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Circadian modulation of dopamine receptor responsiveness in Drosophila melanogaster

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第4期97卷 1873-1878页

作者： Andretic, R Hirsh, J Univ Virginia Dept Biol Charlottesville VA 22903 USA

We investigated the circadian function of Drosophila dopamine receptors by using a behaviorally active decapitated preparation that allows for direct application of drugs to the nerve cord. Quinpirole, a D2-like dopamine receptor agonist, induces reflexive locomotion in decapitated flies. We show that the amount of locomotion induced changes as a function of the time of day, with the highest responsiveness to quinpirole during the subjective night. Furthermore, dopamine receptor responsiveness is under circadian control and depends on the normal function of the period gene. The head pacemaker is at least partly dispensable for the circadian modulation of quinpirole-induced locomotion, because changes in agonist responsiveness persist in decapitated flies that are aged for 12 h, This finding suggests a role for the period-dependent molecular oscillators in the body in the modulation of amine receptor responsiveness.

关键词：昼夜节律/生理学多巴胺激动剂/药理学果蝇蛋白质类黑腹果蝇/代谢行走/药物作用核蛋白质类/遗传学周期昼夜节律蛋白质类喹吡罗/药理学受体多巴胺/代谢动物

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Coding of locomotor phase in populations of neurons in rostral and caudal segments of the neonatal rat lumbar spinal cord

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JOURNAL OF NEUROPHYSIOLOGY 1999年第6期82卷 3563-3574页

作者： Tresch, MC Kiehn, O Univ Copenhagen Panum Inst Sect Neurophysiol Dept Physiol DK-2200 Copenhagen N Denmark

Several experiments have demonstrated that rostral segments of the vertebrate lumbar spinal cord produce a rhythmic motor output more readily and of better quality than caudal segments. Here we examine how this rostrocaudal gradient of rhythmogenic capability is reflected in the spike activity of neurons in the rostral (L-2) and caudal (L-5) lumbar spinal cord of the neonatal rat. The spike activity of interneurons in the ventromedial cord, a region necessary for the production of locomotion, was recorded intracellularly with patch electrodes and extracellularly with tetrodes during pharmacologically induced locomotion. Both L-2 and L-5 neurons tended to be active in phase with their homologous ventral root. L-5 neurons, however, had a wider distribution of their preferred phases of activity throughout the locomotor cycle than L-2 neurons. The strength of modulation of the activity of individual L-2 neurons was also larger than that of L-5 neurons. These differences resulted in a stronger rhythmic signal from the L-2 neuronal population than from the L-5 population. These results demonstrate that the rhythmogenic capability of each spinal segment was reflected in the activity of interneurons located in the same segment. In addition to paralleling the rostrocaudal gradient of rhythmogenic capability, these results further suggest a colocalization of motoneurons and their associated interneurons involved in the production of locomotion.

关键词：动作电位/药物作用动作电位/生理学动物新生/生理学数据库事实型电刺激电生理学兴奋性氨基酸激动剂/药理学中间神经元/药物作用中间神经元/生理学行走/药物作用行走/生理学膜电位/药物作用膜电位/生理学微电极 N-甲基天冬氨酸/药理学膜片钳术血清素/药理学脊髓/细胞学脊髓/药物作用脊髓/生理学脊神经根/细胞学脊神经根/药物作用脊神经根/生理学动物大鼠

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Differential behavioural effects of chronic infusion of CRH1 and CRH2 receptor antisense oligonucleotides into the rat brain

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JOURNAL OF PSYCHIATRIC RESEARCH 1999年第2期33卷 153-163页

作者： Liebsch, G Landgraf, R Engelmann, M Lörscher, P Holsboer, F Max Planck Inst Psychiat D-80804 Munich Germany

