ATP敏感性钾通道与可卡因成瘾的相关性及埃他卡林作用的研究
|
摘要
药物成瘾可被定义为“一种不顾后果强迫性追求用药的行为”，已经成为严重危害人类健康的疾病之一，每年因成瘾死亡的人数众多，给社会带来巨大的损失，随着社会经济的发展，该严重的社会问题将显得尤为突出。可卡因是最常见的成瘾药物之一，它通过抑制三种单胺类转运体：多巴胺(dopamine，DA)、5-羟色胺和去甲肾上腺素能转运体，增强突触间的单胺类传递，其中对多巴胺转运体的抑制作用最强。大量的研究表明，中脑边缘系统内的神经回路与药物成瘾密切相关，其中伏隔核(NAc)及其来自腹侧背盖区(VTA)的多巴胺能神经纤维是研究的热点，其他脑区如杏仁核和额叶皮层(PFC)等边缘系统结构参与了神经回路的形成。DA和谷氨酸(glutamate，Glu)是该回路中最重要的两种神经递质，在成瘾的发生和发展过程中发挥重要作用。药物成瘾的确切机制至今还不十分清楚，目前也无理想药物治疗可卡因及其他药物成瘾。因此，对药物成瘾机制进行深入研究，能够为开拓新一代安全、有效的治疗药物提供有益的靶标。
ATP敏感性钾通道(ATP-sensitive possium channel，K_(ATP))是一类直接偶联细胞代谢活动与电活动的特殊钾离子通道，继1983年Noma在心脏首次发现K_(ATP)后，又先后在许多组织，包括血管平滑肌、胰腺β细胞和神经元等发现该通道，它一种是弱的内向整流K~+选择性通道。分子生物学和电生理学研究证实，K_(ATP)是一类由ABC(ATP-binding cassette，ABC)结合蛋白家族成员磺酰脲类受体(SUR)与内向整流钾通道(inwardly rectified potassium Channel，Kir)组成的异源性八聚体。目前已经克隆了2个Kir家族成员：Kir6.1和Kir6.2，以及2个SUR异构体：SUR1和SUR2。Kir是ATP的结合位点，决定通道的电导性，而SUR是磺脲类、钾通道开放剂和二磷酸核苷酸
南京医科大学硕士学位论文
（NDP户的结合部位。K。P在中枢神经系统不同区域广泛存在，可能发
挥重要的神经保护作用。众所周知，Gill和 DA在可卡因成痛过程中
占据重要地位。K。，可以调节 DA和o 的释放，K。，激动剂在理论
上有助于治疗可卡因成穗，但关于KATP通道和可卡因成痛相关性的
研究至今未见报道。
埃他卡林（iptakalim hydrochloride，IP）k一个由我国学者自行
设计和合成的脂肪仲胺类小分子新化合物，药理学、电生理学以及生
化学研究和受体结合试验Jb表明＊T具有K。，开放剂（。，oh删el
openers，KCOs）的特征。令人兴奋的是，IPT是目前唯一能够透过血
脑屏障的选择性KCOS，故可以通过系统给药方式进行研究。本实验
室已有的研究工作表明，IPT参与调节中枢o 和 DA的代谢。本文
研究工作从整体一递质一分子水平等多层次研究 IPT的作用，阐明
K。。通道与可卡因成痛的相关性，为IPT发展为治疗可卡因成痛的药
物积累学术与实验基础。
一、IPT对忘、馒性可卡囚引起的小么自主活劝以及大鼠脑内DA和
＊山合量变化的影响
1、IPT对急性可卡国引起的小鼠行为活劝变化的形响
目 的：在整体水平研究IPT对可卡因的作用的影响。方法与实砍分
缸：纯种昆明小鼠，雌雄各半，随机分为4组：1）对照组：腹腔注
射生理盐水20ml从g；2）可卡因处理组：腹腔注射可卡因30mg从g
3）1＊T单独处理组：腹腔注射1＊TO．乃二旮k巳4）1＊T干预组：腹腔
注射1＊TO．乃＊旮吨，5加n后再次腹腔注射可卡因30m旮吨。利用自
主活动箱测定小鼠给药前后的活动次数。结 果：急性给予可卡因o
llg／kZ，叫显著增加小鼠的自主活动（P＜0＊ 1，与对月组相上）；单独
给予 IPTo．75rug从g，lp）对小鼠的自主活动没有影响；预先给子 IPT
N．乃二卓吨，呐不影响急性可卡因引起的小鼠活动次数增加。结 沦：
在整体水平 IPT不影响急性给予可卡因引起的小鼠自主活动增加。
〕
南京医科大学顾士学位论文
入IPT对志性可卡因引起的大鼠脑内DA和GItl令量变化的形响
目 的：研究IPT对急性可卡因作用的大鼠伏隔核、纹状体和额
叶皮层的DA和＊ 含量变化的影响。
方法与实验分组：雄性SD大鼠，随机分为4组：1）对照组。
腹腔注射生理盐水2二l吨Z2）可卡因处理组：腹腔注射可卡因扣
mg／kg ； 3）IPT 0．75 mg／kg干预组：腹腔注射 IPT 0＊5 mg／kg s min
后再次腹腔注射可卡因 30 mg从g； 4）IvT．s mg从g ＋预组：腹腔注
射 IPT．5 mg从g，5 min后再次腹腔注射可卡因 30 mg从g。最后一次
给药后 30min处死动物，取出伏隔核、纹状体和额叶皮层，称重，匀
浆，AI。O。吸附法提取 DA，HCIO。酸化沉淀法提取0，利用高效液
相色谱（HPLC）结合电化学检测和荧光检测手段测定各脑区 DA和
Gill的含量。
sl：
1）急性给予可卡因 门 0 mgilig，…显著增加大鼠纹状体和伏隔
核的 DA含量，I匕对照组分另IJ提高了 23．6o和 25．lO（P＜0
Drug addiction remains one of the most serious threats to our nation's public health in terms of lost lives and productivity. Addiction can be defined as the loss of control over drug use, or the compulsive seeking and taking of drug regardless of the consequence. Cocaine is among the most commonly abused psychostimulants and inhibits all three monoamine transporters-dopamine (DA), serotonin, and norepinephrine, especially for dopamine transporter (DAT), thereby potentiating monoaminergic transmission. Underlying mechanism of cocaine addiction is not yet fully understood, however, substantial evidence indicates that several circuits in mesocorticolimbic systems, are known to mediate the addicting actions of cocaine. Most attention has been given to the nucleus accumbens (NAc) and its dopaminergic input from the ventral tegmental area (VTA) of the midbrain as key substrates for the drug effects. Other brain regions interact with the circuit, including the amygdala, prefrontal cortex (PFC) and other limbic reg
