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Author (up) Andersson, D.R.; Bjornsson, E.; Bergquist, F.; Nissbrandt, H. file  url
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  Title Motor activity-induced dopamine release in the substantia nigra is regulated by muscarinic receptors Type Journal Article
  Year 2010 Publication Experimental Neurology Abbreviated Journal Exp Neurol  
  Volume 221 Issue 1 Pages 251-259  
  Keywords Analysis of Variance; Animals; Area Under Curve; Brain Injuries/chemically induced/*pathology; Chromatography, High Pressure Liquid/methods; Dendrites/drug effects/metabolism; Disease Models, Animal; Dopamine/*metabolism; Dose-Response Relationship, Drug; Electrochemistry/methods; Female; Functional Laterality; Mecamylamine/pharmacology; Microdialysis/methods; Motor Activity/drug effects/*physiology; Muscarinic Antagonists/pharmacology; Nicotinic Antagonists/pharmacology; Oxidopamine; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic/*physiology; Rotarod Performance Test/methods; Scopolamine Hydrobromide/pharmacology; Substantia Nigra/drug effects/*metabolism/pathology; gamma-Aminobutyric Acid/metabolism  
  Abstract Nigro-striatal neurons release dopamine not only from their axon terminals in the striatum, but also from somata and dendrites in the substantia nigra. Somatodendritic dopamine release in the substantia nigra can facilitate motor function by mechanisms that may act independently of axon terminal dopamine release in the striatum. The dopamine neurons in the substantia nigra receive a cholinergic input from the pedunculopontine nucleus. Despite recent efforts to introduce this nucleus as a potential target for deep brain stimulation to treat motor symptoms in Parkinson's disease; and the well-known antiparkinsonian effects of anticholinergic drugs; the cholinergic influence on somatodendritic dopamine release is not well understood. The aim of this study was to investigate the possible regulation of locomotor-induced dopamine release in the substantia nigra by endogenous acetylcholine release. In intact and 6-OHDA hemi-lesioned animals alike, the muscarinic antagonist scopolamine, when perfused in the substantia nigra, amplified the locomotor-induced somatodendritic dopamine release to approximately 200% of baseline, compared to 120-130% of baseline in vehicle-treated animals. A functional importance of nigral muscarinic receptor activation was demonstrated in hemi-lesioned animals, where motor performance was significantly improved by scopolamine to 82% of pre-lesion performance, as compared to 56% in vehicle-treated controls. The results indicate that muscarinic activity in the substantia nigra is of functional importance in an animal Parkinson's disease model, and strengthen the notion that nigral dopaminergic regulation of motor activity/performance is independent of striatal dopamine release.  
  Call Number Serial 308  
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Author (up) Arimoto-Kobayashi, S.; Sakata, H.; Mitsu, K.; Tanoue, H. file  url
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  Title A possible photosensitizer: Tobacco-specific nitrosamine, 4-(N-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), induced mutations, DNA strand breaks and oxidative and methylative damage with UVA Type Journal Article
  Year 2007 Publication Mutation Research Abbreviated Journal Mutat Res  
  Volume 632 Issue 1-2 Pages 111-120  
  Keywords Base Sequence; DNA Breaks; DNA Methylation--drug effects, radiation effects; Dose-Response Relationship, Drug; Models, Biological; Molecular Sequence Data; Mutation; Nitrosamines--toxicity; Oxidative Stress--drug effects, radiation effects; Photosensitizing Agents--toxicity; Salmonella typhimurium; Tobacco--chemistry; Ultraviolet Rays--adverse effects  
  Abstract We discovered the directly acting mutagenicity of the tobacco-specific nitrosamine, 4-(N-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), with UVA light (320-400nm) in Ames bacteria and phage M13mp2 in the absence of metabolic activation. We have investigated the spectrum of mutations caused by UVA-activated NNK. The majority (57%) of induced sequence changes were comprised of GC to CG, GC to TA and GC to AT. This suggested that modification of guanine residues was responsible for these mutations. Hence, we explored the formation of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) and O(6)-methylguanine (O(6)meG) in the DNA. When calf thymus DNA was treated with NNK and UVA, the amount of 8-oxodG/dG and O(6)meG/G in the DNA increased up to 20-fold and 100-fold, respectively, compared with the untreated control. DNA strand breaks were observed following NNK and UVA treatment, and the strand breaks were suppressed in the presence of scavengers for oxygen and NO radical. The formation of NO was also observed in NNK solutions irradiated with UVA. We analyzed the photodynamic spectrum of mutation induction, 8-oxodG formation and NO formation using monochromatic radiation. The patterns of the action spectra were comparable to the absorption spectrum of NNK. We conclude that NNK may act as a photosensitizer in response to UVA to produce NO and other oxidative and alkylative intermediates following the formation of 8-oxodG and O(6)meG in DNA, which may lead to mutations and DNA strand breaks.  
