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浙江大学学报（医学版） 2011年第4期40卷 384-390页

作者：叶夷露张建亭钟雅文张纬萍沈香娣魏尔清张琦浙江医学高等专科学校药理教研室浙江杭州310053 浙江大学医学院药理学系浙江杭州310058

目的:比较中枢神经药物对KM小鼠和ICR小鼠开场自发活动和被动回避试验的影响。方法:KM小鼠和ICR小鼠分别腹腔注射不同剂量的中枢兴奋药咖啡因(3、10、30 mg/kg)和麻黄碱(3、10、30、100 mg/kg),以及中枢抑制药地西泮(1、3、10 mg/kg)和... 详细信息

目的:比较中枢神经药物对KM小鼠和ICR小鼠开场自发活动和被动回避试验的影响。方法:KM小鼠和ICR小鼠分别腹腔注射不同剂量的中枢兴奋药咖啡因(3、10、30 mg/kg)和麻黄碱(3、10、30、100 mg/kg),以及中枢抑制药地西泮(1、3、10 mg/kg)和水合氯醛(10、30、100 mg/kg)。给药10 min或30 min后,分别记录小鼠在开场内的自发活动2 h或被动回避试验的潜伏时间。分析小鼠的活动轨迹,以总路程、中央区域活动路程占总路程的比值(中央路程比值)、中央区域停留时间和穿梭的潜伏时间等指标,来评价药物对两种品系小鼠行为学活动特点的影响。结果:咖啡因和地西泮使潜伏期延长,麻黄碱和水合氯醛使潜伏期缩短,两种品系小鼠之间无明显差异。在两种品系小鼠的总活动路程上,麻黄碱10 mg/kg、地西泮3 mg/kg和水合氯醛100 mg/kg有差异。麻黄碱10、30、100 mg/kg对ICR小鼠的中央路程比值较KM小鼠增加、中央区域停留时间延长;地西泮3、10 mg/kg对ICR小鼠的中央路程比值较KM小鼠降低、中央区域停留时间缩短。结论:两种品系小鼠对开场自发活动的总路程、中央路程比值和中央区域停留时间有差异,对被动回避试验的潜伏时间无差异,为今后中枢神经药物的研究中动物品系的选择提供了依据。

关键词：中枢神经系统药物/药理学运动活动/药物作用药物评价品系差异被动回避自发活动小鼠

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The T-superfamily of conotoxins. (vol 274, pg 30664, 1999)

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第50期274卷 36030-36030页

作者： Walker, CS Steel, D Jacobsen, RB Lirazan, MB Cruz, LJ Hooper, D Shetty, R DelaCruz, RC Nielsen, JS Zhou, LM Bandyopadhyay, P Craig, AG Olivera, BM DepartmentofBiology UniversityofUtahSaltLakeCityUtah84112USA.

We report the discovery and initial characterization of the T-superfamily of conotoxins. Eight different T-superfamily peptides from five Conus species were identified; they share a consensus signal sequence, and a conserved arrangement of cysteine residues (- -CC- -CC-). T-superfamily peptides were found expressed in venom ducts of all major feeding types of Conus; the results suggest that the T-superfamily will be a large and diverse group of peptides, widely distributed in the 500 different Conus species. These peptides are likely to be functionally diverse; although the peptides are small (11-17 amino acids), their sequences are strikingly divergent, with different peptides of the superfamily exhibiting varying extents of post-translational modification. Of the three peptides tested for in vivo biological activity, only one was active on mice but all three had effects on fish. The peptides that have been extensively characterized are as follows: p5a, GCCPKQMRCCTL*; tx5a, γCCγDGW+CCT§AAO; and au5a, FCCPFIRYCCW (where γ = γ-carboxyglutamate, W^+ = bromotryptophan, O = hydroxyproline, T§ = glycosylated threonine, and * = COOH-terminal amidation). We also demonstrate that the precursor of tx5a contains a functional γ-carboxylation recognition signal in the -1 to -20 propeptide region, consistent with the presence of γ-carboxyglutamate residues in this peptide.

