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The preclinical pharmacological profile of WAY-132983, a potent M1 preferring agonist

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期292卷 584-596页

作者： Bartolomeo, AC Morris, H Buccafusco, JJ Kille, N Rosenzweig-Lipson, S Husbands, MG Sabb, AL Abou-Gharbia, M Moyer, JA Boast, CA Wyeth Ayerst Res CNS Disorders Div Cent Nervous Syst Med Chem Cent Nervous Syst Res Princeton NJ 08543 USA Med Coll Georgia Dept Pharmacol & Toxicol Alzheimers Res Ctr Augusta GA 30912 USA Vet Adm Med Ctr Augusta GA 30904 USA

Muscarinic M1 preferring agonists may improve cognitive deficits associated with Alzheimer's disease. Side effect assessment of the M1 preferring agonist WAY-132983 showed significant salivation (10 mg/kg i.p. or p.o.) and produced dose-dependent hypothermia after i.p. or p.o. administration. WAY-132983 significantly reduced scopolamine (0.3 mg/kg i.p.) induced hyperswimming in mice. Cognitive assessment in rats used pretrained animals in a forced choice, 1-h delayed non-match-to-sample radial arm maze task. WAY-132983 (0.3 mg/kg i.p) significantly reduced scopolamine (0.3 mg/kg s.c.)-induced errors. Oral WAY-132983 attenuated scopolamine-induced errors;that is, errors produced after combining scopolamine and WAY-132983 (to 3 mg/kg p.o.) were not significantly increased compared with those of vehicle-treated control animals, whereas errors after scopolamine were significantly higher than those of control animals. With the use of miniosmotic pumps, 0.03 mg/kg/day (s.c.) WAY-132983 significantly reduced AF64A (3 nmol/3ml/lateral ventricle)-induced errors. Verification of AF64A cholinotoxicity showed significantly lower choline acetyltransferase activity in the hippocampi of AF64A-treated animals, with no significant changes in the striatal or frontal cortex. Cognitive assessment in primates involved the use of pretrained aged animals in a visual delayed match-to-sample procedure. Oral WAY-132983 significantly increased the number of correct responses during short and long delay interval testing. These effects were also apparent 24 h after administration. WAY-132983 exhibited cognitive benefit at doses lower than those producing undesirable effects;therefore, WAY-132983 is a potential candidate for improving the cognitive status of patients with Alzheimer's disease.

关键词：氮丙啶类/药理学行为动物/药物作用脑/代谢桥基化合物/投药和剂量桥基化合物/药理学桥基化合物/毒性胆碱/类似物和衍生物胆碱/药理学胆碱O-乙酰转移酶/代谢认知/药物作用剂量效应关系药物药物相互作用额叶/药物作用额叶/代谢海马/代谢低温/化学诱导恒河猴毒蕈碱激动剂/投药和剂量毒蕈碱激动剂/药理学毒蕈碱激动剂/毒性神经肌肉阻滞药/药理学吡嗪类/投药和剂量吡嗪类/药理学吡嗪类/毒性吡啶类/药理学大鼠 Sprague-Dawley 唾液分泌/药物作用东莨菪碱/药理学噻二唑类/药理学时间因素视皮质/药物作用视皮质/代谢动物女(雌)性男(雄)性小鼠大鼠

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Effect of pentobarbital on visual processing in man

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HUMAN BRAIN MAPPING 2000年第3期10卷 132-139页

作者： Martin, E Thiel, T Joeri, P Loenneker, T Ekatodramis, D Huisman, T Hennig, J Marcar, VL Univ Zurich Childrens Hosp Div Magnet Resonance CH-8032 Zurich Switzerland Univ Freiburg Dept Radiol Freiburg Germany

To investigate the effect of sedative agents on visual processing in humans, we analysed the BOLD contrast signal response to a visual stimulation paradigm in 15 healthy, adult volunteers using functional magnetic resonance imaging. The subjects were tested during alert state and under sedation following intravenous administration of pentobarbital. The injection of pentobarbital not only significantly reduced the response signal strength but the reduction in BOLD contrast signal was related to the ratio of amount of sedative administered and the subject's body weight. The three subjects with the highest relative sedative dosage even displayed an inverted (negative) BOLD contrast signal. A significant reduction in the number of positively correlating pixels was found 15 min after administration of pentobarbital. All measured parameters returned to near pre-sedative levels by the end of the experimental session. The relative dosage dependence of the strength of the BOLD signal the negative BOLD signal in the three subjects with the highest relative sedative dosage indicates that pentobarbital had a more pronounced effect on cerebral blood flow than on cerebral oxidative metabolism. (C) 2000 Wiley-Liss, Inc.

