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The Scientific World Journal
Volume 2016, Article ID 2601264, 7 pages
http://dx.doi.org/10.1155/2016/2601264
Review Article

Effect of Opioid on Adult Hippocampal Neurogenesis

Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455-0217, USA

Received 27 November 2015; Accepted 17 March 2016

Academic Editor: Masaya Thoyama

Copyright © 2016 Yue Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

During the past decade, the study of the mechanisms and functional implications of adult neurogenesis has significantly progressed. Many studies focus on the factors that regulate proliferation and fate determination of adult neural stem/progenitor cells, including addictive drugs such as opioid. Here, we review the most recent works on opiate drugs’ effect on different developmental stages of adult hippocampal neurogenesis, as well as the possible underlying mechanisms. We conclude that opiate drugs in general cause a loss of newly born neural progenitors in the subgranular zone of dentate gyrus, by either modulating proliferation or interfering with differentiation and maturation. We also discuss the consequent impact of regulation of adult neurogenesis in animal’s opioid addiction behavior. We further look into the future directions in studying the convergence between the adult neurogenesis field and opioid addiction field, since the adult-born granular cells were shown to play a role in neuroplasticity and may help to reduce the vulnerability to drug craving and relapse.

1. Introduction

During the past two decades, it has been well established that new neurons were born continuously throughout life in the brains of many species, including human [1, 2]. In normal conditions, adult neurogenesis appears to be restricted in two discrete brain regions: the subventricular zone (SVZ) of the lateral ventricle [3] and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) [4]. Since then, substantial research has been made to study the intrinsic and extrinsic factors that regulate adult hippocampal neurogenesis, for newborn neurons in the SGZ could contribute to specific hippocampal functions such as spatial learning, pattern discrimination, and mood regulation [5, 6]. Several classes of neural stimulants have been shown to alter adult neurogenesis, including addictive drugs such as methamphetamine [7], cocaine [8], and opioid [9].

Opiate drugs are powerful analgesics which are also among most commonly abused addictive drugs. They can cause long-lasting changes in the brain, which influence many different forms of neural plasticity, such as the stability of dendritic spines [10] and long-term potentiation [11]. Adult hippocampal neurogenesis is also among forms of neural plasticity mechanism regulated by opiates. However, the effects of opiate on hippocampal neural progenitors are controversial in many cases and are largely dependent on the manner in which the drug was administered [12]. Also, since adult neurogenesis is a long and continuous progress which consists of a series of developmental events, opiate drugs could exert their action on multiple types and stages of the neural stem/progenitor cells (NSPCs).

The proliferation, differentiation, and maturation of adult-born granular cells (GCs) are controlled by a series of genetically programmed fate choices [13], and NSPCs in adult hippocampus could be divided into several types according to their different developmental stages. For instance, radial-glia-like stem cells, which express glial fibrillary acidic protein (GFAP) and nestin and have several other astrocytic features, are defined as Type-1 cells [14]. Type-2 cells are oval-shaped, highly proliferative cells with short processes which express nestin but not GFAP [15]. Type-3 cells are neuroblasts which express doublecortin (DCX) and polysialylated form of the neural cell adhesion molecule (PSA-NCAM) [16]. Different opiate drugs may target any of these cell types mentioned above, either directly or indirectly. Here, we summarize the most recent works correlated with opiates’ effect on regulating proliferation, differentiation, or survival of adult-born hippocampal GCs (Table 1).

Table 1: Effects of drugs on different stages of adult neurogenesis.

2. Opioid Modulates Adult Neural Progenitors Proliferation

The most traditional and commonly used method to detect the proliferating cells in adult brain is by using exogenous markers of DNA synthesis, such as thymidine analog bromodeoxyuridine (BrdU), to label and track the birth of new born cells [31, 32]. The first report connecting opioid and adult neurogenesis was in 2000. Eisch et al. showed that chronic morphine, administered via subcutaneous pellet, decreased the number of proliferating cells labeled with BrdU in the SGZ in rodents; similar effect was also observed in rats after chronic self-administration of heroin [9]. Since then, evidences were accumulated from both sides to established opiate’s negative impact on proliferation of adult-born GCs (Table 1). For instance, proliferating cells in SGZ marked by two endogenous cell cycle markers, proliferating cell nuclear antigen (PCNA) and phosphorylated histone H3 (pHisH3), are largely reduced by chronic morphine, and triple labeling for BrdU, PCNA, and pHisH3 revealed that morphine-treated mice have a shorter Gap2/mitosis (G(2)/M) phase [20]. Rats injected with morphine sulfate (20 mg/kg) daily for 1 week were shown to have a strong reduction of cellular proliferation marked by fewer cells immunoreactive (IR) for PSA-NCAM, a cell surface protein that is transiently expressed by newly generated neurons during development. Such reduction was followed by a rebound increase after 1-week withdrawal and a return to normal after 2-week withdrawal [21]. It was demonstrated that morphine pellet implantation for 24–96 hours decreased the proliferating cells labeled by BrdU and cycle marker Ki67 in DG [22]. Other opiate analgesics like buprenorphine, administered via subcutaneous injections (0.05 mg/kg) over a 3-day period in mice, also decreased the number of actively proliferating 5-iodo-2-deoxyuridine (IdU) labeled cells [26], while no such effect was observed with synthetic opiate methadone [27]. Meanwhile, knock-out of mu-opioid receptor, on the contrary, was shown to enhance ischemia-induced generation of immature hippocampal neurons [33]. Following extinction from heroin-seeking behavior, the formation of immature neurons in the DG was increased, represented by DCX-IR cells [25]. In addition, there are also reports which suggest that chronic morphine treatment influences neurogenic microenvironment in DG by regulating certain growth factors, such as increasing the pro-proliferative factor and vascular endothelial growth factor (VEGF) [34].

