Browsing by Subject "Brain Chemistry"

Now showing 1 - 7 of 7
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    The human mu opioid receptor: modulation of functional desensitization by calcium/calmodulin-dependent protein kinase and protein kinase C
    (Society for Neuroscience, 1995-03) Mestek, A.; Hurley, J.H.; Bye, L.S.; Campbell, A.D.; Chen, Y.; Tian, M.; Liu, J.; Schulman, H.; Yu, L.; Medical and Molecular Genetics, School of Medicine
    Opioids are some of the most efficacious analgesics used in humans. Prolonged administration of opioids, however, often causes the development of drug tolerance, thus limiting their effectiveness. To explore the molecular basis of those mechanisms that may contribute to opioid tolerance, we have isolated a cDNA for the human mu opioid receptor, the target of such opioid narcotics as morphine, codeine, methadone, and fentanyl. The receptor encoded by this cDNA is 400 amino acids long with 94% sequence similarity to the rat mu opioid receptor. Transient expression of this cDNA in COS-7 cells produced high-affinity binding sites to mu-selective agonists and antagonists. This receptor displays functional coupling to a recently cloned G-protein-activated K+ channel. When both proteins were expressed in Xenopus oocytes, functional desensitization developed upon repeated stimulation of the mu opioid receptor, as observed by a reduction in K+ current induced by the second mu receptor activation relative to that induced by the first. The extent of desensitization was potentiated by both the multifunctional calcium/calmodulin-dependent protein kinase and protein kinase C. These results demonstrate that kinase modulation is a molecular mechanism by which the desensitization of mu receptor signaling may be regulated at the cellular level, suggesting that this cellular mechanism may contribute to opioid tolerance in humans.
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    Low-level developmental lead exposure does not predispose to adult alcohol self-administration, but does increase the risk of relapsing to alcohol seeking in mice: Contrasting role of GLT1 and xCT brain expression
    (Elsevier, 2020-12-15) Rangel-Barajas, Claudia; Coronel, Israel; Zhang, Yanping; Hernández, Maribel; Boehm, Stephen L., II; Psychology, School of Science
    Lead (Pb) is a neurotoxic heavy metal pollutant. Despite the efforts to reduce Pb environmental exposure and to prevent Pb poisoning, exposure in human populations persists. Studies of adults with history of childhood lead exposure have consistently demonstrated cognitive impairments that have been associated with sustained glutamate signaling. Additionally, some clinical studies have also found correlations between Pb exposure and increased proclivity to drug addiction. Thus, here we sought to investigate if developmental Pb exposure can increase propensity to alcohol consumption and relapse using an alcohol self-administration paradigm. Because Pb exposure is associated with increased glutamatergic tone, we also studied the effects on the expression of synaptic and non-synaptic glutamate transporters in brain regions associated with drug addiction such as the nucleus accumbens (NAc), dorsomedial striatum (DMS), dorsolateral striatum (DLS), and medial prefrontal cortex (mPFC). We found that while developmental Pb exposure did not increase risk for alcohol self-administration, it did play a role in relapsing to alcohol. The effects were associated with differential expression of the glutamate transporter 1 (GLT1) and the glutamate/cystine antiporter (xCT). In the NAc and DLS the expression of GLT1 was found to be significantly reduced, while no changes were found in DMS or mPFC. Contrastingly, xCT was found to be upregulated in NAc but downregulated in DLS, with no changes in DMS or mPFC. Our data suggest that lead exposure is involved in relapse to alcohol seeking, an effect that could be associated with downregulation of GLT1 and xCT in the DLS.
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    Novel tau filament fold in corticobasal degeneration
    (Nature Publishing group, 2020-02-12) Zhang, Wenjuan; Tarutani, Airi; Newell, Kathy L.; Murzin, Alexey G.; Matsubara, Tomoyasu; Falcon, Benjamin; Vidal, Ruben; Garringer, Holly J.; Shi, Yang; Ikeuchi, Takeshi; Murayama, Shigeo; Ghetti, Bernardino; Hasegawa, Masato; Goedert, Michel; Scheres, Sjors H. W.; Pathology and Laboratory Medicine, School of Medicine
    Corticobasal degeneration (CBD) is a neurodegenerative tauopathy that is characterised by motor and cognitive disturbances (1–3). A higher frequency of the H1 haplotype of MAPT, the tau gene, is present in cases of CBD than in controls (4,5) and genome-wide association studies have identified additional risk factors (6). By histology, astrocytic plaques are diagnostic of CBD (7,8), as are detergent-insoluble tau fragments of 37 kDa by SDS-PAGE (9). Like progressive supranuclear palsy (PSP), globular glial tauopathy (GGT) and argyrophilic grain disease (AGD) (10), CBD is characterised by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats (4R) (11–15). This distinguishes 4R tauopathies from Pick’s disease, filaments of which are made of three-repeat (3R) tau isoforms, and from Alzheimer’s disease and chronic traumatic encephalopathy (CTE), where both 3R and 4R tau isoforms are found in the filaments (16). Here we report the structures of tau filaments extracted from the brains of three individuals with CBD using electron cryo-microscopy (cryo-EM). They were identical between cases, but distinct from those of Alzheimer’s disease, Pick’s disease and CTE (17–19). The core of CBD filaments comprises residues K274-E380 of tau, spanning the last residue of R1, the whole of R2, R3 and R4, as well as 12 amino acids after R4. It adopts a novel four-layered fold, which encloses a large non-proteinaceous density. The latter is surrounded by the side chains of lysine residues 290 and 294 from R2 and 370 from the sequence after R4. CBD is the first 4R tauopathy with filaments of known structure.