ions. DA and glutamate (Glu) are the most important neurotransmitiers in both the induction and the expression of cocaine sensitization. Available treatments for addiction remain inadequately effective for most individuals. Consequently, there is intense interest in better understanding the neurobiology of addiction in the hope that such knowledge will lead eventually to more effective treatments.
ATP sensitive potassium (KATp) channels were first described by Akinori Noma in the membrane of cardiac myocytes in 1983. Now it is known that KATP channels are widely expressed in many cell types including neurons. KATp channels consist of two types of subunits: an
inwardly rectifying K+ channel subunit (termed Kir) and a sulfonylurea receptor subunit (SUR), which is a member of the family of ATP-binding cassette transporter proteins. Up until now, two members of the Kir6 family, Kir6.1 and Kir6.2, and two SUR isoforms, SUR1 and SUR2, have been identified. The Kir is thought to confer ATP inhibition and determine conductance, whereas the SUR is considered the primary target for sulfonylureas, KATP channels opener (KCO), and nucleotide diphosphonate (NDP). The open probability of KATP channels directly depends on the intracellular ATP/ADP levels allowing the channels to directly couple the metabolic state of a cell to its electrical activity. KATP channels are distributed widely in brain and may play a critical role in neuroprotection as well as the regulation of DA and Glu transmission.
We developed a new compound iptkalim hydrochloride, which has been demonstrated to be a novel KATP channel opener by pharmacological, electrophysiological and biochemical studies, and receptor binding test. Notably, IPT is the only one of KCOs that can pass through blood-brain-barrier, which makes it possible to investigate its effects systematically. Previous studies in our lab have indicated that IPT was relevant to the regulation of DA and Glu release, the very two neurotransmitters playing a critical role in cocaine addiction. But there is no report on the relationship between KATP channels and cocaine addiction hitherto. In the present study, behavioral experiment, determination of neurotransmitters and molecular biology experiment were employed to investigate the correlation between KATP channels and cocaine addiction so as to obtain the basic evidence to develop IPT into a safe and effective therapeutic drug.