However, opiate’s effect on adult neurogenesis seems to be dependent on the paradigm of the experiment design, such as test in vitro or in vivo, and drug administration paradigm. In isolated rat hippocampal neural progenitor cells, incubation with β-endorphin for 48 h increased the total DNA content and the number of cells expressed of PCNA and pHisH3. This proliferative effect was antagonized by naloxone [17]. The same group also reported that mu- and delta-opioid receptor (MOR and DOR) antagonists decrease proliferation of cultured neural progenitor cells [18]. Similarly, a longer acting opioid antagonist naltrexone was shown to decrease cellular proliferation in the adult rat hippocampus [19]. These results are conflicting with more recent observations, which showed cultured mouse hippocampal neural progenitor cells treated with morphine for 24 h demonstrated decreased BrdU expression in a dose dependent manner [29]. This discrepancy in morphine’s effect on neural proliferation remains within in vivo experiments, in which implantation of morphine pellets resulted in negative effect on adult neurogenesis [9, 22], while intraperitoneally injection of escalating dose of morphine failed to show any significant influence [12]. Such inconsistency of morphine’s effect may be due to difference in blood levels of morphine; when implanted with morphine pellet, the drug level in blood is relevantly stable and caused decrease in number of proliferating cells, whereas the injection paradigms that produced transient spikes in drug blood levels fail to produce significant effect on hippocampal neural proliferation [12]. Nevertheless, studies in our lab support the assumption that opiate negatively regulated neural proliferation, for morphine daily injection in a condition place preferences (CPP) paradigm, decreased the number of neural progenitors in DG labeled by DCX and other neurogenesis markers in mice [28]. Further research in this model revealed that such reduction may be due to morphine’s effect in modulating neural progenitors’ differentiation, rather than regulating proliferation, which will be discussed in detail in the following section.

3. Opioid Modulates Adult Neural Progenitors Differentiation and Maturation

The radial-glia-like neural stem cells in SGZ went through asymmetric cell division and gave rise to different types of progeny, including progenitors retained self-renew capability, neuroblasts, astrocytes, and oligodendrocytes [35, 36]. A growing body of literature indicated that opiate drugs not only influence hippocampal GCs’ proliferation, but also interfered with differentiation and future development process. In adult rat hippocampus, repeated morphine treatment altered the GABAergic phenotype of adult hippocampal GCs by significantly increasing the mRNA transcription of glutamate decarboxylase-67, a GABA synthesizing enzyme [21]. By examining the costaining of BrdU and cell cycle marker ki67 in mouse SGZ, it was found that morphine treatment increases the percent of BrdU-IR cells that were type 2b and decreased the percent of BrdU-IR cells that were immature neurons [22]. Analysis of the double-labeled cells in cultured mouse hippocampal progenitors treated with morphine showed a decrease in cells costained for BrdU with nestin and an increase in cells costained with BrdU and neuron-specific class III beta-tubulin (TUJ1) compared to cells treated with saline [29]. Incubation of adult hippocampal progenitors with endogenous opioid peptide beta-endorphin resulted in a threefold increase in oligodendrogenesis but no significant change in astrogliogenesis [37]. Although having some discordance in conclusions, these observations indicated that opioid could play a role in regulating adult hippocampal neural differentiation and maturation.

