino)phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione; C412373:AG 1879; C121001:NR2B NMDA receptor; C104722:glutamate receptor ionotropic, AMPA 2