关键词：脑图脑血管循环/药物作用脑血管循环/生理学能量代谢/药物作用能量代谢/生理学磁共振成像戊巴比妥/投药和剂量光刺激视皮质/解剖学和组织学视皮质/药物作用视皮质/生理学视知觉/药物作用视知觉/生理学成年人女(雌)性人类男(雄)性中年人

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Effects of feedback projections from area 18 layers 2/3 to area 17 layers 2/3 in the cat visual cortex

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JOURNAL OF NEUROPHYSIOLOGY 1999年第5期82卷 2667-2675页

作者： Martinez-Conde, S Cudeiro, J Grieve, KL Rodriguez, R Rivadulla, C Acuña, C Univ Santiago Complejo Hosp Fac MedCSIC Inst CajalLabs Neurociencia & Computac Neuronal E-15705 Santiago De Compostela Spain Univ Santiago Complejo Hosp Serv Neurofisiol Clin Complejo E-15705 Santiago De Compostela Spain Univ A Coruna Dept Ciencias Salud 2 E-15006 La Coruna Spain Univ Manchester Inst Sci & Technol Dept Optometry & Vis Sci Manchester M60 1QD Lancs England

In the absence of a direct geniculate input, area 17 cells in the cat are nevertheless able to respond to visual stimuli because of feedback connections from area 18. Anatomic studies have shown that, in the cat visual cortex, layer 5 of area 18 projects to layer 5 of area 17, and layers 2/3 of area 18 project to layers 2/3 of area 17. What is the specific role of these connections? Previous studies have examined the effect of area 18 layer 5 blockade on cells in area 17 layer 5. Here we examine whether the feedback connections from layers 2/3 of area 18 influence the orientation tuning and velocity tuning of cells in layers 2/3 of area 17. Experiments were carried out in anesthetized and paralyzed cats. We blocked reversibly a small region (300 mu m radius) in layers 2/3 of area 18 by iontophoretic application of GABA and recorded simultaneously from cells in layers 2/3 of area 17 while stimulating with oriented sweeping bars. Area 17 cells showed either enhanced or suppressed visual responses to sweeping bars of various orientations and velocities during area 18 blockade. For most area 17 cells, orientation bandwidths remained unaltered, and we never observed visual responses during blockade that were absent completely in the preblockade condition. This suggests that area 18 layers 2/3 modulate visual responses in area 17 layers 2/3 without fundamentally altering their specificity.

关键词：脑图反馈神经元/药物作用神经元/生理学光刺激反应时间视网膜/生理学视皮质/药物作用视皮质/生理学视通路/生理学视知觉/生理学 γ氨基丁酸/药理学动物猫

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Cytidine-5′-diphosphocholine (citicoline) improves retinal and cortical responses in patients with glaucoma

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OPHTHALMOLOGY 1999年第6期106卷 1126-1134页

作者： Parisi, V Manni, G Colacino, G Bucci, MG Univ Roma Tor Vergata Cattedra Clin Oculist I-00199 Rome Italy Fdn Oftalmol GB Bietti Rome Italy Osped Fatebenefratelli Div Oculist AFaR CRCCS Rome Italy