Recent study in our lab interpreted in detail that morphine exposure affects hippocampal neurogenesis by modulating cell-lineage in isolated hippocampal progenitor cells. In cultured NSPCs, morphine treatment activates MOR and downstream signaling pathways, including extracellular signal-regulated kinase (ERK) activation [38]. Phosphorylated ERK in cytosol is capable of phosphorylating TAR RNA-binding protein (TRBP), a cofactor of Dicer, and the Dicer activity enhancement promotes the maturation of miR-181a. This drives downregulation of Prospero homeobox protein 1 (Prox1) and an upregulation of Notch1 expression, while the Notch1 signaling plays an important role in regulating cell fate of the adult-born hippocampal GCs [39, 40]. Thus, morphine favors the progenitor cells differentiation into glia instead of neuron by regulating Prox1/Notch1 activities via its control of miR-181a level [41]. Another opiate drug fentanyl did not show such effect, since fentanyl activated ERK via a β-arrestin-dependent pathway, and the activated ERK translocates to the nucleus [42].

Furthermore, the activity of a transcriptional factor, neurogenic differentiation 1 (NeuroD1), was also shown to be regulated by morphine treatment [43]. NeuroD1 is a basic helix-loop-helix transcription factor that is expressed during glutamatergic neurogenesis in the developing cerebellum and in the adult hippocampal DG [13, 44]. It was shown to be involved in the differentiation of the progenitor cells and migration of immature neurons in the dentate gyrus [45]. Several in vivo studies support the fact that NeuroD1 has an important role in neuronal fate determination during both embryonic and adult neurogenesis [46, 47] and is essential for the survival and maturation of adult-born neurons [48]. Thus, by negatively regulating NeuroD1 activity, morphine impaired the differentiation of newborn GCs, leading to a reduction in neuroblasts and immature neurons expressing DCX and TUJ1.

4. Opioid Modulates Adult Neural Progenitors Survival and Apoptosis

After being generated by neural stem cells in the DG of hippocampus, a large portion of these progenitors die within a few days following their birth [49]. It is reasonable to assume that the neural precursors which fail to differentiate into functional immature neurons would go through apoptosis. The massive cell death of adult-born granular neurons may serve as a natural selective mechanism since it has been demonstrated that cell survival and death are both important during learning and memory [50]. Whether opiates interfere with this process remains to be demonstrated.

Chronic morphine and heroin treatment was shown to decrease GCs survival in vivo, by largely decreasing the number of 4-week-old BrdU-labeled cells in the granule layer of the DG in drug-group rats compared to control rats [9]. However, direct evidence of opiate drugs inducing apoptosis of adult hippocampal progenitors is deficient and inconsistent. Chronic morphine transiently increases cell death in the SGZ of mice, for the activated caspase-3 cell counts were increased after 24 but not 96 h [22]. Morphine exposure in cultured NSPCs led to a significant increase in caspase-3 activity in the nestin and GFAP positive cells, but not in TUJ1 positive neurons [29, 51]. Knock-out of mu-opioid receptor, in the contrary, was shown to enhance adult-born hippocampal GCs’ survival, suggesting endogenous opioid has a negative effect on adult hippocampal neurogenesis [52]. However, minimal buprenorphine treatment was shown to increase the survival of newly born cells in mice DG of hippocampus [26]. In other cases, opioid drugs such as morphine were not associated with hippocampal neural apoptosis [53].

Overall, we summarize that the effects of opioid on NSPCs may vary among different drugs and experimental methods, and one opioid receptor agonist may act on multiple stages of NSPCs, including proliferation, differentiation, and survival (Figure 1).

Figure 1: Different types of opioids act on different stages of adult neurogenesis in the DG (with expression pattern of specific markers).

5. Adult Neurogenesis Regulation Correlates with Opioid Addiction

During development, newborn neurons in the adult SGZ migrate into the granule cell layer of the dentate gyrus and integrate into existing hippocampal circuit [54, 55]. The immature neurons have higher input resistance, more depolarized resting membrane potentials, and small, broad action potentials compared to mature neurons [56], so they were more flexible in transition of neural plasticity and may have substantial roles in hippocampus function during learning and memory [57, 58]. Since hippocampus has been implicated in drug reward and relapse [59, 60], recent studies suggested that adult neurogenesis in DG of hippocampus also has substantial roles in opiate drug addiction cycle. For instance, suppression of adult neurogenesis by long-term stress had significant positive relationships with ratings of craving for heroin [61]. Some positive regulators of hippocampal neurogenesis like environment enrichment and voluntary exercise, on the contrary, prevent the development of morphine induced CPP [62, 63], decreased the rewarding effect of heroin [64], and maintained heroin self-administration [65]. These results suggest a negative correlation between opiate drug addiction and level of adult hippocampal neurogenesis.

6. Conclusion and Prospects

So far, accumulating evidences have demonstrated that multiple opiate drugs interfered with proliferation, differentiation, maturation, and survival of developing adult-born hippocampal neural precursors. These studies represent that most of the opiates have an adverse effect on adult hippocampal neurogenesis, by decreasing the total number of proliferating cells and cells survival in the SGZ of DG area, but there are also some exemptions. For neural differentiation, opiate such as morphine is likely to impede early progenitors which differentiate into neuroblasts but favor the differentiation into glia.