Part I. Effect of IPT on acute and chronic cocaine-induced enhancement of locomotor activity of mice and changes of DA and Glu levels in rat brain
1. Effect of IPT on acute cocaine-induced change of locomotor activity of mice
Aim: To investigate the effect of IPT on acute cocaine induced change of locomotor activity. Methods and Groups: Mice of either sex were divided into four groups: 1) control: saline 20 ml/kg ip; 2) cocaine group: cocaine 30 mg/kg ip; 3) IPT group: IPT 0.75mg/kg ip; 4) IPT plus cocaine group: IPT 0.75mg/kg 5 min later followed by cocaine 30 mg/kg ip. Behavioral activity w
ATP敏感性钾通道(ATP-sensitive possium channel，K_(ATP))是一类直接偶联细胞代谢活动与电活动的特殊钾离子通道，继1983年Noma在心脏首次发现K_(ATP)后，又先后在许多组织，包括血管平滑肌、胰腺β细胞和神经元等发现该通道，它一种是弱的内向整流K~+选择性通道。分子生物学和电生理学研究证实，K_(ATP)是一类由ABC(ATP-binding cassette，ABC)结合蛋白家族成员磺酰脲类受体(SUR)与内向整流钾通道(inwardly rectified potassium Channel，Kir)组成的异源性八聚体。目前已经克隆了2个Kir家族成员：Kir6.1和Kir6.2，以及2个SUR异构体：SUR1和SUR2。Kir是ATP的结合位点，决定通道的电导性，而SUR是磺脲类、钾通道开放剂和二磷酸核苷酸
南京医科大学硕士学位论文
（NDP户的结合部位。K。P在中枢神经系统不同区域广泛存在，可能发
挥重要的神经保护作用。众所周知，Gill和 DA在可卡因成痛过程中
占据重要地位。K。，可以调节 DA和o 的释放，K。，激动剂在理论
上有助于治疗可卡因成穗，但关于KATP通道和可卡因成痛相关性的
研究至今未见报道。
埃他卡林（iptakalim hydrochloride，IP）k一个由我国学者自行
设计和合成的脂肪仲胺类小分子新化合物，药理学、电生理学以及生
化学研究和受体结合试验Jb表明＊T具有K。，开放剂（。，oh删el
openers，KCOs）的特征。令人兴奋的是，IPT是目前唯一能够透过血
脑屏障的选择性KCOS，故可以通过系统给药方式进行研究。本实验
室已有的研究工作表明，IPT参与调节中枢o 和 DA的代谢。本文
研究工作从整体一递质一分子水平等多层次研究 IPT的作用，阐明
K。。通道与可卡因成痛的相关性，为IPT发展为治疗可卡因成痛的药
物积累学术与实验基础。
一、IPT对忘、馒性可卡囚引起的小么自主活劝以及大鼠脑内DA和
＊山合量变化的影响
1、IPT对急性可卡国引起的小鼠行为活劝变化的形响
目 的：在整体水平研究IPT对可卡因的作用的影响。方法与实砍分
缸：纯种昆明小鼠，雌雄各半，随机分为4组：1）对照组：腹腔注
射生理盐水20ml从g；2）可卡因处理组：腹腔注射可卡因30mg从g
3）1＊T单独处理组：腹腔注射1＊TO．乃二旮k巳4）1＊T干预组：腹腔
注射1＊TO．乃＊旮吨，5加n后再次腹腔注射可卡因30m旮吨。利用自
主活动箱测定小鼠给药前后的活动次数。结 果：急性给予可卡因o
llg／kZ，叫显著增加小鼠的自主活动（P＜0＊ 1，与对月组相上）；单独
给予 IPTo．75rug从g，lp）对小鼠的自主活动没有影响；预先给子 IPT
N．乃二卓吨，呐不影响急性可卡因引起的小鼠活动次数增加。结 沦：
在整体水平 IPT不影响急性给予可卡因引起的小鼠自主活动增加。
〕
南京医科大学顾士学位论文
入IPT对志性可卡因引起的大鼠脑内DA和GItl令量变化的形响
目 的：研究IPT对急性可卡因作用的大鼠伏隔核、纹状体和额
叶皮层的DA和＊ 含量变化的影响。
方法与实验分组：雄性SD大鼠，随机分为4组：1）对照组。
腹腔注射生理盐水2二l吨Z2）可卡因处理组：腹腔注射可卡因扣
mg／kg ； 3）IPT 0．75 mg／kg干预组：腹腔注射 IPT 0＊5 mg／kg s min
后再次腹腔注射可卡因 30 mg从g； 4）IvT．s mg从g ＋预组：腹腔注
射 IPT．5 mg从g，5 min后再次腹腔注射可卡因 30 mg从g。最后一次
给药后 30min处死动物，取出伏隔核、纹状体和额叶皮层，称重，匀
浆，AI。O。吸附法提取 DA，HCIO。酸化沉淀法提取0，利用高效液
相色谱（HPLC）结合电化学检测和荧光检测手段测定各脑区 DA和
Gill的含量。
sl：
1）急性给予可卡因 门 0 mgilig，…显著增加大鼠纹状体和伏隔
核的 DA含量，I匕对照组分另IJ提高了 23．6o和 25．lO（P＜0
Drug addiction remains one of the most serious threats to our nation's public health in terms of lost lives and productivity. Addiction can be defined as the loss of control over drug use, or the compulsive seeking and taking of drug regardless of the consequence. Cocaine is among the most commonly abused psychostimulants and inhibits all three monoamine transporters-dopamine (DA), serotonin, and norepinephrine, especially for dopamine transporter (DAT), thereby potentiating monoaminergic transmission. Underlying mechanism of cocaine addiction is not yet fully understood, however, substantial evidence indicates that several circuits in mesocorticolimbic systems, are known to mediate the addicting actions of cocaine. Most attention has been given to the nucleus accumbens (NAc) and its dopaminergic input from the ventral tegmental area (VTA) of the midbrain as key substrates for the drug effects. Other brain regions interact with the circuit, including the amygdala, prefrontal cortex (PFC) and other limbic reg