Purpose: To evaluate the effects of cytidine-5'-diphosphocholine (citicoline) on retinal function and on cortical responses in patients with glaucoma. Design: Randomized clinical trial. Participants: Forty patients with open-angle glaucoma were randomly divided into two age-matched groups: citicoline group ([GC] n = 25) and placebo group ([GP] n = 15). Methods: The GC patients were treated with Neuroton (citicoline, 1000 mg/day intramuscularly) for 60 days;GP patients were treated with placebo (physiologic solution with additives) for 60 days. After 120 days of washout (day 180), the GC patients were divided into two age-matched groups: in 10 patients (GC1 group) the washout was prolonged for a further 120 days;in 15 patients (GC2 group) a second 60-day period of citicoline treatment was followed by a second 120-day period of washout. At day 180, the washout was extended for another 180 days in GP patients. In all subjects, retinal and cortical responses were evaluated by simultaneous recordings of visual evoked potentials (VEPs) and pattern-electroretinograms (PERGs) at baseline, after 60 days, and after 180 days. At day 300, VEPs and PERGs were also evaluated in GC1 patients, and at 240 and 360 days in GC2 and GP patients. Main Outcome Measures: Visual evoked potential parameters (P100 latency and N75-P100 amplitude);PERG parameters (P50 latency and P50-N95 amplitude);and intraocular pressure. Results: The GP patients displayed similar VEP and PERG parameters in all examinations performed. In GC patients, the treatment with citicoline induced a significant (P < 0.01) improvement of VEP and PERG parameters, and their values were significantly different (P < 0.01) with respect to those of GP patients (P < 0.01). Visual evoked potentials and PERGs, recorded in GC patients after washout, revealed that although there was a worsening trend, the electrophysiologic improvement was still maintained. After a second period of washout, GC1 patients had VEP and PERG parameters

关键词：胞苷二磷酸胆碱/治疗应用视网膜电描记术诱发电位视觉青光眼开角型/药物疗法青光眼开角型/病理生理学注射肌肉内眼内压脑代谢改善药/治疗应用视网膜/药物作用视网膜/病理生理学视皮质/药物作用视皮质/病理生理学视通路/病理生理学人类中年人

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Effect of the group II metabotropic glutamate agonist, 2R,4R-APDC, varies with age, layer, and visual experience in the visual cortex

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JOURNAL OF NEUROPHYSIOLOGY 1999年第1期82卷 86-93页

作者： Beaver, CJ Ji, QH Daw, NW Yale Univ Sch Med Dept Ophthalmol & Visual Sci New Haven CT 06520 USA

Group II metabotropic glutamate receptors (mGluR 2/3) are distributed differentially across the layers of cat visual cortex, and this distribution varies with age. At 3-4 wk, mGluR 2/3 receptor immunoreactivity is present in all layers. By 6-8 wk of age, it is still present in extragranular layers (2, 3, 5, and 6) but has disappeared from layer 4, and dark-rearing postpones the disappearance of Group II receptors from layer 4. We examined the physiological effects of Group II activation, to see if these effects varied similarly. The responses of single neurons in cat primary visual cortex were recorded to visual stimulation, then the effect of iontophoresis of 2R,4R-4 aminopyrrolidine-2,4-decarboxylate (2R,4R-APDC), a Group II specific agonist, was observed in animals between 3 wk and adulthood. The effect of 2R,4R-APDC was generally suppressive, reducing both the visual response and spontaneous activity of single neurons. The developmental changes were in agreement with the immunohistochemical results: 2R,4R-APDC had effects on cells in all layers in animals of 3-4 wk but not in layer 4 of animals >6 wk old. Moreover, the effect of 2R,4R-APDC was reduced in the cortex of older animals (>22 wk). Dark-rearing animals to 47-54 days maintained the effects of 2R,4R-APDC in layer 4. The disappearance of Group II mGluRs from layer 4 between 3 and 6 wk of age is correlated with the segregation of ocular dominance columns in that layer, raising the possibility that mGluRs 2/3 are involved in this process.

关键词：衰老/生理学黑暗兴奋性氨基酸激动剂/药理学光神经元/药物作用神经元/生理学脯氨酸/类似物和衍生物脯氨酸/药理学反应时间受体亲代谢性谷氨酸盐/激动剂视皮质/药物作用视皮质/生长和发育视皮质/生理学视知觉动物猫

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Actions of brain-derived neurotrophic factor on evoked and spontaneous EPSCs dissociate with maturation of neurones cultured from rat visual cortex

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JOURNAL OF PHYSIOLOGY-LONDON 2000年第3期527卷 579-592页

作者： Taniguchi, N Takada, N Kimura, F Tsumoto, T Osaka Univ Grad Sch Med D14 Biomed Res Ctr Div Neurophysiol Suita Osaka 5650871 Japan Japan Sci & Technol Corp CREST Suita Osaka 5650871 Japan