The detailed mechanism of such regulation on hippocampal neurogenesis of opiates remains to be clarified. There are assumptions of opiate directly acting on neural progenitors with MOR and DOR on the cell surface [17, 18] and also evidences that opiate modulates the neurogenic microenvironment of the DG, to indirectly influence the cell proliferation by growth factors in the hippocampus [23]. An alternative explanation is that progenitors of certain stage (3–7 days after birth) start to form dendrites, which receive neurotransmitters from intermediate neurons [66]. It has been reported that immature neurons (14–28-day postmitotic) are not inhibited but excited by GABAergic activity [54]. Also, exposure to novel environments increases GABAergic tone in the DG and facilitates the generation of LTP [58]. Thus, a possible mechanism for regulation of adult hippocampal neurogenesis is that early neural progenitors need exciting signals from existing circuit for future differentiation and maturation, and opioid agonists interfere with this process by decreasing GABA release in the interneuron [67, 68]. It is intriguing to further investigate these possible mechanisms and to determine whether morphine exhibits its effect directly or indirectly on neural progenitors in the SGZ of hippocampus.

Current studies also indicate that opiates’ rewarding effect and drug associate memory are related with the manipulation of adult hippocampal neurogenesis. When hippocampal neurogenesis is enhanced by physical excise or environment enrichment, the animals show a lower response to drug craving and reward [6265]. When overexpressing NeuroD1 in dentate gyrus to induce neural differentiation, the animal shows much longer memory of their drug experience, represented by condition place preference (CPP) extinction time; when knocking down NeuroD with RNA interference method it has an opposite effect [28]. These results suggest that the progenitors at certain stage of development may serve as key players during memory formation of drug experience associated with environmental cues. In summary, current studies suggest that opiates are involved in the proliferation and fate determination of adult-born GCs in the SGZ of hippocampus, and the manipulation of adult hippocampal neurogenesis in return influences rewarding effect and drug-experience memory that associate with the opioid addition. These studies provide a creative aspect to examine the subject of adult neurogenesis’ contribution to opioid addiction.

Abbreviations

BrdU:5-Bromo-2-deoxyuridine
CPP:Conditioned place preference
DCX:Doublecortin
DG:Dentate gyrus
DOR:Delta-opioid receptor
ERK:Extracellular signal-regulated kinase
GCs:Granular cells
GFAP:Glial fibrillary acidic protein
MOR:Mu-opioid receptor
NeuroD1:Neurogenic differentiation 1
NSPC:Neural stem/progenitor cells
IR:Immunoreactive
PCNA:Proliferating cell nuclear antigen
pHisH3:Phosphorylated histone H3
Prox1:Prospero homeobox protein 1
PSA-NCAM:Polysialylated form of the neural cell adhesion molecule
SGZ:Subgranular zone
SVZ:Subventricle zone
TRBP:TAR RNA-binding protein
TUJ1:β-III tubulin
VEGF:Vascular endothelial growth factor.

Competing Interests

The authors declare that they have no competing interests.

