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Interactions between distinct GABA_A circuits in hippocampus

NEURON 2000年第2期25卷 449-457页

作者： Banks, MI White, JA Pearce, RA Univ Wisconsin Dept Anesthesiol Madison WI 53706 USA Boston Univ Dept Biomed Engn Boston MA 02215 USA

Synchronous activity among synaptically connected interneurons is thought to organize temporal patterns such as gamma and theta rhythms in cortical circuits. Interactions between distinct interneuron circuits may underlie more complex patterns, such as nested rhythms. Here, we demonstrate such an interaction between two groups of CA1 interneurons, GAB(A,) (slow) and GABA(A,fast) cells, that may contribute to theta and gamma rhythms, respectively. Stratum lacunosum-moleculare (SL-M) stimuli that activate GABA(A,slow) inhibitory postsynaptic currents (IPSCs) in pyramidal cells simultaneously depress the rate and amplitude of spontaneous GABA(A,fast) IPSCs for several hundred milliseconds. This suppression has a similar pharmacological profile to GABA(A,slow) IPSCs, and SL-M stimuli elicit GABA(A,slow) IPSCs in interneurons. We conclude that GABA(A,slow) cells inhibit both pyramidal cells and GABA(A,fast) interneurons and postulate that this interaction contributes to nested theta/gamma rhythms in hippocampus.

关键词：计算机模拟海马/细胞学中间神经元/化学中间神经元/细胞学中间神经元/代谢膜电位/药物作用膜电位/生理学模型神经学神经抑制/生理学神经通路/生理学神经递质摄取抑制药/药理学哌啶甲酸类/药理学肟类/药理学膜片钳术锥体细胞/化学锥体细胞/细胞学锥体细胞/代谢受体 GABA-A/生理学 θ节律 γ氨基丁酸/代谢动物大鼠

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Identification and characterization of the high-affinity choline transporter

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NATURE NEUROSCIENCE 2000年第2期3卷 120-125页

作者： Okuda, T Haga, T Kanai, Y Endou, H Ishihara, T Katsura, I Univ Tokyo Fac Med Dept Neurochem Bunkyo Ku Tokyo 1130033 Japan Japan Sci & Technol Corp CREST Bunkyo Ku Tokyo 1130033 Japan Kyorin Univ Sch Med Dept Pharmacol & Toxicol Tokyo 1818611 Japan Japan Sci & Technol Corp PRESTO Tokyo 1818611 Japan Grad Univ Adv Studies Sch Life Sci Dept Genet Mishima Shizuoka 4118540 Japan Grad Univ Adv Studies Natl Inst Genet Struct Biol Ctr Mishima Shizuoka 4118540 Japan

In cholinergic neurons, high-affinity choline uptake in presynaptic terminals is the rate-limiting step in acetylcholine synthesis. Using information provided by the Caenorhabditis elegans Genome Project, we cloned a cDNA encoding the high-affinity choline transporter from C. elegans (cho-1). We subsequently used this clone to isolate the corresponding cDNA from rat (CHT1). CHT1 is not homologous to neurotransmitter transporters, but is homologous to members of the Na+-dependent glucose transporter family. Expression of CHT1 mRNA is restricted to cholinergic neurons. The characteristics of CHT1-mediated choline uptake essentially match those of high-affinity choline uptake in rat brain synaptosomes.

关键词：氨基酸序列结合竞争性/药物作用 CHO细胞新小杆线虫漂亮载体蛋白质类/化学载体蛋白质类/遗传学载体蛋白质类/代谢细胞膜/代谢胆碱/代谢胆碱/药代动力学克隆分子仓鼠亚科 DNA 互补/遗传学半胆碱3/药理学膜转运蛋白质类分子序列数据单糖转运蛋白质类/遗传学神经元/代谢神经递质摄取抑制药/药理学卵母细胞/细胞学卵母细胞/代谢器官特异性种系发生 RNA 信使/生物合成序列同源性氨基酸钠/代谢动物大鼠

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Methamphetamine dependence: Medication development efforts based on the dual deficit model of stimulant addiction

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NEUROBIOLOGICAL MECHANISMS OF DRUGS OF ABUSE: COCAINE, IBOGAINE, AND SUBSTITUTED AMPHETAMINES 2000年第1期914卷 71-81页

作者： Rothman, RB Partilla, JS Dersch, CM Carroll, FI Rice, KC Baumann, MH NIDA Clin Psyhcopharmacol Sect Intramural Res Program DIRNIH Baltimore MD 21224 USA Res Triangle Inst Res Triangle Pk NC 27709 USA NIDDK Med Chem Lab NIH Bethesda MD 20892 USA

Converging lines of evidence indicate that withdrawal from prolonged exposure to stimulants and alcohol results in synaptic deficits of both dopamine (DA) and serotonin (5-HT). According to the dual deficit model proposed by the authors, DA dysfunction during cocaine or alcohol withdrawal underlies anhedonia and psychomotor retardation, whereas 5-HT dysfunction gives rise to depressed mood, obsessional thoughts, and lack of impulse control. This model predicts that pharmacotherapies which correct only one of the two neurochemical deficits will not be effective. On the other hand, pharmacotherapies which "correct" both of the proposed DA and 5-HT abnormalities should be effective in treating stimulant and alcohol dependence. This paper reviews two approaches, based on the dual deficit model, taken by our laboratory to develop medications to treat stimulant abuse.