关键词：氨基酸序列碱基序列克隆分子芋螺毒素类/化学芋螺毒素类/遗传学芋螺毒素类/毒性共有序列半胱氨酸鱼类分子序列数据运动活动/药物作用蛋白质加工转译后蛋白分选信号/化学重组蛋白质类/化学序列比对序列同源性氨基酸螺/遗传学动物小鼠

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Mice with reduced NMDA receptor expression display behaviors related to schizophrenia

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CELL 1999年第4期98卷 427-436页

作者： Mohn, AR Gainetdinov, RR Caron, MG Koller, BH Univ N Carolina Curriculum Genet & Mol Biol Chapel Hill NC 27599 USA Univ N Carolina Dept Med Chapel Hill NC 27599 USA Duke Univ Med Ctr Howard Hughes Med Inst Labs Dept Cell Biol & Med Durham NC 27710 USA

N-methyl-D-aspartate receptors (NMDARs) represent a subclass of glutamate receptors that play a critical role in neuronal development and physiology. We report here the generation of mice expressing only 5% of normal levels of the essential NMDAR1 (NR1) subunit. Unlike NR1 null mice, these mice survive to adulthood and display behavioral abnormalities, including increased motor activity and stereotypy and deficits in social and sexual interactions. These behavioral alterations are similar to those observed in pharmacologically induced animal models of schizophrenia and can be ameliorated by treatment with haloperidol or clozapine, antipsychotic drugs that antagonize dopaminergic and serotonergic receptors. These findings support a model in which reduced NMDA receptor activity results in schizophrenic-like behavior and reveals how pharmacological manipulation of monoaminergic pathways can affect this phenotype.

关键词：抗精神病药/治疗应用反社会性人格障碍/药物疗法反社会性人格障碍/遗传学行为动物/药物作用钙信号/药物作用氯氮平/药理学氯氮平/治疗应用疾病模型动物地卓西平马来酸盐/毒性多巴胺拮抗剂/药理学多巴胺拮抗剂/治疗应用兴奋性氨基酸拮抗剂/毒性谷氨酸/生理学氟哌啶醇/药理学氟哌啶醇/治疗应用小鼠基因敲除运动活动/药物作用运动活动/遗传学苯环利定/毒性受体 N-甲基-D-天冬氨酸/缺乏受体 N-甲基-D-天冬氨酸/遗传学受体 N-甲基-D-天冬氨酸/生理学精神分裂症心理学血清素拮抗药/药理学血清素拮抗药/治疗应用性行为动物/药物作用社会行为刻板行为/药物作用动物女(雌)性男(雄)性小鼠

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Selectively bred lines of mice show response and drug specificity for genetic regulation of acute functional tolerance to ethanol and pentobarbital

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第1期293卷 188-195页

作者： Erwin, VG Gehle, VM Deitrich, RA Univ Colorado Hlth Sci Ctr Sch Pharm Alcohol Res CtrDept Pharmaceut Sci Denver CO 80262 USA Univ Colorado Hlth Sci Ctr Dept Pharmacol Alcohol Res Ctr Denver CO 80262 USA

Genetic regulation of acute tolerance to ethanol may be associated with ethanol consumption and other ethanol-related behaviors in rodents. We have used lines of mice, selectively bred for high and low acute functional tolerance (HAFT and LAFT, respectively) to ethanol-induced loss of balance to test this hypothesis. Replicate HAFT and LAFT lines differ in AFT to ethanol-induced loss of balance by 4.4- and 5-fold, respectively. Frequency distributions and mean AFT scores for those lines, F-1, and backcrosses show a dominance for the HAFT phenotype. Time courses for acquisition and decay showed that AFT to ethanol-induced loss of balance developed rapidly, could be maintained up to 6 h with repeated doses, and decayed 6 h after peak tolerance and discontinuance of ethanol administration. The lines did not differ in initial sensitivity as measured by brain ethanol concentration at loss of balance, indicating that initial sensitivity and AFT to loss of balance were not coselected traits. Surprisingly, HAFT versus LAFT lines did not differ in development of AFT to loss of righting response, or hypothermia, indicating different mechanisms or neuronal systems mediate genetic influences on these measures. Voluntary ethanol consumption was low in both of the replicate lines, but HAFT lines consumed greater amounts of ethanol than LAFT lines. The HAFT and LAFT lines developed AFT to pentobarbital-induced loss of balance, however, there were no line differences in rates or extent of the AFT development. These results show that genetic regulation of AFT development is drug- as well as response-specific.