References

  1. P. E. S. E. Riksson, E. K. P. Erfilieva, T. H. B. J. Riksson et al., “Neurogenesis in the adult human hippocampus,” Nature, vol. 4, no. 11, pp. 1313–1317, 1998. View at Google Scholar
  2. F. H. Gage, “Mammalian neural stem cells,” Science, vol. 287, no. 5457, pp. 1433–1438, 2000. View at Publisher · View at Google Scholar · View at Scopus
  3. F. Doetsch, J. M. García-Verdugo, and A. Alvarez-Buylla, “Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain,” Journal of Neuroscience, vol. 17, no. 13, pp. 5046–5061, 1997. View at Google Scholar · View at Scopus
  4. H. Georg and F. H. Gage, “Neurogenesis in the dentate gyrus of the adult decrease of neuronal progenitor proliferation rat?: age-related,” The Journal of Neuroscience, vol. 76, no. 6, pp. 2027–2033, 1996. View at Google Scholar
  5. W. Deng, J. B. Aimone, and F. H. Gage, “New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?” Nature Reviews Neuroscience, vol. 11, no. 5, pp. 339–350, 2010. View at Publisher · View at Google Scholar · View at Scopus
  6. J. B. Aimone, Y. Li, S. W. Lee, G. D. Clemenson, W. Deng, and F. H. Gage, “Regulation and function of adult neurogenesis: from genes to cognition,” Physiological Reviews, vol. 94, no. 4, pp. 991–1026, 2014. View at Publisher · View at Google Scholar · View at Scopus
  7. G. Teuchert-Noodt, R. R. Dawirs, and K. Hildebrandt, “Adult treatment with methamphetamine transiently decreases dentate granule cell proliferation in the gerbil hippocampus,” Journal of Neural Transmission, vol. 107, no. 2, pp. 133–143, 2000. View at Publisher · View at Google Scholar · View at Scopus
  8. M. A. Noonan, K. H. Choi, D. W. Self, and A. J. Eisch, “Withdrawal from cocaine self-administration normalizes deficits in proliferation and enhances maturity of adult-generated hippocampal neurons,” Journal of Neuroscience, vol. 28, no. 10, pp. 2516–2526, 2008. View at Publisher · View at Google Scholar · View at Scopus
  9. A. J. Eisch, M. Barrot, C. A. Schad, D. W. Self, and E. J. Nestler, “Opiates inhibit neurogenesis in the adult rat hippocampus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 13, pp. 7579–7584, 2000. View at Publisher · View at Google Scholar · View at Scopus
  10. D. Liao, H. Lin, Y. L. Ping, and H. H. Loh, “Mu-opioid receptors modulate the stability of dendritic spines,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 5, pp. 1725–1730, 2005. View at Publisher · View at Google Scholar · View at Scopus
  11. F. S. Nugent, E. C. Penick, and J. A. Kauer, “Opioids block long-term potentiation of inhibitory synapses,” Nature, vol. 446, no. 7139, pp. 1086–1090, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. S. J. Fischer, A. A. Arguello, J. J. Charlton, D. C. Fuller, V. Zachariou, and A. J. Eisch, “Morphine blood levels, dependence, and regulation of hippocampal subgranular zone proliferation rely on administration paradigm,” Neuroscience, vol. 151, no. 4, pp. 1217–1224, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. R. F. Hevner, R. D. Hodge, R. A. M. Daza, and C. Englund, “Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus,” Neuroscience Research, vol. 55, no. 3, pp. 223–233, 2006. View at Publisher · View at Google Scholar · View at Scopus
  14. S. Fukuda, F. Kato, Y. Tozuka, M. Yamaguchi, Y. Miyamoto, and T. Hisatsune, “Two distinct subpopulations of nestin-positive cells in adult mouse dentate gyrus,” Journal of Neuroscience, vol. 23, no. 28, pp. 9357–9366, 2003. View at Google Scholar · View at Scopus
  15. V. Filippov, G. Kronenberg, T. Pivneva et al., “Subpopulation of nestin-expressing progenitor cells in the adult murine hippocampus shows electrophysiological and morphological characteristics of astrocytes,” Molecular and Cellular Neuroscience, vol. 23, no. 3, pp. 373–382, 2003. View at Publisher · View at Google Scholar · View at Scopus
  16. G. Kempermann, S. Jessberger, B. Steiner, and G. Kronenberg, “Milestones of neuronal development in the adult hippocampus,” Trends in Neurosciences, vol. 27, no. 8, pp. 447–452, 2004. View at Publisher · View at Google Scholar · View at Scopus
  17. A. I. Persson, T. Thorlin, C. Bull, and P. S. Eriksson, “Opioid-induced proliferation through the MAPK pathway in cultures of adult hippocampal progenitors,” Molecular and Cellular Neuroscience, vol. 23, no. 3, pp. 360–372, 2003. View at Publisher · View at Google Scholar · View at Scopus
  18. A. I. Persson, T. Thorlin, C. Bull et al., “Mu- and delta-opioid receptor antagonists decrease proliferation and increase neurogenesis in cultures of rat adult hippocampal progenitors,” European Journal of Neuroscience, vol. 17, no. 6, pp. 1159–1172, 2003. View at Publisher · View at Google Scholar · View at Scopus