关键词：行为成瘾/化学诱导行为成瘾/代谢生物胺类/药代动力学疾病模型动物剂量效应关系药物药物相互作用半数抑制浓度甲基苯丙胺/毒性神经递质摄取抑制药/药理学突触体/药物作用突触体/代谢氚/药代动力学动物大鼠

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Effect of ω-conotoxin GVIA on noradrenaline release from postganglionic sympathetic neurones in rabbit aorta

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PHARMACOLOGY & TOXICOLOGY 2000年第1期86卷 30-35页

作者： Nedergaard, OA Odense Univ Sch Med Dept Pharmacol DK-5000 Odense C Denmark

The aim of the present work was to examine the effect of the selective N-type calcium blocking agent omega-conotoxin GVIA on stimulation-evoked release of noradrenaline from sympathetic nerves in rabbit isolated aorta with regard to stimulation frequency, extracellular Ca2+ concentration, and transmitter uptake. Rings of rabbit isolated aorta were preloaded with (-)-H-3-noradrenaline and the fractional H-3-overflow evoked by electrical-field stimulation was determined by liquid scintillation spectrometry. omega-Conotoxin GVIA (3 x 10(-10) - 3 x 10(-8) M) did not alter the spontaneous H-3-outflow omega-Conotoxin GVIA (3 x 10(-10) - 3 x 10(-8) M) caused a slowly developing reduction of stimulation-evoked H-3-overflow at 1 and 30 Hz. The Emax for the omega-conotoxin-induced inhibition was less (70%) at 30 Hz than that (96%) seen at 1 Hz. Short-term incubation with omega-conotoxin GVIA caused a subsequent steady-state inhibition. The inhibitory action of omega-conotoxin GVIA (3 x 10(-10) - 3 x 10(-9) M) was inversely related to the extracellular Ca2+ concentration (6.5 X 10(-4) - 2.7 x 10(-3) M). Cocaine (3 x 10(-5) M) plus corticosterone (4 x 10(-5) M), neuronal and extraneuronal uptake inhibitors, respectively, did not alter the inhibitory effect of omega-conotoxin GVIA (3 x 10(-9) M) on H-3-overflow evoked by stimulation at a frequency of either 1 or 30 Hz. It is concluded that omega-conotoxin GVIA acts on prejunctional N-type calcium channels to inhibit stimulation-evoked noradrenaline release from sympathetic neurone terminals in rabbit aorta. At a high frequency, another subtype calcium channel may possibly be involved. The action of omega-conotoxin GVIA is independent of neuronal and extraneuronal uptake mechanisms for noradrenaline, but dependent on the amount of Ca2+ to be transported across the neurilemma from the extracellular space into the neurone.

关键词：主动脉胸/神经支配钙/代谢钙/生理学钙通道阻滞药/药理学钙通道 L型/生理学可卡因/药理学皮质酮/药理学剂量效应关系药物电刺激神经元/药物作用神经元/分泌神经递质摄取抑制药/药理学去甲肾上腺素/分泌交感神经纤维节后/药物作用交感神经纤维节后/分泌氚 ω蜗牛毒素GVIA/药理学动物女(雌)性男(雄)性兔

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Increased mesolimbic GABA concentration blocks heroin self-administration in the rat

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期294卷 613-619页

作者： Xi, ZX Stein, EA Med Coll Wisconsin Dept Cell Biol Neurobiol & Anat Milwaukee WI 53226 USA Med Coll Wisconsin Dept Psychiat & Behav Med Milwaukee WI 53226 USA Med Coll Wisconsin Dept Pharmacol & Toxicol Milwaukee WI 53226 USA Med Coll Wisconsin Biophys Res Inst Milwaukee WI 53226 USA

Opiate reinforcement has been hypothesized to be mediated by an inhibition of mesolimbic gamma-aminobutyric acid (GABA) release that subsequently disinhibits ventral tegmental area (VTA) dopamine neurons. In support of this hypothesis, this study demonstrates that when administered directly into the lateral ventricle, the VTA, or the ventral pallidum, but not the nucleus accumbens, gamma-vinyl-GABA (GVG, an irreversible GABA-transaminase inhibitor, 20-50 mu g) dose dependently blocked heroin (0.06 mg/kg) self-administration (SA), as assessed by an increase in heroin SA at low doses of GVG and an initial increase followed 1 to 2 h later by a blockade of heroin SA at higher GVG doses. This effect lasted 3 to 5 days. In drug-naive rats, intra-VTA GVG pretreatment also prevented or delayed acquisition of heroin SA for 2 days. This GVG effect was prevented or reversed by systemic or intra-VTA pretreatment with the GABA(B) antagonist 2-hydroxysaclofen, but not the GABA(A) antagonist bicuculline. Similarly, coadministration of heroin with aminooxy-acetic acid (1-4 mg/kg) or ethanolamine-O-sulfate (50-100 mg/kg), two reversible GABA transaminase inhibitors, dose dependently reduced heroin reinforcement. Coadministration of (+/-)-nipecotic acid (0.1-5 mg/kg) with heroin, or intra-VTA or -ventral pallidum pretreatment with (+/-)-nipecotic acid (10 mu g) or NO-711 (2 mu g), two GABA uptake inhibitors, significantly increased heroin SA behavior, an effect also blocked by systemic 2-hydroxysaclofen, but not bicuculline. Taken together, these experiments, for the first time, demonstrate that pharmacological elevation of mesolimbic GABA concentration blocks heroin reinforcement by activating GABA(B) receptors, supporting the GABAergic hypothesis of opiate reinforcement and the incorporation of GABA agents in opiate abuse treatment.