The purpose of this study was to investigate the functional role the two corticotropin-releasing hormone (CRH) receptor subtypes play in regulating the behavioural performance of rats in various well-defined test situations. Antisense oligodeoxynucleotides (ODNs) corresponding to either the rat CRH1 or CRH2 receptor mRNA were infused chronically into the lateral ventricle of male rats via osmotic minipumps (5 mu g/0.5 mu l/h over 6 days). Control groups received infusions of either a scrambled sequence ODN or mixed bases ODN or vehicle. On day 4 after surgery, the rats were subjected to 10 min of social defeat and immediately afterwards tested on the elevated plus-maze. Compared to a scrambled sequence control ODN, CRH1 receptor antisense ODN infusion was found to exert an anxiolytic-like effect whereas CRH2 receptor antisense ODN infusion had no effect on defeat-induced anxiety-related behaviour. In contrast, the CRH2 receptor antisense ODN increased immobility in a forced swim test whereas CRH1 receptor ODN-treated rats did not differ from controls. No influence of either ODN was found on general locomotor activity in an open field or on short-term memory performance in a social discrimination test. Furthermore, the CRH2 receptor antisense ODN did not affect spatial learning in a Morris water maze task. An additional experiment comparing a mixture of both missense ODNs and a vehicle control group confirmed that the former failed to induce non-specific (toxic) side effects, further substantiating the specificity of the respective antisense effects measured in this study. The results support the hypothesis that the two CRH receptor subtypes selectively mediate differential effects of endogenous CRH or CRH-related peptides at the brain level with the CRH1 receptor contributing predominantly to emotional behaviour and the CRH2 receptor being involved in the regulation of stress coping behaviour. (C) 1999 Elsevier Science Ltd. All rights reserved.

关键词：适应心理学行为动物/药物作用脑/药物作用行走/药物作用寡核苷酸类反义/药理学 RNA 信使/药物作用大鼠 Wistar 受体促肾上腺皮质素释放激素/血液受体促肾上腺皮质素释放激素/药物作用动物男(雄)性大鼠

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The effects of the 5-hydroxytryptamine_1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin on spontaneous activity, cocaine-induced hyperactivity and behavioral sensitization:: A microanalysis of locomotor activity

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期292卷 610-617页

作者： De la Garza, R Cunningham, KA Univ Texas Med Branch Dept Pharmacol & Toxicol Galveston TX 77555 USA

The influence of the 5-hydroxytryptamine(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT) on locomotor hyperactivity induced by the acute and chronic administration of cocaine was assessed. Horizontal activity was measured in the periphery and center of an open field test enclosure equipped with photobeams;vertical activity was also recorded. Peripheral hyperactivity induced by an acute administration of cocaine (10 or 20 mg/kg) was significantly enhanced by 0.2 mg/kg DPAT. In contrast, central and vertical activities were reduced in a dose-related manner by DPAT (0.1 and 0.2 mg/kg);DPAT also suppressed central (0.2 mg/kg) and vertical (0.1 and 0.2 mg/ kg) activities when administered alone. Similar observations were made on day 1 of chronic treatment with DPAT (0, 0.1, or 0.2 mg/kg) injected 15 min before an injection of cocaine (0, 10, or 15 mg/kg) administered twice daily for 7 days. By day 7 of repeated DPAT treatment, sensitization of DPAT-evoked peripheral activity developed, which contrasted with tolerance to the central and vertical hypoactivity evoked by DPAT. Sensitization developed to the repeated treatment with 15 mg/ kg cocaine but not 10 mg/kg cocaine. Interestingly, enhancements of all activity measures were observed between days 1 and 7 in rats cotreated with DPAT plus either dose of cocaine. This sensitization to DPAT plus cocaine was expressed on challenge with DPAT and cocaine but not with cocaine alone. The present study implies that the stimulation of 5-hydroxytryptamine(1A) receptors is capable of modulating the hyperactivity evoked by cocaine, possibly via modulation of the mesoaccumbens dopamine circuit thought to mediate the behavioral effects of cocaine.

关键词：行为动物/药物作用可卡因/药理学剂量效应关系药物药物相互作用运动过度/化学诱导行走/药物作用大鼠 Sprague-Dawley 血清素激动药/投药和剂量血清素激动药/药理学时间因素动物男(雄)性大鼠

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Behavioral activation induced by D₂-like receptor stimulation during opiate withdrawal

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期294卷 531-538页

作者： Druhan, JP Walters, CL Aston-Jones, G Univ Penn Med Ctr Ctr Neurobiol & Behav Dept Psychiat Philadelphia PA 19104 USA