关键词：饮酒/遗传学饮酒/心理学体温/药物作用体温/遗传学中枢神经系统抑制药/药理学交叉遗传剂量效应关系药物药物耐受性/遗传学乙醇/药理学催眠药和镇静药/药理学小鼠近交系运动活动/药物作用运动活动/遗传学肌肉骨骼平衡/药物作用戊巴比妥/药理学种特异性时间因素动物小鼠

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Unique analogues of anandamide: Arachidonyl ethers and carbamates and norarachidonyl carbamates and ureas

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JOURNAL OF MEDICINAL CHEMISTRY 1999年第11期42卷 1975-1981页

作者： Ng, EW Aung, MM Abood, ME Martin, BR Razdan, RK Organix Inc Woburn MA 01801 USA Virginia Commonwealth Univ Med Coll Virginia Dept Pharmacol & Toxicol Richmond VA 23298 USA

To examine the effect of changing the amide bond of anandamide (5, AN) to a less hydrolyzable moiety, analogues 1a-1l, 2a-2c, 3a-3c, and 4a-4h. were synthesized from commercially available arachidonyl alcohol or arachidonic acid and tested for their pharmacological activity. Arachidonyl ethers 1a-1k were obtained through the coupling of the arachidonyl mesylate (6) (generated from the mesylation of arachidonyl alcohol) with the appropriate alcohol in potassium hydroxide. Arachidonyl ether 1l was obtained through the phase-transfer coupling of arachidonyl alcohol with 2-(2-iodoethoxy)tetrahydropyran (which was generated from its bromide) followed by cleavage of the tetrahydropyran group with Dowex resin. Arachidonyl carbamates 2a-2c were obtained through the coupling of arachidonyl alcohol with the appropriate isocyanates. Norarachidonyl carbamates 3a-3c and ureas 4a-4h were obtained through the coupling of the norarachidonyl isocyanate (generated from arachidonic acid using diphenyl phosphorazidate and triethylamine upon heating) with the appropriate alcohols and amines, respectively. AN analogues 1-3 have shown poor binding affinities to the CB1 receptor and fail to produce significant pharmacological effect at doses up to 30 mg/kg. Several ether analogues 1 were also evaluated in the CB2 binding assay and were found to be of low affinity. However, norarachidonyl urea analogues 4 have shown generally good binding affinities to the CB1 receptor (K-i = 55-746 nM) and pharmacological activity with AN-like profiles. The most potent analogue of this series is the 2-fluoroethyl analogue 4f which binds 2 times better than AN and was more active in several mouse behavioral assays. It was also observed that urea analogues 4a and 4g, which have weak binding affinities to the CBI receptor (K-i = 436 and 347 nM, respectively), produced surprisingly potent pharmacological activity. These urea analogues have also shown hydrolytic stability toward the amidase enzymes, responsible

关键词：花生四烯酸类/化学合成花生四烯酸类/化学花生四烯酸类/代谢花生四烯酸类/药理学体温/药物作用大麻酚类/代谢氨甲酸酯类/化学合成氨甲酸酯类/化学氨甲酸酯类/代谢氨甲酸酯类/药理学水解作用配体运动活动/药物作用多不饱和脂肪酸酰胺类放射配体测定受体大麻酚受体药物/代谢构效关系尿素/类似物和衍生物动物小鼠

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PRECIPITATION OF ABSTINENCE-LIKE SYNDROME IN MORPHINE-DEPENDENT MICE BY PARGYLINE

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1976年第2期199卷 400-407页

作者： WAY, EL IWAMOTO, ET KHANNA, S HO, IK SHEN, F LOH, HH UNIV CALIF SAN FRANCISCO MED CTR SCH MED DEPT PHARMACOL SAN FRANCISCO CA 94143 USA