ions. DA and glutamate (Glu) are the most important neurotransmitiers in both the induction and the expression of cocaine sensitization. Available treatments for addiction remain inadequately effective for most individuals. Consequently, there is intense interest in better understanding the neurobiology of addiction in the hope that such knowledge will lead eventually to more effective treatments.
ATP sensitive potassium (KATp) channels were first described by Akinori Noma in the membrane of cardiac myocytes in 1983. Now it is known that KATP channels are widely expressed in many cell types including neurons. KATp channels consist of two types of subunits: an
inwardly rectifying K+ channel subunit (termed Kir) and a sulfonylurea receptor subunit (SUR), which is a member of the family of ATP-binding cassette transporter proteins. Up until now, two members of the Kir6 family, Kir6.1 and Kir6.2, and two SUR isoforms, SUR1 and SUR2, have been identified. The Kir is thought to confer ATP inhibition and determine conductance, whereas the SUR is considered the primary target for sulfonylureas, KATP channels opener (KCO), and nucleotide diphosphonate (NDP). The open probability of KATP channels directly depends on the intracellular ATP/ADP levels allowing the channels to directly couple the metabolic state of a cell to its electrical activity. KATP channels are distributed widely in brain and may play a critical role in neuroprotection as well as the regulation of DA and Glu transmission.
We developed a new compound iptkalim hydrochloride, which has been demonstrated to be a novel KATP channel opener by pharmacological, electrophysiological and biochemical studies, and receptor binding test. Notably, IPT is the only one of KCOs that can pass through blood-brain-barrier, which makes it possible to investigate its effects systematically. Previous studies in our lab have indicated that IPT was relevant to the regulation of DA and Glu release, the very two neurotransmitters playing a critical role in cocaine addiction. But there is no report on the relationship between KATP channels and cocaine addiction hitherto. In the present study, behavioral experiment, determination of neurotransmitters and molecular biology experiment were employed to investigate the correlation between KATP channels and cocaine addiction so as to obtain the basic evidence to develop IPT into a safe and effective therapeutic drug.
Part I. Effect of IPT on acute and chronic cocaine-induced enhancement of locomotor activity of mice and changes of DA and Glu levels in rat brain
1. Effect of IPT on acute cocaine-induced change of locomotor activity of mice
Aim: To investigate the effect of IPT on acute cocaine induced change of locomotor activity. Methods and Groups: Mice of either sex were divided into four groups: 1) control: saline 20 ml/kg ip; 2) cocaine group: cocaine 30 mg/kg ip; 3) IPT group: IPT 0.75mg/kg ip; 4) IPT plus cocaine group: IPT 0.75mg/kg 5 min later followed by cocaine 30 mg/kg ip. Behavioral activity w
引文
1. Koob GF. Neurobiology of addiction toward the development of new therapies. Ann N Y Acad Sci 2001; 937: 170-85.
2. Nestler EJ. Molecular neurobiology of addiction. The American journal on addiction 2001; 10: 201-17.
3. Nestler EJ, Hope BT, Widnell KL. Drug addiction: a model for the molecular basis of neural plasticity. Neuron 1993; 11: 995-1006.
