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

Abstract

Opiates, such as morphine, decrease neurogenesis in the adult hippocampal subgranular zone (SGZ), raising the possibility that decreased neurogenesis contributes to opiate-induced cognitive deficits. However, there is an incomplete understanding of how alterations in cell cycle progression and progenitor maturation contribute to this decrease. The present study examined how morphine regulates progenitor cell cycle, cell death and immature SGZ neurons (Experiment 1) as well as the progression of SGZ progenitors through key stages of maturation (Experiment 2). In Experiment 1, mice received sham or morphine pellets (subcutaneous, 0 and 48 hrs) and bromodeoxyuridine (BrdU) 2 hrs prior to sacrifice (24, 72 or 96 hrs). Morphine decreased both the number of S phase and total cycling cells, as there were fewer cells immunoreactive (IR) for the S phase marker BrdU and the cell cycle marker Ki67. The percentage of Ki67-IR cells that were BrdU-IR was decreased after 24 but not 96 hrs of morphine, suggesting a disproportionate effect on S phase cells relative to all cycling cells at this time point. Cell death (activated caspase-3 counts) was increased after 24 but not 96 hrs. In Experiment 2, nestin-GFP mice given BrdU 1 day prior to morphine or sham surgery (0 and 48 hrs, sacrifice 96 hrs) had fewer Ki67-IR cells, but no change in BrdU-IR cell number, suggesting that this population of BrdU-IR cells were less sensitive to morphine. Interestingly, examination of key stages of progenitor cell maturation revealed that morphine increased the percent of BrdU-IR cells that were Type 2b and decreased the percent that were immature neurons. These data suggest that chronic morphine decreases SGZ neurogenesis by inhibiting dividing cells, particularly those in S phase, and progenitor cell progression to a more mature neuronal stage.

Adult hippocampal neurogenesis is functionally important for stress-induced social avoidance

“…Although nestin-GFP mice have been used to determine the neurogenic stage affected by stimuli like running or drugs of abuse (e.g., 9, 31), the current data reveal how stress affects different stages of dentate gyrus neurogenesis. Because the populations of stem-like Type-1 and mature progenitor Type-3 cells appear to be largely unaffected by chronic stress, our data are consistent with previous work that manipulation of the rapidly dividing Type-2 population is a prime and robust way to modulate neurogenesis (9,31).…”

Cognitive Impairments in Drug Addicts

“…An opioid-induced attenuation of neurogenesis in hippocampus was earlier seen in male rats exposed to morphine (Eisch et al, 2000). Thus, opiates, such as morphine, is seen to reduce neurogenesis in the adult hippocampal subgranular zone (SGZ), suggesting that a waning neurogenesis contributes to opioidinduced deficits in cognitive function (Arguello et al, 2008). Enhanced apoptosis following exposure to opioids was reported to involve an upregulation of the proapoptotic caspase-3 and Bax proteins following NMDA receptor activation (Mao et al, 2002).…”

“…These observations suggest that the opioid regulation of neurogenesis in the adult rat hippocampus may be mediated by direct effects of the opioid drugs on the hippocampal function. The recent study by Arguello and co-workers, as mentioned above, demonstrated that chronic morphine attenuates neurogenesis in the SGZ by impeding cell-dividing, primarily in the S-phase, and inhibiting progenitor cell progression to a more mature stage (Arguello et al, 2008). In order to find strategies to reverse the opioid-induced damage to the hippocampal function it is essential to look for agents that may stimulate hippocampal progenitors and thereby increase neurogenesis and regeneration of nerve cells.…”

“…A remarked neuroadaptation caused by addictive drugs, such as alcohol, central stimulants and opiates involves diminished neurogenesis in the subgranular zone (SGZ) of the hippocampus. Indeed, it has been proposed that decreased adult neurogenesis in the SGZ could modify the hippocampal function in such a way that it contributes to relapse and a maintained addictive behavior (Arguello et al, 2008). It also raises the possibility that decreased neurogenesis may contribute to cognitive deficits elicited by these abusing drugs.…”

NeuN Expression Alterations in the Hippocampus Following Ecstasy Treatment

“…Neurogenesis includes distinct stages, such as cell proliferation, neuronal differentiation, and survival, that can be influenced by various environmental features. For example, morphine implantation decreases the proliferation of cells in the hippocampus DG (7). In one study, buprenorphine used as an opiate analgesic decreased the number of proliferating cells (8).…”