关键词： 4-氨基丁酸转氨酶/拮抗剂和抑制剂巴氯芬/类似物和衍生物巴氯芬/药理学行为动物/药物作用荷包牡丹碱/药理学酶抑制剂/药理学 GABA拮抗剂/药理学苍白球/药物作用苍白球/代谢海洛因/投药和剂量注射脑室内侧脑室/药物作用侧脑室/代谢微量注射麻醉品/投药和剂量神经递质摄取抑制药/药理学伏核/药物作用伏核/代谢阿片相关性障碍/药物疗法阿片相关性障碍/代谢阿片相关性障碍/病理生理学大鼠 Sprague-Dawley 受体 GABA-A/拮抗剂和抑制剂受体 GABA-B/拮抗剂和抑制剂自我遵嘱服药端脑/药物作用端脑/代谢腹侧被盖区/药物作用腹侧被盖区/代谢氨己烯酸/药理学 γ氨基丁酸/代谢 γ氨基丁酸/生理学动物男(雄)性大鼠

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Visual input induces long-term potentiation of developing retinotectal synapses

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NATURE NEUROSCIENCE 2000年第7期3卷 708-715页

作者： Zhang, LI Tao, HW Poo, M Univ Calif San Diego Dept Biol La Jolla CA 92093 USA

Early visual experience is essential in the refinement of developing neural connections. In vivo whole-cell recording from the tectum of Xenopus tadpoles showed that repetitive dimming-light stimulation applied to the contralateral eye resulted in persistent enhancement of glutamatergic inputs, but not GABAergic or glycinergic inputs, on tectal neurons. This enhancement can be attributed to potentiation of retinotectal synapses. It required spiking of postsynaptic tectal cells as well as activation of NMDA receptors, and effectively occluded long-term potentiation (LTP) of retinotectal synapses induced by direct electrical stimulation of retinal ganglion cells. Thus, LTP-like synaptic modification can be induced by natural visual inputs and may be part of the underlying mechanism for the activity-dependent refinement of developing connections.

关键词： 2-氨基-5-膦酰基戊酸盐/药理学 6-氰-7-硝基喹喔啉-2 3-二酮/药理学荷包牡丹碱/类似物和衍生物荷包牡丹碱/药理学二羧酸类/药理学光长时程增强/药物作用长时程增强/生理学神经元/药物作用神经元/生理学神经递质摄取抑制药/药理学光刺激吡咯烷类/药理学视网膜/生理学突触/药物作用突触/生理学视通路/生理学视知觉/生理学爪蟾属动物

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An enantioselective synthesis and biobehavioral evaluation of 7-fluoro-3-(p-fluorophenyl)-2-propyltropanes

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2000年第13期10卷 1443-1446页

作者： Prakash, KRC Trzcinska, M Johnson, KM Kozikowski, AP Georgetown Univ Med Ctr Inst Cognit & Computat Sci Drug Discovery Program Washington DC 20007 USA Northeastern Univ Dept Psychol Boston MA 02115 USA Univ Texas Med Branch Dept Pharmacol & Toxicol Galveston TX 77555 USA

Optically pure 7-fluorotropanes 3a-c, were synthesized as structural probes of the dopamine transporter. The synthesis of these compounds was accomplished through the asymmetric 1,3-dipolar cycloaddition reaction of the oxidopyridinium betaine 4 with the chiral dipolarophile (R)-p-tolyl vinyl sulfoxide. In the preliminary analysis, tropane 3a was found to reduce the rewarding effects of cocaine in the brain stimulation reward paradigm. (C) 2000 Elsevier Science Ltd, All rights reserved.

关键词：行为动物/药物作用生物转运脑/药物作用脑/代谢载体蛋白质类/代谢可卡因/类似物和衍生物可卡因/代谢多巴胺/代谢多巴胺质膜转运蛋白质类药物设计配体马吲哚/化学马吲哚/代谢膜糖蛋白类膜转运蛋白质类分子探针分子结构神经组织蛋白质类神经递质摄取抑制药/药理学去甲肾上腺素/代谢放射配体测定奖励血清素/代谢托烷类/化学合成动物大鼠

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