4. Nestler EJ. Molecular basis of long-lived neural plasticity to drugs of abuse. Nature Rev Ncurosci 2001; 2: 119-28.
5. Chang JY, Janak PH, Woodward DJ. Neuronal and behavioral correlations in the medial prefrontal cortex and nucleus accumbens during cocaine self-administration by rats. Neuroscience 2000; 99: 433-43.
6. Kuroda M, Murakami K, Igarashi H ct al. The convergence of axon terminals from the mediodorsal thalamin nucleus and ventral tegmental area on pyramidal cells in layer V of the rat prelimbic cortex. Eur. J. Neurosci. 1996; 8: 1340-49.
7. O'Donnell P, Lavin A, Enquist LW et al. Interconnected parallel circuits between rat nucleus accumbens and thalamus revealed by retrograde transynaptic transport of pseudorabies virus. J. Neurosci. 1997; 17: 2143-67a.
8. Kalivas PW, Nakamura M. Neural systems for behavioral activation and reward. Curr Opin Neurobiol 1999; 9: 223-27.
9. Kalivas PW, Pierce RC. A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Rev 1997; 25: 192-216.
10. Wolf ME. The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol 1998; 54: 679-720.
11. Vanderschuren LJMJ, Kalivas PW. Alterations in dopaminergic and
glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 2000; 151: 99-120.
12.Noma A. ATP-regulated K+ channels in cardiac muscle. Nature 1983; 305: 147-8.
13.Sakura H, Ammala C, Smith PA et al. Cloning and functional expression of the cDNA encoding a novel ATP-senstive potassium channel subunit expressed in pancreatic beta-cells, brain, heart and skeletal muscle. FEBS Lett 1995; 77: 338-44.
14.Meyer M, Chudziak F, Schwanstecher C, Schwanstecher M, Panten U. Structural requirements of sulphonylureas and analogues for interaction with sulphonylurea receptor subtypes. Br J Pharmacol 1999; 128: 27-34.
15.Babenko AP, Aguilar-Bryan L, Bryan J. A view of SUR/Kir6.x K_(ATP) channels. Annu Rev Physiol 1998; 60: 667-687.
16.Quayle JM, Nelson MT, Standen NB. ATP-sensitive and inwardly rectifying potassium channels in smooth muscle. Physiol Rev 1997; 77: 1165-232.
17.Ashcroft FM Gribble FM. Correlating structure and function in ATP-sensitive K~+ channels. Trends Neurosci 1998; 21: 288-94.
18.Seino S, Inagaki N, Namba N et al. Molecular basisi of functional diversity of ATP-sensitive K~+ channels. Japan J Physiol 1997; 47: S3-S4.
19.Liss B, Roeper J. Molecular physiology of neuronal K-ATP channels. Mol Membr Biol 2001; 18: 117-27.
20.Tusnady GE, Bakos E, Varadi A et al. Membrane topology distinguishes a subfamily of the ATP-binding cassette (ABC) transporters. FEBS Lett 1997; 402: 1-3.
21.Clement JPIV, Kunjilwar K, Gonzalez G et al. Association and stoichiometry of K_(ATP) channel subunits. Neuron 1997; 18: 827-38.
22.Yokoshiki H, Sunagawa M, Seki T et al. ATP-sensitive K~+ channels
in pancreatic, cardiac and vascular smooth muscle cells. Am J Physiol 1998; 274: C25.
23.Deutsch N, Weiss JN. Effects of trypsin on cardiac ATP-sensitive K~+ channel. Am J Physiol 1994; 266: H613-22.
24.Ye GL, Leung CK, Yung WH et al. Pre-synaptic effect of the ATP-senstive potassium channel opener diazoxide on rat substantia nigra pars reticulata neurons. Brain Res 1997; 753: 1-7.
25.Inagaki N, Gonoi T, Clement Ⅳ JP et al. Reconstitution of Ⅰ_(KATe): An inward rectifier subunit plus the sulfonylurea receptor. Science 1995; 270: 1166-70.
26.Dunn-Meynell AA, Rawson NE, Levin BE. Distribution and phenotype of neurons containing the ATP-sensitive K~+ channel in rat brain. Brain Res 1998; 814: 41-54.