  19. M. M. Holmes and L. A. M. Galea, “Defensive behavior and hippocampal cell proliferation: differential modulation by naltrexone during stress,” Behavioral Neuroscience, vol. 116, no. 1, pp. 160–168, 2002. View at Publisher · View at Google Scholar · View at Scopus
  20. C. D. Mandyam, R. D. Norris, and A. J. Eisch, “Chronic morphine induces premature mitosis of proliferating cells in the adult mouse subgranular zone,” Journal of Neuroscience Research, vol. 76, no. 6, pp. 783–794, 2004. View at Publisher · View at Google Scholar · View at Scopus
  21. L. Kahn, G. Alonso, E. Normand, and O. J. Manzoni, “Repeated morphine treatment alters polysialylated neural cell adhesion molecule, glutamate decarboxylase-67 expression and cell proliferation in the adult rat hippocampus,” European Journal of Neuroscience, vol. 21, no. 2, pp. 493–500, 2005. View at Publisher · View at Google Scholar · View at Scopus
  22. A. A. Arguello, G. C. Harburg, J. R. Schonborn, C. D. Mandyam, M. Yamaguchi, and A. J. Eisch, “Time course of morphine's effects on adult hippocampal subgranular zone reveals preferential inhibition of cells in S phase of the cell cycle and a subpopulation of immature neurons,” Neuroscience, vol. 157, no. 1, pp. 70–79, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. A. A. Arguello, S. J. Fischer, J. R. Schonborn, R. W. Markus, R. A. Brekken, and A. J. Eisch, “Effect of chronic morphine on the dentate gyrus neurogenic microenvironment,” Neuroscience, vol. 159, no. 3, pp. 1003–1010, 2009. View at Publisher · View at Google Scholar · View at Scopus
  24. N. Khurshid, L. S. Hameed, S. Mohanasundaram, and S. Iyengar, “Opioid modulation of cell proliferation in the ventricular zone of adult zebra finches (Taenopygia guttata),” The FASEB Journal, vol. 24, no. 10, pp. 3681–3695, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. M. P. Hicks, K. C. Wischerath, A. L. Lacrosse, and M. F. Olive, “Increases in doublecortin immunoreactivity in the dentate gyrus following extinction of heroin-seeking behavior,” Neural Plasticity, vol. 2012, Article ID 283829, 9 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  26. A. S. Pettit, R. DesRoches, and S. A. L. Bennett, “The opiate analgesic buprenorphine decreases proliferation of adult hippocampal neuroblasts and increases survival of their progeny,” Neuroscience, vol. 200, pp. 211–222, 2012. View at Publisher · View at Google Scholar · View at Scopus
  27. A. Sankararaman, I. Masiulis, D. R. Richardson, J. M. Andersen, J. Mørland, and A. J. Eisch, “Methadone does not alter key parameters of adult hippocampal neurogenesis in the heroin-naïve rat,” Neuroscience Letters, vol. 516, no. 1, pp. 99–104, 2012. View at Publisher · View at Google Scholar · View at Scopus
  28. H. Zheng, Y. Zhang, W. Li, H. H. Loh, and P.-Y. Law, “NeuroD modulates opioid agonist-selective regulation of adult neurogenesis and contextual memory extinction,” Neuropsychopharmacology, vol. 38, no. 5, pp. 770–777, 2013. View at Publisher · View at Google Scholar · View at Scopus
  29. D. Willner, A. Cohen-Yeshurun, A. Avidan, V. Ozersky, E. Shohami, and R. R. Leker, “Short term morphine exposure in vitro alters proliferation and differentiation of neural progenitor cells and promotes apoptosis via Mu receptors,” PLoS ONE, vol. 9, no. 7, Article ID e103043, 2014. View at Publisher · View at Google Scholar · View at Scopus
  30. C. Xu, Y. Zhang, H. Zheng, H. H. Loh, and P.-Y. Law, “Morphine modulates mouse hippocampal progenitor cell lineages by upregulating miR-181a level,” STEM CELLS, vol. 32, no. 11, pp. 2961–2972, 2014. View at Publisher · View at Google Scholar · View at Scopus
  31. J. P. Kriss and L. Revesz, “The distribution and fate of bromodeoxyuridine and bromodeoxycytidine in the mouse and rat,” Cancer Research, vol. 22, pp. 254–265, 1962. View at Google Scholar · View at Scopus
  32. J. A. del Rio and E. Soriano, “Immunocytochemical detection of 5′-bromodeoxyuridine incorporation in the central nervous system of the mouse,” Developmental Brain Research, vol. 49, no. 2, pp. 311–317, 1989. View at Publisher · View at Google Scholar · View at Scopus
  33. A. Kolodziej, R. Stumm, A. Becker, and V. Höllt, “Endogenous opioids inhibit ischemia-induced generation of immature hippocampal neurons via the μ-opioid receptor,” European Journal of Neuroscience, vol. 27, no. 6, pp. 1311–1319, 2008. View at Publisher · View at Google Scholar · View at Scopus