  Call Number Serial 86  
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Author (up) Arolfo, M.P.; Brioni, J.D. file  url
openurl 
  Title Diazepam impairs place learning in the Morris water maze Type Journal Article
  Year 1991 Publication Behavioral and Neural Biology Abbreviated Journal Behav Neural Biol  
  Volume 55 Issue 1 Pages 131-136  
  Keywords Animals; Diazepam/*pharmacology; Discrimination Learning/*drug effects; Dose-Response Relationship, Drug; Escape Reaction/*drug effects; Male; Mental Recall/drug effects; Orientation/*drug effects; Rats; Rats, Inbred Strains; Reaction Time/drug effects; Retention (Psychology)/*drug effects  
  Abstract The effect of diazepam (0.3, 1.0, and 3.0 mg/kg) on the acquisition and retention of place learning was evaluated. The analysis of escape latencies indicates that 1.0 and 3.0 mg/kg diazepam significantly impaired the retention of spatial information. When a free swim trial was carried out only control animals showed spatial bias to the target quadrant. The absence of spatial bias in the group that received 0.3 mg/kg suggests that the amnesic effect of diazepam can be seen at doses similar to or even lower than the anxiolytic ones, and that the GABA/benzodiazepine receptor complex is highly sensitive to the cognitive impairment induced by diazepam in spatial tasks.  
  Call Number Serial 249  
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Author (up) Baselga, J.; Pfister, D.; Cooper, M.R.; Cohen, R.; Burtness, B.; Bos, M.; D'Andrea, G.; Seidman, A.; Norton, L.; Gunnett, K.; Falcey, J.; Anderson, V.; Waksal, H.; Mendelsohn, J. file  url
openurl 
  Title Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin Type Journal Article
  Year 2000 Publication Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology Abbreviated Journal J Clin Oncol  
  Volume 18 Issue 4 Pages 904-914  
  Keywords Adult; Antibodies, Monoclonal/adverse effects/pharmacokinetics/*therapeutic use; Antibodies, Monoclonal, Humanized; Antineoplastic Agents/adverse effects/pharmacokinetics/*therapeutic use; Area Under Curve; Carcinoma, Non-Small-Cell Lung/drug therapy/therapy; Carcinoma, Squamous Cell/drug therapy/therapy; Cetuximab; Cisplatin/*therapeutic use; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms/drug therapy/therapy; Humans; Infusions, Intravenous; Lung Neoplasms/drug therapy/therapy; Male; Neoplasms, Glandular and Epithelial/drug therapy/*therapy; Receptor, Epidermal Growth Factor/*antagonists & inhibitors/genetics; Recombinant Fusion Proteins/adverse effects/pharmacokinetics/*therapeutic use; Remission Induction; Safety  
  Abstract PURPOSE: The epidermal growth factor (EGF) receptor is frequently overexpressed in epithelial tumors. C225 is a human-to-murine chimeric monoclonal antibody that binds to the receptor and inhibits growth of cancer cells expressing the receptor. We evaluated the pharmacokinetics and toxicity of C225 in patients with advanced tumors overexpressing EGF receptors. PATIENTS AND METHODS: We treated 52 patients in three successive phase I clinical trials of C225 as a single dose (n = 13), weekly multiple dose (n = 17), and weekly multiple dose with cisplatin (n = 22). C225 dose levels were 5, 20, 50, and 100 mg/m(2). In the study combining C225 with cisplatin, limited to patients with either head and neck or non-small-cell lung cancer, C225 was further escalated to 200 and 400 mg/m(2). Cisplatin was given at a dose of 60 mg/m(2) once every 4 weeks, and treatment was continued for up to 12 weeks if no disease progression occurred. RESULTS: C225 displayed nonlinear pharmacokinetics, with