27.Zhou M, Tanaka O, Sekiguchi M et al. Localization of the ATP-senstive potassium channel subunit (Kir6.1/uK(ATP)-1) in rat brain. Brain Res Mol Brain Res 1999; 74: 15-25.
28.Sun XD, Lee EW, Wong EH, Lee KS. ATP-sensitive potassium channels in freshly dissociated adult rat striatal neurons: activation by metabolic inhibitors and the dopaminergic receptor agonist qunipirole. Pfitigers Arch 2000; 440: 530-47.
29.Cui Y, Tran S, Tinker A et al. The molecular composition of K_(ATP) channels in human pulmonary artery smooth muscle cells and their modulation by growth. Am. J. Respir. Cell Mol. Biol. 2002; 26: 135-43.
30.Wang H. Pharmacological characteristics of the novel antihypertensive drug IP Takalim hydrochloride and its molecular mechanisms. Drug Dev Res 2002; 54: 240-1.
31.Koob GF. The role of the striatopallidal and extended amygdala systems in drug addiction. Ann N Y Acad Sci 1999; 877: 445-460.
32.Wikler A. Dynamics of drug dependence: implications of a conditioning theory for research and treatment. Arch. Gen.
Psychiatry 1973; 28: 611-16.
33.Koob GF, Le Moal M. Drug abuse: hedonic homeostatic dysregulation. Science 1997; 278: 52-8.
34.Pierce RC, Bell K, Duffy P, Kalivas PW. Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization. J Neurosci 1996; 16: 1550-60.
35.O'Brien CP. A range of research-based pharmacotherapies for addiction. Science 1997; 278: 66-70.
36.Nestler EJ. From neurobiology to treatment: progress against addiction. Nature neuroscience supplement 2002; 5: 1076-79.
37.Platt DM, Rodefer JS, Rowlett JK et al. Suppression of cocaine- and food-maintained behavior by the D2-like receptor partial agonist terguride in squirrel monkeys. Psychopharmacology (Berl) 2003; 166: 298-305.
38.Koob GF. Circuits, drugs, and drug addiction. Adv Pharmacol 1998; 42: 978-82.
39.Dunn-Meynell AA, Rawson NE, Levin BE. Distribution and phenotype of neurons containing the ATP-sensitive K~+ channel in rat brain. Brain Res 1998; 814: 41-54.
40.Levin BE, Dunn-Meynell AA, Routh VH. Brain glucose sending and body energy homeostasis: role in obesity and diabetes. American Journal of Physiology 1999; 276: R1223-31.
41.Schulaz R, Rose J, Heusch G. Involvement of activation of ATP-dependent potassium channel in ischemic preconditioning in swine. Am J Physiol. 1994:; 267: H1341-52.
42.Kalivas PW. Neurotransmitter regulation ofdopamine neurons in the ventral tegmental area. Brain Res. Brain Res. Rev. 1993; 18: 75-113.
43.Zhang Y, Loonam TM, Noailles PA, Angulo JA. Comparison of cocaine- and methamphetamine-evoked dopamine and glutamate overflow in somatodendritic and terminal field regions of the rat brain
during acute, chronic, and early withdrawal conditions. Ann N Y Acad Sci 2001; 937: 93-120.
44.Heidbreder CA, Thompson AC, Shippenberg TS. Role of extracellular dopamine in the initiation and long term expression of behavioral sensitization to cocaine. J. Pharmacol. Exp. Ther. 1996; 278: 490-502.
45.Pierce RC, Kalivas PW. Amphetamine produces sensitized locomotion and dopamine release preferentially in the nucleus accumbens shell of rats administered repeated cocaine. J. Pharmacol. Exp. Ther. 1996; 275: 1019-29.
46.Williams JEG, Wieczore W, Willner P. Parametric analysis of the effects of cocaine and cocaine pretreatment on dopamine release in the nucleus accumbens measured by fast cyclic voltammetry. Brain Res. 1995; 678: 225-32.
47.Masserano JM, Baker I, Natsukari N. Chronic cocaine administration increases tyrosine hydroxylase activity in the ventral tegmental area through glutaminergic- and dopaminergic D2-receptor mechanisms. Neurosci. Lett. 1996; 217: 73-6.
48.Kuhar MJ, Pilotte NS. Neurochemical changes in cocaine withdrawal. Trends Pharmacol. Sci. 1996; 17: 260-4.