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    Prediction of brain clozapine and norclozapine concentrations in humans from a scaled pharmacokinetic model for rat brain and plasma pharmacokinetics
    (Springer (Biomed Central Ltd.), 2014) Li, Claire H.; Stratford, Robert E.; Velez de Mendizabal, Nieves; Cremers, Thomas I. F. H.; Pollock, Bruce G.; Mulsant, Benoit H.; Remington, Gary; Bies, Robert R.; Department of Medicine, IU School of Medicine
    BACKGROUND: Clozapine is highly effective in treatment-resistant schizophrenia, although, there remains significant variability in the response to this drug. To better understand this variability, the objective of this study was to predict brain extracellular fluid (ECF) concentrations and receptor occupancy of clozapine and norclozapine in human central nervous system by translating plasma and brain ECF pharmacokinetic (PK) relationships in the rat and coupling these with known human disposition of clozapine in the plasma. METHODS: Unbound concentrations of clozapine and norclozapine were measured in rat brain ECF using quantitative microdialysis after subcutaneous administration of a 10 mg/kg single dose of clozapine or norclozapine. These data were linked with plasma concentrations obtained in the same rats to develop a plasma-brain ECF compartmental model. Parameters describing brain ECF disposition were then allometrically scaled and linked with published human plasma PK to predict human ECF concentrations. Subsequently, prediction of human receptor occupancy at several CNS receptors was based on an effect model that related the predicted ECF concentrations to published concentration-driven receptor occupancy parameters. RESULTS: A one compartment model with first order absorption and elimination best described clozapine and norclozapine plasma concentrations in rats. A delay in the transfer of clozapine and norclozapine from plasma to the brain ECF compartment was captured using a transit compartment model approach. Human clozapine and norclozapine concentrations in brain ECF were simulated, and from these the median percentage of receptor occupancy of dopamine-2, serotonin-2A, muscarinic-1, alpha-1 adrenergic, alpha-2 adrenergic and histamine-1 for clozapine, and dopamine-2 for norclozapine were consistent with values reported in the literature. CONCLUSIONS: A PK model that relates clozapine and norclozapine disposition in rat plasma and brain, including blood-brain barrier transport, was developed. Using allometry and published human plasma PK, the model was successfully translated to predict clozapine and norclozapine concentrations and accordant receptor occupancy of both agents in human brain. These predicted exposure and occupancy measures at several receptors that bind clozapine may be employed to extend our understanding of clozapine's complex behavioral effects in humans.
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    Vulnerability of welders to manganese exposure--a neuroimaging study
    (Elsevier, 2014-12) Zaiyang, Long; Yue-Ming, Jiang; Xiang-Rong, Li; William, Fadel; Jun, Xu; Chien-Lin, Yeh; Li-Ling, Long; Hai-Lan, Luo; Jaroslaw, Harezlak; James B, Murdoch; Wei, Zheng; Ulrike, Dydak; Department of Radiology and Imaging Sciences, IU School of Medicine
    Increased manganese (Mn) exposure is known to cause cognitive, psychiatric and motor deficits. Mn exposure occurs in different occupational settings, where the airborne Mn level and the size of respirable particulates may vary considerably. Recently the importance of the role of the cerebral cortex in Mn toxicity has been highlighted, especially in Mn-induced neuropsychological effects. In this study we used magnetic resonance imaging (MRI) to evaluate brain Mn accumulation using T1 signal intensity indices and to examine changes in brain iron content using T2* contrast, as well as magnetic resonance spectroscopy (MRS) to measure exposure-induced metabolite changes non-invasively in cortical and deep brain regions in Mn-exposed welders, Mn-exposed smelter workers and control factory workers with no measurable exposure to Mn. MRS data as well as T1 signal intensity indices and T2* values were acquired from the frontal cortex, posterior cingulate cortex, hippocampus, and thalamus. Smelters were exposed to higher air Mn levels and had a longer duration of exposure, which was reflected in higher Mn levels in erythrocytes and urine than in welders. Nonetheless, welders had more significant metabolic differences compared to controls than did the smelter workers, especially in the frontal cortex. T1 hyperintensities in the globus pallidus were observed in both Mn-exposed groups, but only welders showed significantly higher thalamic and hippocampal T1 hyperintensities, as well as significantly reduced T2* values in the frontal cortex. Our results indicate that (1) the cerebral cortex, in particular the frontal cortex, is clearly involved in Mn neurotoxic effects and (2) in spite of the lower air Mn levels and shorter duration of exposure, welders exhibit more extensive neuroimaging changes compared to controls than smelters, including measurable deposition of Mn in more brain areas. These results indicate that the type of exposure (particulate sizes, dust versus fume) and route of exposure play an important role in the extent of Mn-induced toxic effects on the brain.