In mice rendered morphine-dependent by pellet implantation for 3 days, the administration of pargyline 6 h after pellet removal intensified narcotic abstinence behavior, particularly the narcotic withdrawal jumping response. Pargyline, 75 mg/kg i.p., caused a 6 to 9-fold increase in the incidence of jumping in mice withdrawing from morphine 6 h after removal of the pellet, whereas this effect was not observed 1 h after the injection of pargyline or in animals still implanted with the morphine pellet. The median effective dose (ED50) of pargyline required to elicit withdrawal jumping in mice implanted with morphine decreased with increasing physical dependence. The ED50 for 72 h .apprx. 1/6 that after 24 h of implantation. Additionally, pargyline potentiated naloxone-precipitated withdrawal jumping as evidenced by a reduction of naloxone ED50 by .apprx. 1/2. Administration of other monoamine oxidase inhibitors such as pheniprazine, iproniazid or tranylcypromine failed to alter the incidence of jumping in dependent mice undergoing abrupt morphine withdrawal. Dopamine receptor stimulation by amphetamine, pheniprazine or amantadine antagonized the pargyline-induced jumping response. The increased incidence of withdrawal jumping observed after pargyline in morphine-dependent mice was probably not related to monoamine oxidase inhibition but rather to a possible pargyline-induced decrease in dopaminergic activity.

关键词：金刚烷胺/药理学苯丙胺/药理学行为动物/药物作用剂量效应关系药物药物协同作用肼类/药理学异丙烟肼/药理学小鼠近交ICR 吗啡依赖/病理生理学运动活动/药物作用纳洛酮/药理学帕吉林/药理学物质戒断综合征/化学诱导时间因素反苯环丙铵/药理学动物人类男(雄)性小鼠

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SPONTANEOUS AND AMPHETAMINE INDUCED HEAD-SHAKING IN INFANT RATS

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PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR 1976年第1期5卷 23-28页

作者： HOLMGREN, B URBAHOLMGREN, R VALDES, M CTR NACL INVEST CIENT LA HABANA CUBA

A variable proportion of albino rats 6-11 days old exhibit spontaneous and infrequent rotatory head-shaking episodes. This motor pattern is slightly anticipated and significantly increased in occurrence and duration by the administration of D-amphetamine (5 mg/kg), with a maximal effect of the drug on the 9th day. The rate of amphetamine induced rhythmic head oscillations increases with age from below 5 cps on the 5th day to about 9 cps on the 10th day. The results are discussed in relation to maturation of both the underlying catecholaminergic pathways, activated by D-amphetamine, and the stretch reflex systems of the head and neck muscles participating in the rhythmic activity. Emphasis is placed on the difference between head-shaking and stereotyped activity.

关键词：衰老动物新生/生理学行为/生理学右苯丙胺/药理学剂量效应关系药物运动活动/药物作用大鼠/生长和发育大鼠/生理学刻板行为/药物作用刻板行为/生理学时间因素动物女(雌)性人类男(雄)性

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SELECTIVE 6OHDA-INDUCED DESTRUCTION OF MESOLIMBIC DOPAMINE NEURONS - ABOLITION OF PSYCHOSTIMULANT-INDUCED LOCOMOTOR-ACTIVITY IN RATS

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EUROPEAN JOURNAL OF PHARMACOLOGY 1976年第1期40卷 45-56页

