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Neuropsychopharmacology. 2016 Feb;41(3):675-85. doi: 10.1038/npp.2015.217. Epub 2015 Jul 23.

Contribution of an SFK-Mediated Signaling Pathway in the Dorsal Hippocampus to Cocaine-Memory Reconsolidation in Rats.

Author information

1
Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, CA, USA.
2
Department of Chemistry, North Carolina State University, Raleigh, NC, USA.
3
Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, WA, USA.
4
Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

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.

PMID:
26202103
PMCID:
PMC4707834
DOI:
10.1038/npp.2015.217
[Indexed for MEDLINE]
Free PMC Article

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