Abstract
The regulation of adult neurogenesis by opiates has been implicated in modulating different addiction cycles. At which neurogenesis stage opiates exert their action remains unresolved. We attempt to define the temporal window of morphine’s inhibition effect on adult neurogenesis by using the POMC-EGFP mouse model, in which newborn granular cells (GCs) can be visualized between days 3–28 post-mitotic. The POMC-EGFP mice were trained under the 3-chambers conditioned place preference (CPP) paradigm with either saline or morphine. We observed after 4 days of CPP training with saline, the number of EGFP-labeled newborn GCs in sub-granular zone (SGZ) hippocampus significantly increased compared to mice injected with saline in their homecage. CPP training with morphine significantly decreased the number of EGFP-labeled GCs, whereas no significant difference in the number of EGFP-labeled GCs was observed with the homecage mice injected with the same dose of morphine. Using cell-type selective markers, we observed that morphine reduced the number of late stage progenitors and immature neurons such as Doublecortin (DCX) and βIII Tubulin (TuJ1) positive cells in the SGZ but did not reduce the number of early progenitors such as Nestin, SOX2, or neurogenic differentiation-1 (NeuroD1) positive cells. Analysis of co-localization between different cell markers shows that morphine reduced the number of adult-born GCs by interfering with differentiation of early progenitors, but not by inducing apoptosis. In addition, when NeuroD1 was over-expressed in DG by stereotaxic injection of lentivirus, it rescued the loss of immature neurons and prolonged the extinction of morphine-trained CPP. These results suggest that under the condition of CPP training paradigm, morphine affects the transition of neural progenitor/stem cells to immature neurons via a mechanism involving NeuroD1.
Highlights
Addictive drugs such as opiates cause long-lasting changes in the brain, which influences many different forms of neural plasticity [1,2]
Among the multiple forms of neural plasticity mechanisms that contribute to drug memory, adult neurogenesis in the sub-granular zone (SGZ) of the dentate gyrus (DG) in the hippocampus has been implicated in drug reward and relapse due to the substantial roles that adult neurogenesis has in hippocampus function during learning and memory [3,4]
Comparing the fluorescent images of BrdU labeled cells under the microscope, we found that 50%-60% of the BrdU-labeled cells were EGFP positive (Fig 1F, left panel) from mice injected with BrdU on days 1–3, while there was no colocalization between BrdU and EGFP positive cells (Fig 1F, right panel) from mice injected with BrdU on day 9
Summary
Addictive drugs such as opiates cause long-lasting changes in the brain, which influences many different forms of neural plasticity [1,2]. Several addictive drugs have been shown to alter adult neurogenesis. The psychomotor stimulants methamphetamine and cocaine decreased proliferation or maturation of hippocampal neural stem cells [5], and withdrawal from cocaine normalizes deficits in the proliferation of adult-born granular cells (GCs) [6]. Chronic morphine, administered via subcutaneous pellet implantation, was shown to decrease the number of proliferating cells in the SGZ in rodents; a similar effect was observed in rats after chronic self-administration of heroin [7], while following extinction from heroin-seeking behavior, the formation of immature neurons in the DG was increased [8]. A recent study in our lab showed in detail that morphine exposure affects neurogenesis by modulating the cell-lineage in cultured neural stem cells [12]
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