49.Wellman GC, Quayle JM, Standen NB. ATP-sensitive K+ channel activation by calcitonin gene-related peptide and protein kinase A in pig coronary arterial smooth muscle. J Physiol 1998; 507: 117-29.
50.Robinson SE, Maher JR, Mcdowell KP et al. Effects of cocaine and the cocaine analog CFT on glutamatergic neurons. Pharmacol. Biochem. Behav. 1995; 50: 627-33.
51.Reid MS, Hsu K Jr, Berger SP. Cocaine and amphetamine preferentially stimulate glutamate release in the limbic system: study on the involment of dopamine. Synapse, 1997; 27: 95-105.
52.Reid MS, Berger SP. Evidence for sensitization of cocaine-induced nucleus accumbens glutamate release. Neuroreport, 1996; 7:
1325-9.
53.Pierce RC, Bell K, Duffy P et al. Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behaviral sensitization. J. Neurosci, 1996; 16:1550-60.
54.Cha XY, Pierce RC, Zuckerman JB et al. Cocaine alters mRNA levels for the Na/K ATPase pump in vivo and in vitro. Soc. Neurosci. Abstr. 1996; 22: 1880.
55.Meyer M, Chudziak F, Schwanstecher C et al. Structural requirements of sulphonylureas and analogues for interaction with sulphonylurea receptor subtypes. Br J Pharmacol, 1999; 128(1):27-34.
56.Nestler EJ, Aghajanian GK. Molecular and cellular basis of addiction. Science 1997; 278: 58-63.
57.Lane-Ladd SB, Pineda J, Boundy V et al. CREB (cAMP response element binding protein) in the locus coeruleus: biochemical, physiological, and behavioral evidence for a role in opiate dependence. J Neurosci 1997; 17:7890-901.
58.Kelz MB, Chen JS, Carlezon WA et al. Expression of the transcr IP Tion factor σ FosB in the brain controls sensitivity to cocaine. Nature 1999; 401:272-76.
59.Kelz MB, Nestler EJ. ∑ FosB: a molecular switch underlying long-term neural plasticity. Curr Opin Neurol 2000; 13: 715-20.
60.Nakao N, Nakai K, Itakura T. Metabolic inhibition enhances selective toxicity of L-DOPA toward mesencephalic dopamine neurons in vitro. Brain Res 1997; 777:202-9.
2. Nestler EJ. Molecular neurobiology of addiction. The American journal on addiction 2001; 10: 201-17.
3. Nestler EJ, Hope BT, Widnell KL. Drug addiction: a model for the molecular basis of neural plasticity. Neuron 1993; 11: 995-1006.
4. Nestler EJ. Molecular basis of long-lived neural plasticity to drugs of abuse. Nature Rev Ncurosci 2001; 2: 119-28.
5. Chang JY, Janak PH, Woodward DJ. Neuronal and behavioral correlations in the medial prefrontal cortex and nucleus accumbens during cocaine self-administration by rats. Neuroscience 2000; 99: 433-43.
6. Kuroda M, Murakami K, Igarashi H ct al. The convergence of axon terminals from the mediodorsal thalamin nucleus and ventral tegmental area on pyramidal cells in layer V of the rat prelimbic cortex. Eur. J. Neurosci. 1996; 8: 1340-49.
7. O'Donnell P, Lavin A, Enquist LW et al. Interconnected parallel circuits between rat nucleus accumbens and thalamus revealed by retrograde transynaptic transport of pseudorabies virus. J. Neurosci. 1997; 17: 2143-67a.
8. Kalivas PW, Nakamura M. Neural systems for behavioral activation and reward. Curr Opin Neurobiol 1999; 9: 223-27.
9. Kalivas PW, Pierce RC. A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Rev 1997; 25: 192-216.
10. Wolf ME. The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol 1998; 54: 679-720.
11. Vanderschuren LJMJ, Kalivas PW. Alterations in dopaminergic and
glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 2000; 151: 99-120.
12.Noma A. ATP-regulated K+ channels in cardiac muscle. Nature 1983; 305: 147-8.
13.Sakura H, Ammala C, Smith PA et al. Cloning and functional expression of the cDNA encoding a novel ATP-senstive potassium channel subunit expressed in pancreatic beta-cells, brain, heart and skeletal muscle. FEBS Lett 1995; 77: 338-44.
14.Meyer M, Chudziak F, Schwanstecher C, Schwanstecher M, Panten U. Structural requirements of sulphonylureas and analogues for interaction with sulphonylurea receptor subtypes. Br J Pharmacol 1999; 128: 27-34.
