Browsing by Subject "Morphine"
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Item The Impact of Chronic Morphine on Adult Hippocampal Progenitor Cells and the Neurogenic Niche(2009-06-15) Arguello, Amy; Eisch, Amelia J.The birth of new neurons persists in the adult hippocampal subgranular zone (SGZ). Adult neurogenesis is dynamically regulated and thought to be important for certain types of spatial learning and memory. SGZ proliferation and neurogenesis are decreased by chronic morphine, yet how this alteration occurs is unknown. It is unclear if morphine causes alterations in cell cycle progression, progenitor cell maturation, or indirectly inhibits progenitor cells by altering the hippocampal neurogenic niche. I first examined a time course of morphine's effect on the progenitor cell cycle, cell death and immature SGZ neurons. I found that S phase cycling cells were vulnerable to morphine at early time points with a concurrent increase in cell death. I found that although the total population of SGZ immature neurons remained unchanged, the proportion of progenitor cells that progressed to a more mature stage decreased. I next asked whether decreased levels of proliferation resulted from shortened S phase length. Using a modified double injection paradigm of halogenated thymidine analogs, I found that chronic morphine did not alter the length of S phase of progenitor cells. Next, I asked if chronic morphine could have an indirect inhibitory effect on progenitor cells by altering growth factors and neurovasculature within the hippocampal neurogenic niche. I found that protein levels of factors within the niche were maintained or upregulated (e.g. vascular endothelial growth factor) to compensate for the morphine-induced decrease in proliferation. Lastly, I asked whether chronic morphine would decrease proliferation in an inducible nestin-CreERT2/R26R-yellow fluorescent protein transgenic mouse. I found that proliferation in this transgenic mouse was not altered after a particular paradigm of morphine exposure. Together these findings suggest that morphine alters adult hippocampal proliferation through multiple effects: both on the progenitor cells themselves (cell cycle, maturation) and indirectly by alteration of the neurogenic niche. Additional work is needed to understand the mechanism of the morphine-induced changes in progenitor cell cycle and the neurogenic niche. The present findings will benefit both the addiction field by offering new avenues for treatment and neural stem cell biology by demonstrating stages of neurogenesis that are more vulnerable to exogenous stimuli.Item The Impact of Opioids and Opiates on Adult Hippocampal Neurogenesis(2007-12-17) Harburg, Gwyndolen Colleen; Eisch, Amelia J.Opiate addiction is a growing problem in today's society. Thus, it is of crucial importance that we understand the physiological basis for opiate addiction and the long-term consequences of opiate use in order to develop more effective means of treatment. Chronic morphine and heroin have previously been shown to decrease proliferation and survival of progenitor cells in the adult rat and mouse hippocampus. Here, I show that endogenous opioids may act through the mu opioid receptor (MOR) to similarly decrease survival of new hippocampal neurons. An exon 1 MOR knockout mouse showed increased survival of new neurons independent of effects on cell proliferation or cell death. In concordance with the increased numbers of granule cells maturing into neurons, knockout mice also had larger hippocampal granule cells layers and increased numbers of granule cells. Exploration of the impact of chronic morphine on different stages of neurogenesis showed that chronic morphine decreased numbers of Type 1 stem cells and proliferating progenitor cells. Progenitor cells exposed to chronic morphine during early maturation were not significantly decreased in number, but appeared to have retarded cell maturation since fewer had reached the immature neuron stage in chronic morphine mice. Chronic morphine also appeared to result in anterior hippocampus specific decreases in stem cells as well as maturation retardation. These findings show that morphine has distinct effects on different stages of neurogenesis, and that the anterior hippocampus may be more sensitive to some effects. Cell proliferation levels in the brains of human heroin abusers and normal controls were assessed using the endogenous proliferation marker Ki67. Heroin abusers had decreased numbers, but larger clusters of proliferating cells in the dentate gyrus hilus as compared with controls. There was also a trend towards a decrease in number of proliferating cells in the granule cell layer of heroin abusers. Although these findings are preliminary, they suggest that chronic heroin use in humans, as in rodents, may negatively impact neurogenesis. Together, these findings support a negative role for opioids and opiates in regulating adult hippocampal neurogenesis.Item The Role of Adult Hippocampal Neurogenesis in Morphine Addiction(2015-04-09) Bulin, Sarah Elizabeth; Hsieh, Jenny; Self, David W.; Powell, Craig M.; Eisch, Amelia J.The hippocampus plays a large role in modulating the reward pathway, being especially important in craving and context-dependent relapse. One form a neuroplasticity within the hippocampus is adult neurogenesis, which occurs in the subgranular zone of the dentate gyrus. While a growing amount of literature has explored the effects of drugs of abuse on adult DG neurogenesis, the relationship between self-administered opiates and adult DG neurogenesis remains unexplored. This dissertation investigates both the role of adult DG neurogenesis in morphine-related behaviors and the effects of self-administered opiates (morphine and heroin) on adult DG neurogenesis. I first explore the background literature important in the work completed within this dissertation (Chapter 1). Next, using a self-administration paradigm, I proceed to show that ablation of adult neurogenesis via cranial irradiation results in increased in morphine intake, decreased extinction, and decreased cognitive flexibility. Additionally, rats lacking adult DG neurogenesis exhibited increased morphine locomotor sensitization with increased DG activation in the infrablade after a low dose morphine challenge (Chapter 2). I will then go on to investigate the consequences of long-term self-administered opiates (morphine and heroin) on the different stages of maturation of adult-generated neurons. I demonstrate that morphine self-administration has no effect on proliferation, survival, or maturation immediately after exposure or after 28 days of withdrawal (Chapter 3). Additionally, I demonstrate that heroin self-administration does not alter DCX+ cell density or granule cell layer volume (Chapter 4). Taken together, my data suggests the adult DG neurogenesis is robust and normally unaffected by self-administered opiates. However, preexisting deficits in DG neurogenesis may lead to an increased vulnerability to addiction-related behaviors. In the final chapter (Chapter 5), I discuss potential implications of this work and future directions in which it may be taken.