Withdrawal is a potent motivator of drug-seeking behavior in human opiate addicts. Paradoxically, opiate withdrawal reduces dopamine release and suppresses behavioral responding in several animal models of addiction. These findings pose critical questions about how a withdrawal state that depresses dopaminergic and behavioral functioning contributes to drug seeking. This study addressed this issue by investigating factors that increase behavioral activity during opiate withdrawal. Initial experiments revealed that the D-2-like agonists propylnorapomorphine HCl (NPA;0.05-0.4 mg/kg, i.p.) and quinpirole (0.2-0.4 mg/kg, s.c.) each produced strong locomotor activating effects during opiate withdrawal that were not apparent in the absence of withdrawal. Concurrent stereotypy ratings indicated that these effects of NPA and quinpirole during withdrawal were not an indirect consequence of changes in the stereotypy-inducing effects of these drugs. Subsequent experiments showed that locomotion was not increased when opiate withdrawal was induced in the presence of the D-1-like agonist SKF 38393 (1.0-8.0 mg/kg, i.p.), that the locomotor activation produced by NPA during withdrawal could be attenuated by the D-2-like antagonist eticlopride (0.1-0.2 mg/kg, i.p.), and that locomotor activating effects of NPA could be observed when withdrawal was induced by extracting the implanted morphine pellets, but not when the NPA was given after naltrexone antagonism of acute morphine treatment in nondependent rats. These findings indicate that opiate withdrawal regulates the behavioral impact of D-2-like receptor stimulation so that locomotion is markedly increased when these receptors are stimulated during periods of withdrawal. This potentiation may be important for facilitating behavioral responses during periods of opiate detoxification.

关键词：镇痛药阿片类/拮抗剂和抑制剂阿朴吗啡/类似物和衍生物阿朴吗啡/药理学行为动物/药物作用行为动物/生理学多巴胺激动剂/药理学多巴胺拮抗剂/药理学药物协同作用行走/药物作用行走/生理学吗啡/拮抗剂和抑制剂吗啡依赖/病理生理学纳曲酮/药理学麻醉品拮抗药/药理学大鼠 Sprague-Dawley 受体多巴胺D2/激动剂受体多巴胺D2/生理学刻板行为/药物作用刻板行为/生理学物质戒断综合征/病因学物质戒断综合征/病理生理学动物男(雄)性大鼠

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Spike coding during locomotor network activity in ventrally located neurons in the isolated spinal cord from neonatal rat

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JOURNAL OF NEUROPHYSIOLOGY 2000年第5期83卷 2825-2834页

作者： Raastad, M Kiehn, O Univ Copenhagen Panum Inst Sect Neurophysiol Dept Neurophysiol DK-2200 Copenhagen N Denmark

To characterize spike coding in spinal neurons during rhythmic locomotor activity, we recorded from individual cells in the lumbar spinal cord of neonatal rats by using the on-cell patch-clamp technique. Locomotor activity was induced by N-methyl-D aspartate (NMDA) and 5-hydroxytryptamine (5-HT) and monitored by ventral root recording. We made an estimator based on the assumption that the number of spikes arriving during two halves of the locomotor cycle could be a code used by the neuronal network to distinguish between the halves. This estimator, termed the spike contrast, was calculated as the difference between the number of spikes in the most and least active half of an average cycle. The root activity defined the individual cycles and the positions of the spikes were calculated relative to these cycles. By comparing the average spike contrast to the spike contrast in noncyclic, randomized spike trains we found that approximately one half the cells (19 of 42) contained a significant spike contrast, averaging 1.25 +/- 0.23 (SE) spikes/cycle. The distribution of spike contrasts in the total population of cells was exponential, showing that weak modulation was more typical than strong modulation. To investigate if this low spike contrast was misleading because a higher spike contrast averaged out by occurring at different positions in the individual cycles we compared the spike contrast obtained from the average cycle to its maximal value in the individual cycles. The value was larger (3.13 +/- 0.25 spikes) than the spike contrast in the average cycle but not larger than the spike contrast in the individual cycles of a random, noncyclic spike trains (3.21 +/- 0.21 spikes). This result suggested that the important distinction between cyclic and noncyclic cells was only the repeated cycle position of the spike contrast and not its magnitude. Low spike frequencies (5.2 +/- 0.82 spikes/cycle, that were on average 3.5 s long) and a minimal spike interval of 100-200 ms

关键词：动作电位/生理学动物新生行走/药物作用行走/生理学 N-甲基天冬氨酸/药理学神经网/细胞学神经网/药物作用神经网/生理学神经元/细胞学神经元/药物作用神经元/生理学膜片钳术周期性血清素/药理学脊髓/细胞学脊髓/药物作用脊髓/生理学脊神经根/药物作用脊神经根/生理学动物大鼠

