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Neuropsychopharmacology. 2019 Jan;44(2):334-343. doi: 10.1038/s41386-018-0068-y. Epub 2018 Apr 17.

Opiate-associated contextual memory formation and retrieval are differentially modulated by dopamine D1 and D2 signaling in hippocampal-prefrontal connectivity.

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College of Forensic Science, Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China.
Intensive Care Unit, Shaanxi Provincial People's Hospital, 710061, Xi'an, Shaanxi, China.
Xi'an Mental Health Center, 710061, Xi'an, Shaanxi, China.
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, 19129, USA.


Contextual memory driven by abused drugs such as opiates has a central role in maintenance and relapse of drug-taking behaviors. Although dopamine (DA) signaling favors memory storage and retrieval via regulation of hippocampal-prefrontal connectivity, its role in modulating opiate-associated contextual memory is largely unknown. Here, we report roles of DA signaling within the hippocampal-prefrontal circuit for opiate-related memories. Combining-conditioned place preference (CPP) with molecular analyses, we investigated the DA D1 receptor (D1R) and extracellular signal-regulated kinase (ERK)-cAMP-response element binding protein (CREB) signaling, as well as DA D2 receptor (D2R) and protein kinase B (PKB or Akt)/glycogen synthase kinase 3 (GSK3) signaling in the ventral hippocampus (vHip) and medial prefrontal cortex (mPFC) during the formation of opiate-related associative memories. Morphine-CPP acquisition increased the activity of the D1R-ERK-CREB pathway in both the vHip and mPFC. Morphine-CPP reinstatement was associated with the D2R-mediated hyperactive GSK3 via Akt inhibition in the vHip and PFC. Furthermore, integrated D1R-ERK-CREB and D2R-Akt-GSK3 pathways in the vHip-mPFC circuit are required for the acquisition and retrieval of the morphine contextual memory, respectively. Moreover, blockage of D1R or D2R signaling could alleviate normal Hip-dependent spatial memory. These results suggest that D1R and D2R signaling are differentially involved in the acquisition and retrieval of morphine contextual memory, and DA signaling in the vHip-mPFC connection contributes to morphine-associated and normal memory, largely depending on opiate exposure states.

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