  34. A. A. Arguello, S. J. Fischer, J. R. Schonborn, R. W. Markus, R. A. Brekken, and A. J. Eisch, “Effect of chronic morphine on the dentate gyrus neurogenic microenvironment,” Neuroscience, vol. 29, no. 6, pp. 997–1003, 2012. View at Publisher · View at Google Scholar
  35. F. H. Gage, G. Kempermann, T. D. Palmer, D. A. Peterson, and J. Ray, “Multipotent progenitor cells in the adult dentate gyrus,” Journal of Neurobiology, vol. 36, no. 2, pp. 249–266, 1998. View at Publisher · View at Google Scholar · View at Scopus
  36. M. S. Espósito, V. C. Piatti, D. A. Laplagne et al., “Neuronal differentiation in the adult hippocampus recapitulates embryonic development,” Journal of Neuroscience, vol. 25, no. 44, pp. 10074–10086, 2005. View at Publisher · View at Google Scholar · View at Scopus
  37. A. I. Persson, C. Bull, and P. S. Eriksson, “Requirement for Id1 in opioid-induced oligodendrogenesis in cultured adult rat hippocampal progenitors,” European Journal of Neuroscience, vol. 23, no. 9, pp. 2277–2288, 2006. View at Publisher · View at Google Scholar · View at Scopus
  38. M. M. Belcheva, M. Szùcs, D. Wang, W. Sadee, and C. J. Coscia, “μ-opioid receptor-mediated ERK activation involves calmodulin-dependent epidermal growth factor receptor transactivation,” Journal of Biological Chemistry, vol. 276, no. 36, pp. 33847–33853, 2001. View at Publisher · View at Google Scholar · View at Scopus
  39. J. J. Breunig, J. Silbereis, F. M. Vaccarino, N. Šestan, and P. Rakic, “Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 51, pp. 20558–20563, 2007. View at Publisher · View at Google Scholar · View at Scopus
  40. J. L. Ables, N. A. DeCarolis, M. A. Johnson et al., “Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells,” Journal of Neuroscience, vol. 30, no. 31, pp. 10484–10492, 2010. View at Publisher · View at Google Scholar · View at Scopus
  41. C. Xu, H. Zheng, H. H. Loh, and P.-Y. Law, “Morphine promotes astrocyte-preferential differentiation of mouse hippocampal progenitor cells via PKCε-dependent ERK activation and TRBP phosphorylation,” STEM CELLS, vol. 33, no. 9, pp. 2762–2772, 2015. View at Publisher · View at Google Scholar
  42. H. Zheng, H. H. Loh, and P. Law, “Extracellular signal-regulated kinases (ERKs) translocate to nucleus in contrast to g protein-dependent erk activation,” Molecular Pharmacology, vol. 73, no. 1, pp. 178–190, 2008. View at Google Scholar
  43. H. Zheng, Y. Zeng, J. Chu, A. Y. Kam, H. H. Loh, and P.-Y. Law, “Modulations of NeuroD activity contribute to the differential effects of morphine and fentanyl on dendritic spine stability,” Journal of Neuroscience, vol. 30, no. 24, pp. 8102–8110, 2010. View at Publisher · View at Google Scholar · View at Scopus
  44. T. Miyachi, H. Maruyama, T. Kitamura, S. Nakamura, and H. Kawakami, “Structure and regulation of the human NeuroD (BETA2/BHF1) gene,” Molecular Brain Research, vol. 69, no. 2, pp. 223–231, 1999. View at Publisher · View at Google Scholar · View at Scopus
  45. M. Liu, S. J. Pleasure, A. E. Collins et al., “Loss of BETA2/NeuroD leads to malformation of the dentate gyrus and epilepsy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 2, pp. 865–870, 2000. View at Publisher · View at Google Scholar · View at Scopus
  46. J. E. Lee, “Basic helix-loop-helix genes in neural development,” Current Opinion in Neurobiology, vol. 7, no. 1, pp. 13–20, 1997. View at Publisher · View at Google Scholar · View at Scopus
  47. L. Roybon, T. Hjalt, S. Stott, F. Guillemot, J.-Y. Li, and P. Brundin, “Neurogenin2 directs granule neuroblast production and amplification while neuroD1 specifies neuronal fate during hippocampal neurogenesis,” PLoS ONE, vol. 4, no. 3, Article ID e4779, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. Z. Gao, K. Ure, J. L. Ables et al., “Neurod1 is essential for the survival and maturation of adult-born neurons,” Nature Neuroscience, vol. 12, no. 9, pp. 1090–1092, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. A. G. Dayer, A. A. Ford, K. M. Cleaver, M. Yassaee, and H. A. Cameron, “Short-term and long-term survival of new neurons in the rat dentate gyrus,” Journal of Comparative Neurology, vol. 460, no. 4, pp. 563–572, 2003. View at Publisher · View at Google Scholar · View at Scopus
  50. D. Dupret, A. Fabre, M. D. Döbrössy et al., “Spatial learning depends on both the addition and removal of new hippocampal neurons,” PLoS Biology, vol. 5, no. 8, article e214, 2007. View at Publisher · View at Google Scholar · View at Scopus
