Opiate drugs with abuse liability disrupt the genesis of neurons, astrocytes, and oligodendrocytes in the developing brain through their principal action on mu opioid receptors. In excess-opiates profoundly reduce the number of neurons and astrocytes in the brain. Despite the established importance of opioids in growth, the mechanisms by which mu opiate drugs with abuse liability intrinsically affect cell production are not completely understood. This grant focuses on the developmental neurobiology of opiate drugs of abuse and the intrinsic role of the mu opioid receptor in neuronal and glial maturation. Our goal is (1) to identify the populations of developing neural cells that intrinsically respond to mu opiate drugs, and (2) to determine the developmental consequences of opiate action per se on cell proliferation and survival. Our hypothesis is mu opioid receptors nominally regulate development and opiate drugs adversely affect CNS development by disrupting the maturation of mu receptor-expressing neuronal and glial populations. We predict that mu opiates affect CNS organization by reducing numbers of neurons, astrocytes, and by increasing oligodendrocyte numbers-thereby disrupting the numerical balance of cell types in the brain. To address this hypothesis, cellular and molecular development will be assessed in morphine-treated wild type and mu-opioid receptor knockout mice. Cell number as determined by cell proliferation and death.
Aim 1 will examine the intrinsic effect of mu opioid receptor activation on the proliferation and survival of neuroblasts, astroglia, and oligodendroglia in vitro.
Aim 2 consists of parallel studies that will explore mu receptor expression, as well as the developmental effects of mu-opioid receptor activation, in neurons, astrocytes, and oligodendrocytes in vivo. This research will systematically and unambiguously assess the effect of opiate drugs and the intrinsic role of the mu opioid receptor on neurogenesis and gliogenesis. The timing of our studies in mice mimics pre- and perinatal development in the humans. Our long-term goal is to understand the basic mechanisms by which the opioid system regulates CNS maturation.
|Arnatt, Christopher K; Falls, Bethany A; Yuan, Yunyun et al. (2016) Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization. Bioorg Med Chem 24:5969-5987|
|Hauser, Kurt F; Khurdayan, Valeriya K; Goody, Robin J et al. (2003) Selective vulnerability of cerebellar granule neuroblasts and their progeny to drugs with abuse liability. Cerebellum 2:184-95|
|Opanashuk, L A; Pauly, J R; Hauser, K F (2001) Effect of nicotine on cerebellar granule neuron development. Eur J Neurosci 13:48-56|
|Gurwell, J A; Nath, A; Sun, Q et al. (2001) Synergistic neurotoxicity of opioids and human immunodeficiency virus-1 Tat protein in striatal neurons in vitro. Neuroscience 102:555-63|
|Knapp, P E; Itkis, O S; Zhang, L et al. (2001) Endogenous opioids and oligodendroglial function: possible autocrine/paracrine effects on cell survival and development. Glia 35:156-65|
|Hauser, K F; Knapp, P E; Turbek, C S (2001) Structure-activity analysis of dynorphin A toxicity in spinal cord neurons: intrinsic neurotoxicity of dynorphin A and its carboxyl-terminal, nonopioid metabolites. Exp Neurol 168:78-87|
|Hauser, K F; Houdi, A A; Turbek, C S et al. (2000) Opioids intrinsically inhibit the genesis of mouse cerebellar granule neuron precursors in vitro: differential impact of mu and delta receptor activation on proliferation and neurite elongation. Eur J Neurosci 12:1281-93|
|Siems, W; Maul, B; Krause, W et al. (2000) Neutral endopeptidase and alcohol consumption, experiments in neutral endopeptidase-deficient mice. Eur J Pharmacol 397:327-34|
|Knapp, P E; Ismaili, S; Hauser, K F et al. (1999) Abnormal Ca(2+) regulation in oligodendrocytes from the dysmyelinating jimpy mouse. Brain Res 847:332-7|
|Reznikov, K; Hauser, K F; Nazarevskaja, G et al. (1999) Opioids modulate cell division in the germinal zone of the late embryonic neocortex. Eur J Neurosci 11:2711-9|
Showing the most recent 10 out of 34 publications