作者： KELLY, PH IVERSEN, SD UNIV CAMBRIDGE DEPT EXPTL PSYCHOL CAMBRIDGE ENGLAND

Selective large scale destruction of mesolimbic dopamine-containing terminals was produced by bilateral injection of 8 .mu.g of 6-hydroxydopamine (6OHDA) into the nucleus accumbens septi (NAS) of rats pretreated with pargyline and desipramine (DMI). DMI prevented the destruction of the noradrenergic innervation of the forebrain normally produced by the NAS 6OHDA lesion, without affecting the destruction of dopamine-containing neurons. The locomotor stimulation produced by the psychostimulants d-amphetamine (1.5 mg/kg) and cocaine (20 mg/kg) was blocked with selective destruction of the mesolimbic dopamine system. The locomotor stimulation produced by the directly acting dopamine agonist apomorphine (1.0 mg/kg) was enhanced, which may indicate supersensitivity of the denervated dopamine receptors. The view that psychostimulant-induced locomotor stimulation results from effects on mesolimbic dopamine neurons was supported. The protection by DMI of noradrenergic neurons from the toxic effects of 6OHDA is evidence that 6OHDA, as used here, destroys catecholamine neurons mainly by an uptake-dependent specific mechanism.

关键词：苯丙胺/药理学阿朴吗啡/药理学可卡因/药理学地昔帕明/药理学羟基多巴胺类/药理学边缘系统/药物作用运动活动/药物作用帕吉林/药理学受体多巴胺/药物作用刻板行为/药物作用刺激化学性动物人类男(雄)性大鼠

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Pretreatment with fragments of substance-P or with cholecystokinin differentially affects recovery from sub-total nigrostriatal 6-hydroxydopamine lesion

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NEURAL PLASTICITY 1999年第4期6卷 77-89页

作者： Nikolaus, S Huston, JP Schwarting, RKW Univ Dusseldorf Inst Phys Psychol 1 D-40225 Dusseldorf Germany

The neuropeptide substance P is known to have mnemogenic and reinforcing actions and can exert neurotrophic and regenerative effects in vitro as well as in vivo. Furthermore, our previous work in the rat showed that either pre- or post-lesion treatment with substance P can promote functional recovery in cases of partial nigrostriatal dopamine lesions, other work has provided evidence that the effects of substance P might be differentially encoded by its C- and N-terminal fragments, The C-terminal fragment was found to be reinforcing, whereas the mnemogenic as well as neurotrophic properties have been ascribed to the N-terminal sequences. Given these relations, we asked here whether pre-lesion treatment with either a C- or an N-terminal fragment of substance P might differentially affect the behavioral and neurochemical outcome of nigrostriatal dopamine lesions, Therefore, either substance P1-7 or substance P5-11 (37 nmol/kg each) was administered intraperitoneally daily for eight consecutive days before unilateral 6-hydroxy-dopamine lesions of the substantia nigra, Control rats received prelesion treatment with vehicle. Furthermore, we investigated the effects of pre-treatment with Boc-cholecystokinin-4 (0.91 nmol/kg), as we had found an increase in dopamine metabolism in animals that were pre-treated with cholecystokinin-8 in a former study. In accordance with our previous work, drug treatment effects were observed when excluding animals with most severe dopamine lesions: In animals with partial lesions (residual neostriatal dopamine levels of more than 10%), lesion-dependent asymmetries in turning behavior were observed in animals that were pre-treated with vehicle-, substance P1-7, or Boc-cholecysto-kinin-4, whereas fuming after pre-treatment with substance P5-11 was not significantly asymmetrical, Furthermore, the ipsi- and contra-lateral neostriatal dopamine levels did not differ significantly in this group, Moreover, pretreatment with substance P5-11 affected

关键词：纹状体/药物作用纹状体/病理学纹状体/生理学多巴胺/代谢功能偏侧化运动活动/药物作用羟多巴胺/毒性肽碎片/药理学吡咯烷酮羧酸/类似物和衍生物大鼠 Wistar P物质/类似物和衍生物 P物质/药理学黑质/药物作用黑质/病理学黑质/生理学四肽胃泌素/类似物和衍生物四肽胃泌素/药理学动物男(雄)性大鼠

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INTERACTION BETWEEN ENDOGENOUS OPIOIDS AND DOPAMINE WITHIN THE NUCLEUS-ACCUMBENS

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ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 1992年第1期654卷 254-273页

作者： STINUS, L CADOR, M LEMOAL, M Laboratoire de Psychobiologie des Comportements Adaptatifs INSERM U. 259 Universit&eacute de Bordeaux II Domaine de Carreire-Rue Camille Saint-Sa&euml ns 33077 Bordeaux Cedex France

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