Reexposure to the context associated with heroin intake provokes relapse to drug taking after abstinence. The dorsal dentate gyrus (dDG) and entorhinal cortex (EC) have been implicated in contextual memory processing, but the underlying circuit mechanisms in context-induced relapse remain poorly understood. In this study, using a self-administration rat model, we found that activation and synaptic transmission of glutamatergic projections from the EC to the upper blade of dentate gyrus (dDGub) were significantly enhanced during context-induced reinstatement of heroin seeking. This effect was associated with increased of phosphorylation of GluN2B-containing NMDA receptors (GluN2B) at Y1472, ratio of GluN2B membrane/total protein levels, and expression of downstream extracellular signal-regulated kinase-1/2 (ERK1/2) in the dDG region. Furthermore, DREADD-mediated specific inactivation of the EC–dDG pathway or disconnection of the pathway with local postsynaptic GluN2B–ERK1/2 signaling both decreased context-induced reinstatement of heroin seeking. These experimental manipulations had no effect on saccharin-reinforced responding and general locomotor activity in rats. Our results indicate that the EC–dDG pathway mediates context-induced reinstatement of heroin seeking, via the activation of postsynaptic GluN2B–ERK1/2 signaling in the dDG.
There is evidence that the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP-dependent protein kinase (PKG) signaling pathway in the basal lateral amygdala and hippocampus plays a key role in memory processing, but it is not known if this NO signaling pathway in the nucleus accumbens (Gomes et al., 2006), a known pivotal region in reward memory, is essential for drug-associated reward memory. We therefore investigated the effect of the NO/sGC/PKG signaling pathway in the nucleus accumbens (NAc) on morphine-induced conditioned place preference (CPP). Results showed that a preconditioning microinjection of the NO synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) into the NAc shell, but not into the core, significantly blocked the acquisition of morphine CPP. The blockage effect of L-NAME on the acquisition of CPP was imitated by the neuronal NOS inhibitor 7-nitroindazole, 3-bromo-, sodium salt (7-NI), the sGC inhibitor 1H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), and the PKG inhibitor Rp-8Br-PET-cGMPS. The 7-NI- or ODQ-induced effect was reversed by premicroinjection of the sGC activator YC-1 or the PKG activator 8-Br-cGMP in the NAc shell. However, microinfusion of 7-NI, ODQ, or Rp-8Br-PET-cGMPS into the NAc shell or the core had no effect on the expression of morphine CPP. These findings indicate that the NO/sGC/PKG signaling pathway in the NAc shell is critical for the acquisition of morphine-induced place preference, whereas the same signaling pathway in the NAc shell or core is not involved in the retrieval of morphine-induced place preference.
Background. The apolipoprotein E (APOE) gene polymorphisms have been intensively studied in patients with type 2 diabetes mellitus (T2DM) and ischemic stroke (IS) in recent years. However, it is unclear whether APOE gene polymorphisms are correlated with increased risk for developing IS in T2DM patients. Thus, this study was designed to examine the association between APOE gene polymorphisms and risks of IS in Chinese patients with T2DM. Methods. This case-control study enrolled 243 subjects with T2DM as controls, and 210 subjects with T2DM complicated with IS as case patients. The genotypes were determined using real-time PCR while HbA1c and lipid levels were detected using commercially available kits. Results. The systolic blood pressure (SBP), diastolic blood pressure (DBP), and the proportion of patients with a history of hypertension were higher in the case patients than that in the controls. We confirmed that the ε2/ε3 genotype, as well as SBP and history of hypertension, was the independent risk factor for developing IS in T2DM patients. Conclusions. We conclude that the ε2/ε3 genotype might contribute to the increased risk for developing IS in Chinese patients with T2DM.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.