1. To address the question of whether brain-derived neurotrophic factor (BDNF) directly enhances excitatory synaptic transmission, we recorded excitatory postsynaptic currents (EPSCs) from solitary neurones cultured on glial microislands for 7-38 days, and observed changes in EPSCs after the application of BDNF. In this preparation the possible action of BDNF on GABAergic inhibition was not involved, and evoked and spontaneous (miniature) EPSCs were derived from the same group of synapses (autapses). 2. The application of BDNF at a concentration of 200 ng ml(-1) rapidly enhanced the frequency of miniature EPSCs (mEPSCs) in almost all the neurones tested. On the other hand, the amplitude of mEPSCs did not change at all, suggesting that the site of BDNF action is presynaptic. 3. In contrast to the enhanced frequency of mEPSCs, evoked EPSCs were not potentiated in 61% of the cells tested. Most of these BDNF-insensitive EPSCs had a peak amplitude larger than 1 nA, while most of the other BDNF-sensitive EPSCs had a smaller amplitude. The former EPSCs had smaller coefficients of variation (CVs) of amplitude, while the latter had larger CVs, suggesting the possibility that the presynaptic release probability for the former groups of EPSCs might have beeen saturated so that the BDNF action was occluded. 4. To test, this possibility we applied a low Ca2+ solution to 17 cells and reduced the amplitude of their evoked EPSCs to less than or near to 1 nA. It was found, however, that BDNF did not enhance these EPSCs. Rather, evoked EPSCs of almost all the cells cultured for less than 15 days were enhanced by BDNF, while those of most of the cells cultured for longer than 16 days were not enhanced. 5. These results suggest that BDNF enhances transmitter release from presynaptic sites through its action on the release machinery, which can be differentiated into a BDNF-insensitive form for evoked release and a BDNF-sensitive form for spontaneous release with maturation of synapses.

关键词：抗体封闭/药理学脑源性神经营养因子/免疫学脑源性神经营养因子/药理学细胞培养的电生理学兴奋性突触后电位/药物作用膜电位/生理学神经胶质/细胞学神经胶质/药物作用神经胶质/代谢神经元/药物作用神经元/生理学膜片钳术大鼠 Sprague-Dawley 受体蛋白质酪氨酸激酶类/免疫学受体蛋白质酪氨酸激酶类/代谢受体突触前/药物作用视皮质/细胞学视皮质/药物作用 γ氨基丁酸/生理学动物男(雄)性大鼠

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The acute effect in rats of 3,4-methylenedioxyethamphetamine (MDEA,"eve") on body temperature and long term degeneration of 5-HT neurones in brain: A comparison with MDMA ("ecstasy")

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PHARMACOLOGY & TOXICOLOGY 1999年第6期84卷 261-266页

作者： Colado, MI Granados, R O'Shea, E Esteban, B Green, AR Univ Complutense Fac Med Dept Pharmacol Madrid 28040 Spain De Montfort Univ Sch Pharm & Pharmaceut Sci Leicester LE1 9RH Leics England

Administration of a single dose of the recreationally used drug 3,4-methylenedioxyethamphetamine (MDEA or "eve") to Dark Agouti rats resulted in an acute dose-dependent hyperthermic response. The peak effect and duration of hyperthermia of a dose of MDEA of 35 mg/kg intraperitoneally was similar to a dose of 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") of 15 mg/kg intraperitoneally. Seven days later this dose of MDMA produced a marked (approximate to 50%) loss of 5-HT and its metabolite 5-HIAA in cortex, hippocampus and striatum and a similar loss of [H-3]-paroxetine binding in cortex;these losses reflecting the MDMA-induced neurotoxic degeneration of 5-HT nerve endings. In contrast, administration of MDEA (15, 25 or 35 mg/kg), even at the highest dose, produced only a 20% loss in cortex and hippocampus and no decrease in striatum. The neurotoxic effect of MDEA was only weakly dose-dependent. Neither MDEA (35 mg/kg) nor MDMA (15 mg/kg) altered striatal dopamine content 7 days later. MDEA appeared to have about half the potency of MDMA in inducing acute hyperthermia and 25% of the potency in inducing degeneration of cerebral 5-HT neurones. However since higher doses of MDEA (compared to MDMA) are probably necessary to induce mood changing effects, these data do not support any contention that this compound is a "safer" recreational drug than MDMA in terms of either acute toxicity or long term neurodegeneration.