antibody doses in the range of 200 to 400 mg/m(2) being associated with complete saturation of systemic clearance. C225 clearance did not change with repeated administration or with coadministration of cisplatin. Antibodies against C225 were detected in only one patient, and C225-associated toxicity was minimal. Patients experiencing disease stabilization were seen in all studies. In the study combining C225 and cisplatin, nine (69%) of 13 patients treated with antibody doses >/= 50 mg/m(2) completed 12 weeks of therapy, and two partial responses were observed. CONCLUSION: C225 has dose-dependent pharmacokinetics, and doses that achieve saturation of systemic clearance are well tolerated. C225 given in combination with cisplatin has biologic activity at pharmacologically relevant doses.  
  Call Number Serial 2015  
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Author (up) Bencan, Z.; Sledge, D.; Levin, E.D. file  url
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  Title Buspirone, chlordiazepoxide and diazepam effects in a zebrafish model of anxiety Type Journal Article
  Year 2009 Publication Pharmacology, Biochemistry, and Behavior Abbreviated Journal Pharmacol Biochem Behav  
  Volume 94 Issue 1 Pages 75-80  
  Keywords Animals; Anti-Anxiety Agents/*therapeutic use; Anxiety/*drug therapy; Behavior, Animal/drug effects; Benzodiazepines/administration & dosage/therapeutic use; Buspirone/administration & dosage/*therapeutic use; Chlordiazepoxide/administration & dosage/*therapeutic use; Cholinergic Agents/administration & dosage/therapeutic use; Diazepam/administration & dosage/*therapeutic use; *Disease Models, Animal; Diving; Dose-Response Relationship, Drug; Exploratory Behavior/drug effects; Imaging, Three-Dimensional/methods; Serotonin Agents/administration & dosage/therapeutic use; Stress, Psychological; Time Factors; *Zebrafish  
  Abstract Zebrafish are becoming more widely used to study neurobehavioral pharmacology. We have developed a method to assess novel environment diving behavior of zebrafish as a model of stress response and anxiolytic drug effects. In a novel tank, zebrafish dwell in the bottom of the tank initially and then increase their swimming exploration to higher levels over time. We previously found that nicotine, which has anxiolytic effects in rodents and humans, significantly lessens the novel tank diving response in zebrafish. The specificity of the diving effect was validated with a novel vs. non-novel test tank. The novel tank diving response of zebrafish was tested when given three anxiolytic drugs from two different chemical and pharmacological classes: buspirone, chlordiazepoxide and diazepam. When the test tank was novel the diving response was clearly seen whereas it was significantly reduced when the test tank was not novel. Buspirone, a serotonergic (5HT(1A) receptor agonist) anxiolytic drug with some D(2) dopaminergic effect, had a pronounced anxiolytic-like effect in the zebrafish diving model at doses that did not have sedative effects. In contrast, chlordiazepoxide, a benzodiazepine anxiolytic drug, which is an effective agonist at GABA-A receptors, did not produce signs of anxiolysis in zebrafish over a broad dose range up to those that caused sedation. Diazepam another benzodiazepine anxiolytic drug did produce an anxiolytic effect at doses that did not cause sedation. The zebrafish novel tank diving task can be useful in discriminating anxiolytic drugs of several classes (serotonergic, benzodiazepines and nicotinic).  
  Call Number Serial 209  
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