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Hindlimb locomotor and postural training modulates glycinergic inhibition in the spinal cord of the adult spinal cat

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JOURNAL OF NEUROPHYSIOLOGY 1999年第1期82卷 359-369页

作者： de Leon, RD Tamaki, H Hodgson, JA Roy, RR Edgerton, VR Univ Calif Los Angeles Dept Physiol Sci Los Angeles CA 90095 USA Univ Calif Los Angeles Brain Res Inst Los Angeles CA 90095 USA Natl Inst Fitness & Sports Dept Physiol Sci Kagoshima 89123 Japan

Adult spinal cats were trained initially to perform either bipedal hindlimb locomotion on a treadmill or full-weight-bearing hindlimb standing. After 12 wk of training, stepping ability was tested before and after the administration (intraperitoneal) of the glycinergic receptor antagonist, strychnine. Spinal cats that were trained to stand after spinalization had poor locomotor ability as reported previously, but strychnine administration induced full-weight-bearing: stepping in their hindlimbs within 30-45 min. in the cats that were trained to step after spinalization, full-weightbearing stepping occurred and was unaffected by strychnine. Each cat then was retrained to perform the other task;for 12 wk and locomotor ability was retested. The spinal cats that were trained initially to stand recovered the ability to step after they received 12 wk of treadmill training and strychnine was no longer effective in facilitating their locomotion. Locomotor ability declined in the spinal cats that were retrained to stand and strychnine restored the ability to step to the levels that were acquired after the step-training period. Based on analyses of hindlimb muscle electromyographic activity patterns and kinematic characteristics, strychnine improved the consistency of the stepping and enhanced the execution of hindlimb flexion during full-weight-hearing step cycles in the spinal cats when they were trained to stand but not when they were trained to step. The present findings provide evidence that 1) the neural circuits that generate full-weight-bearing hindlimb stepping are present in the spinal cord of chronic spinal cats that can and cannot step;however, the ability of these circuits to interpret sensory input to drive stepping is mediated at least in part by glycinergic inhibition;and 2) these spinal circuits adapt to the specific motor task imposed, and that these adaptations may include modifications in the glycinergic pathways that provide inhibition.

关键词：肌电描记术后肢/神经支配后肢/生理学行走/药物作用行走/生理学运动活动/药物作用运动活动/生理学肌骨骼/神经支配肌骨骼/生理学体位脊髓/生理学士的宁/药理学录像动物猫女(雌)性

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Intra-ventral tegmental area injection of rat cocaine and amphetamine-regulated transcript peptide 55-102 induces locomotor activity and promotes conditioned place preference

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期294卷 784-792页

作者： Kimmel, HL Gong, WH Dall Vechia, S Hunter, RG Kuhar, MJ Emory Univ Yerkes Reg Primate Res Ctr Atlanta GA 30329 USA

Cocaine- and amphetamine-regulated transcript (CART) is a novel mRNA that has been reported to be increased by acute psychostimulant administration, and that may be involved in the effects of psychostimulants. In this study, we examined the effect of centrally administered CART peptides on locomotor activity and conditioned place preference in the rat. CART peptide fragments were bilaterally injected into the ventral tegmental area. CART 55-102 (0.2-5.0 mu g/side), an endogenously occurring peptide, dose dependently increased locomotor activity, whereas CART 1-26 (0.1-2.5 mu g/side;not found endogenously) did not. The locomotor effects of CART 55-102 were dose dependently blocked by the dopamine D-2 receptor antagonist haloperidol (0.03-1.0 mg/kg i.p.). Four injections of 1.0 mu g/side CART 55-102 induced a significant place preference, suggesting that CART 55-102 is reinforcing. Increases in locomotor activity after each of these CART 55-102 injections were similar and did not show tolerance or sensitization. This treatment regimen of CART 55-102 also did not produce sensitization to locomotor activity after a subsequent challenge with cocaine or amphetamine. When CART 55-102 (0.2-1.0 mu g/side) was injected into the substantia nigra, no significant change in motor activity was observed. However, a higher dose of CART 55-102 (5.0 mu g/side) induced a delayed increase in motor activity, suggesting a possible diffusion from the substantia nigra into the ventral tegmental area. Our findings suggest that CART 55-102 is behaviorally active and may be involved in the actions of psychostimulants. This is the first demonstration of the psychostimulant-like effects of CART peptides.