关键词： 3 4-亚甲二氧苯丙胺/类似物和衍生物 3 4-亚甲二氧苯丙胺/毒性苯丙胺类/毒性脑/药物作用脑/代谢大脑皮质/药物作用大脑皮质/代谢剂量效应关系药物发热/化学诱导海马/药物作用海马/代谢 N-甲基-3 4-亚甲二氧苯丙胺/毒性神经末梢/药物作用帕罗西汀/分析血清素/分析时间因素视皮质/药物作用视皮质/代谢动物男(雄)性大鼠

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EFFECTS OF N,N-DIMETHYLTRYPTAMINE ON ELECTRICALLY EVOKED-RESPONSES IN CAT VISUAL-SYSTEM AND MODIFICATION BY NEUROLEPTIC AGENTS

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NEUROPHARMACOLOGY 1976年第9期15卷 535-539页

作者： MOORE, RH HATADA, K DOMINO, EF LAFAYETTE CLIN DEPT PHARMACOL DETROIT MI 48207 USA UNIV MICHIGAN ANN ARBOR MI 48109 USA

Dimethyltryptamine caused a dose-dependent decrease in the amplitude of the response evoked by stimulation of the optic chiasm as recorded in the lateral geniculate nucleus and the visual cortex. It had no significant effect on antidromically evoked potentials in the lateral geniculate nucleus or potentials in the visual cortex produced by optic radiation stimulation. A dose-dependent biphasic effect was found in animals pretreated with various doses of chlorpromazine, haloperidol, thiothixene, molindone, methiothepin and octoclothepin. Methiothepin and octoclothepin were the most potent antagonists of dimethyltryptamine, while molindone was essentially ineffective. Low doses of the neuroleptics, with the exception of molindone, potentiated the inhibitory action of dimethyltryptamine on evoked responses.

关键词：氯丙嗪/药理学二苯硫|艹卓|类/药理学剂量效应关系药物药物相互作用诱发电位/药物作用氟哌啶醇/药理学甲硫替平/药理学 N N-二甲基色胺/药理学视交叉/药物作用替沃噻吨/药理学安定药/药理学色胺类/药理学视皮质/药物作用视通路/药物作用动物猫

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Induction of NMDA receptor-dependent long-term depression in visual cortex does not require metabotropic glutamate receptors

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JOURNAL OF NEUROPHYSIOLOGY 1999年第6期82卷 3594-3597页

作者： Sawtell, NB Huber, KM Roder, JC Bear, MF Brown Univ Dept Neurosci Howard Hughes Med Inst Providence RI 02912 USA Mt Sinai Hosp Samuel Lunenfeld Res Inst Program Dev & Fetal Hlth Toronto ON M5G 1X5 Canada Univ Toronto Dept Mol & Med Genet Toronto ON M5S 1A8 Canada

We tested the role of group I mGluRs in the induction of long-term depression (LTD) in the visual cortex, using the novel mGluR antagonist LY341495 and mice lacking mGluR5, the predominant phosphoinositide (PI)-linked mGluR in the visual cortex. We find that LY341495 is a potent blocker of glutamate-stimulated PI hydrolysis in visual cortical synaptoneurosomes, and that it effectively antagonizes the actions of the mGluR agonist 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (ACPD) on synaptic transmission in visual cortical slices. However, LY341495 has no effect on the induction of LTD by low-frequency stimulation. Furthermore, mice lacking mGluR5 show normal NMDA receptor-dependent LTD. These results indicate that group I mGluR activation is not required for the induction of NMDA receptor-dependent LTD in the visual cortex.

关键词：氨基酸类/药理学环亮氨酸/类似物和衍生物环亮氨酸/药理学抑制化学性兴奋性氨基酸拮抗剂/药理学水解作用甲氧基羟基苯乙二醇/类似物和衍生物甲氧基羟基苯乙二醇/药理学小鼠基因敲除神经元可塑性/药物作用神经元可塑性/生理学磷脂酰肌醇类/代谢受体亲代谢性谷氨酸盐/激动剂受体亲代谢性谷氨酸盐/拮抗剂和抑制剂受体亲代谢性谷氨酸盐/生理学受体 N-甲基-D-天冬氨酸/拮抗剂和抑制剂受体 N-甲基-D-天冬氨酸/遗传学受体 N-甲基-D-天冬氨酸/生理学突触体/药物作用突触体/代谢视皮质/药物作用视皮质/生理学呫吨类/药理学动物小鼠大鼠

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