  51. V. Meneghini, B. Cuccurazzu, V. Bortolotto et al., “The noradrenergic component in tapentadol action counteracts μ-opioid receptor-mediated adverse effects on adult neurogenesis,” Molecular Pharmacology, vol. 85, no. 5, pp. 658–670, 2014. View at Publisher · View at Google Scholar · View at Scopus
  52. G. C. Harburg, F. S. Hall, A. V. Harrist, I. Sora, G. R. Uhl, and A. J. Eisch, “Knockout of the mu opioid receptor enhances the survival of adult-generated hippocampal granule cell neurons,” Neuroscience, vol. 144, no. 1, pp. 77–87, 2007. View at Publisher · View at Google Scholar · View at Scopus
  53. D. Bajic, K. G. Commons, and S. G. Soriano, “Morphine-enhanced apoptosis in selective brain regions of neonatal rats,” International Journal of Developmental Neuroscience, vol. 31, no. 4, pp. 258–266, 2013. View at Publisher · View at Google Scholar · View at Scopus
  54. S. Ge, E. L. K. Goh, K. A. Sailor, Y. Kitabatake, G.-L. Ming, and H. Song, “GABA regulates synaptic integration of newly generated neurons in the adult brain,” Nature, vol. 439, no. 7076, pp. 589–593, 2006. View at Publisher · View at Google Scholar · View at Scopus
  55. X. Duan, J. H. Chang, S. Ge et al., “Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain,” Cell, vol. 130, no. 6, pp. 1146–1158, 2007. View at Publisher · View at Google Scholar · View at Scopus
  56. X.-S. Liu, S. Tilwalli, G.-L. Ye, P. A. Lio, J. F. Pasternak, and B. L. Trommer, “Morphologic and electrophysiologic maturation in developing dentate gyrus granule cells,” Brain Research, vol. 856, no. 1-2, pp. 202–212, 2000. View at Publisher · View at Google Scholar · View at Scopus
  57. T. J. Shors, G. Miesegaes, A. Beylin, M. Zhao, T. Rydel, and E. Gould, “Neurogenesis in the adult is involved in the formation of trace memories,” Nature, vol. 410, no. 6826, pp. 372–376, 2001. View at Publisher · View at Google Scholar · View at Scopus
  58. M. D. Saxe, F. Battaglia, J.-W. Wang et al., “Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 46, pp. 17501–17506, 2006. View at Publisher · View at Google Scholar · View at Scopus
  59. A. E. Kelley, “Memory and addiction: shared neural circuitry and molecular mechanisms,” Neuron, vol. 44, no. 1, pp. 161–179, 2004. View at Publisher · View at Google Scholar · View at Scopus
  60. G. F. Koob and N. D. Volkow, “Neurocircuitry of addiction,” Neuropsychopharmacology, vol. 35, no. 1, pp. 217–238, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. K. L. Preston and D. H. Epstein, “Stress in the daily lives of cocaine and heroin users: relationship to mood, craving, relapse triggers, and cocaine use,” Psychopharmacology, vol. 218, no. 1, pp. 29–37, 2011. View at Publisher · View at Google Scholar · View at Scopus
  62. B. T. Lett, V. L. Grant, M. T. Koh, and G. Flynn, “Prior experience with wheel running produces cross-tolerance to the rewarding effect of morphine,” Pharmacology Biochemistry and Behavior, vol. 72, no. 1-2, pp. 101–105, 2002. View at Publisher · View at Google Scholar · View at Scopus
  63. R. R. Rozeske, B. N. Greenwood, M. Fleshner, L. R. Watkins, and S. F. Maier, “Voluntary wheel running produces resistance to inescapable stress-induced potentiation of morphine conditioned place preference,” Behavioural Brain Research, vol. 219, no. 2, pp. 378–381, 2011. View at Publisher · View at Google Scholar · View at Scopus
  64. R. El Rawas, N. Thiriet, V. Lardeux, M. Jaber, and M. Solinas, “Environmental enrichment decreases the rewarding but not the activating effects of heroin,” Psychopharmacology, vol. 203, no. 3, pp. 561–570, 2009. View at Publisher · View at Google Scholar · View at Scopus
  65. M. A. Smith and E. G. Pitts, “Wheel running decreases the positive reinforcing effects of heroin,” Pharmacological Reports, vol. 64, no. 4, pp. 960–964, 2012. View at Publisher · View at Google Scholar · View at Scopus
  66. C. Zhao, E. M. Teng, R. G. Summers Jr., G.-L. Ming, and F. H. Gage, “Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus,” Journal of Neuroscience, vol. 26, no. 1, pp. 3–11, 2006. View at Publisher · View at Google Scholar · View at Scopus
  67. W. Zieglgänsberger, E. D. French, G. R. Seggins, and F. E. Bloom, “Opioid peptides may excite hippocampal pyramidal neurons by inhibiting adjacent inhibitory interneurons,” Science, vol. 205, no. 4404, pp. 415–417, 1979. View at Publisher · View at Google Scholar · View at Scopus
  68. J. F. Neumaier, S. Mailheau, and C. Chavkin, “Opioid receptor-mediated responses in the dentate gyrus and CA1 region of the rat hippocampus,” Journal of Pharmacology and Experimental Therapeutics, vol. 244, no. 2, pp. 564–570, 1988. View at Google Scholar · View at Scopus