关键词：选择行为/药物作用条件反射操作式/药物作用注射脑室内行走/药物作用运动活动/药物作用神经组织蛋白质类/投药和剂量肽碎片/投药和剂量大鼠 Sprague-Dawley 腹侧被盖区/解剖学和组织学腹侧被盖区/药物作用腹侧被盖区/生理学动物男(雄)性大鼠

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Fictive rhythmic motor patterns induced by NMDA in an in vitro brain stem-spinal cord preparation from an adult urodele

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JOURNAL OF NEUROPHYSIOLOGY 1999年第2期82卷 1074-1077页

作者： Delvolvé, I Branchereau, P Dubuc, R Cabelguen, JM INSERM EP9914 F-33077 Bordeaux France Univ Bordeaux 1 Lab Neurobiol Reseaux F-33405 Talence France CNRS F-33405 Talence France Univ Montreal Ctr Rech Sci Neurol Montreal PQ H3C 3J7 Canada

An in vitro brain stem-spinal cord preparation from an adult urodele (Pleurodeles waltl) was developed in which two fictive rhythmic motor patterns were evoked by bath application of N-methyl-D-aspartate (NMDA;2.5-10 mu M) with D-serine (10 mu M). Both motor patterns displayed left-right alternation. The first pattern was characterized by cycle periods ranging between 2.4 and 9.0 s (4.9 +/- 1.2 s, mean +/- SD) and a rostrocaudal propagation of the activity in consecutive ventral roots. The second pattern displayed longer cycle periods (8.1-28.3 s;14.2 +/- 3.6 s) with a caudorostral propagation. The two patterns were inducible after a spinal transection at the first segment. Preliminary experiments on small pieces of spinal cord further suggested that the ability for rhythm generation is distributed along the spinal cord of this preparation. This study shows that the in vitro brain stem-spinal cord preparation from Pleurodeles waltl may be a useful model to study the mechanisms underlying the different axial motor patterns and the flexibility of the neural networks involved.

关键词：脑干/药物作用行走/药物作用 N-甲基天冬氨酸/药理学神经网/药物作用周期性肋突螈属脊髓/药物作用动物

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Effects of lead on birds (Laridae): A review of laboratory and field studies

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JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART B-CRITICAL REVIEWS 2000年第2期3卷 59-78页

作者： Burger, J Gochfeld, M Univ Med & Dent New Jersey Robert Wood Johnson Med Sch Div Life SciEnvironm & Occupat Hlth Sci Inst Consortium Risk Evaluat Stakeholder Participat Piscataway NJ 08854 USA

Lead is one of the most common metals in contaminated ecosystems. Although lead poisoning and mortality have long been known, little is known of the behavioral effects produced by low levels of lead in wild animals. Herein a 15-yr research program on the behavioral effects of lead using herring gulls (Larus argentatus) and common terns (Sterna hirundo), referred to as larids, as models is reviewed. The doses used in laboratory studies were sufficient to produce lead concentrations in feathers that were equivalent to those found in some birds living in the wild. The exposure consisted of a single or multiple intraperitoneal lip) injection of lead acetate. Both dose and day of exposure influenced behavioral development in young larids, with most effects increasing with dose, and decreasing with age. Low-level lead affected growth, locomotion, balance, food begging, feeding thermoregulation, depth perception, and individual recognition in laboratory and in wild birds. The accuracy of individual recognition was most affected by lead exposure from 2 to 6 d of age;exposure at 12 d did not affect accuracy, but it delayed response time significantly. Behavioral deficits observed in lead-injected young in the wild were similar to those observed in the laboratory, except that recovery was more complete by fledging than it was in laboratory-raised chicks. Further, parents in the wild were able to provision lead-exposed chicks sufficiently so that they fledged at similar weights as control chicks, a feat that is difficult to achieve in the laboratory. The lead-induced behavioral deficits observed in the laboratory and in the wild are sufficient to affect growth and survival in wild herring gulls. Lead treatment altered the expression of cell adhesion molecules (CAMs), which play a crucial role in the formation and deployment of neurons in the developing brain. The timing and sequencing of CAM expression is critical to normal development, and the different consequences of lead e

关键词：动物野生行为动物/药物作用鸟类体温调节/药物作用脑/药物作用脑/生长和发育细胞黏附分子/生物合成环境暴露铅中毒/兽医学行走/药物作用动物

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