15.Babenko AP, Aguilar-Bryan L, Bryan J. A view of SUR/Kir6.x K_(ATP) channels. Annu Rev Physiol 1998; 60: 667-687.
16.Quayle JM, Nelson MT, Standen NB. ATP-sensitive and inwardly rectifying potassium channels in smooth muscle. Physiol Rev 1997; 77: 1165-232.
17.Ashcroft FM Gribble FM. Correlating structure and function in ATP-sensitive K~+ channels. Trends Neurosci 1998; 21: 288-94.
18.Seino S, Inagaki N, Namba N et al. Molecular basisi of functional diversity of ATP-sensitive K~+ channels. Japan J Physiol 1997; 47: S3-S4.
19.Liss B, Roeper J. Molecular physiology of neuronal K-ATP channels. Mol Membr Biol 2001; 18: 117-27.
20.Tusnady GE, Bakos E, Varadi A et al. Membrane topology distinguishes a subfamily of the ATP-binding cassette (ABC) transporters. FEBS Lett 1997; 402: 1-3.
21.Clement JPIV, Kunjilwar K, Gonzalez G et al. Association and stoichiometry of K_(ATP) channel subunits. Neuron 1997; 18: 827-38.
22.Yokoshiki H, Sunagawa M, Seki T et al. ATP-sensitive K~+ channels
in pancreatic, cardiac and vascular smooth muscle cells. Am J Physiol 1998; 274: C25.
23.Deutsch N, Weiss JN. Effects of trypsin on cardiac ATP-sensitive K~+ channel. Am J Physiol 1994; 266: H613-22.
24.Ye GL, Leung CK, Yung WH et al. Pre-synaptic effect of the ATP-senstive potassium channel opener diazoxide on rat substantia nigra pars reticulata neurons. Brain Res 1997; 753: 1-7.
25.Inagaki N, Gonoi T, Clement Ⅳ JP et al. Reconstitution of Ⅰ_(KATe): An inward rectifier subunit plus the sulfonylurea receptor. Science 1995; 270: 1166-70.
26.Dunn-Meynell AA, Rawson NE, Levin BE. Distribution and phenotype of neurons containing the ATP-sensitive K~+ channel in rat brain. Brain Res 1998; 814: 41-54.
27.Zhou M, Tanaka O, Sekiguchi M et al. Localization of the ATP-senstive potassium channel subunit (Kir6.1/uK(ATP)-1) in rat brain. Brain Res Mol Brain Res 1999; 74: 15-25.
28.Sun XD, Lee EW, Wong EH, Lee KS. ATP-sensitive potassium channels in freshly dissociated adult rat striatal neurons: activation by metabolic inhibitors and the dopaminergic receptor agonist qunipirole. Pfitigers Arch 2000; 440: 530-47.
29.Cui Y, Tran S, Tinker A et al. The molecular composition of K_(ATP) channels in human pulmonary artery smooth muscle cells and their modulation by growth. Am. J. Respir. Cell Mol. Biol. 2002; 26: 135-43.
30.Wang H. Pharmacological characteristics of the novel antihypertensive drug IP Takalim hydrochloride and its molecular mechanisms. Drug Dev Res 2002; 54: 240-1.
31.Koob GF. The role of the striatopallidal and extended amygdala systems in drug addiction. Ann N Y Acad Sci 1999; 877: 445-460.
32.Wikler A. Dynamics of drug dependence: implications of a conditioning theory for research and treatment. Arch. Gen.
Psychiatry 1973; 28: 611-16.
33.Koob GF, Le Moal M. Drug abuse: hedonic homeostatic dysregulation. Science 1997; 278: 52-8.
34.Pierce RC, Bell K, Duffy P, Kalivas PW. Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization. J Neurosci 1996; 16: 1550-60.
35.O'Brien CP. A range of research-based pharmacotherapies for addiction. Science 1997; 278: 66-70.
36.Nestler EJ. From neurobiology to treatment: progress against addiction. Nature neuroscience supplement 2002; 5: 1076-79.
37.Platt DM, Rodefer JS, Rowlett JK et al. Suppression of cocaine- and food-maintained behavior by the D2-like receptor partial agonist terguride in squirrel monkeys. Psychopharmacology (Berl) 2003; 166: 298-305.
38.Koob GF. Circuits, drugs, and drug addiction. Adv Pharmacol 1998; 42: 978-82.
39.Dunn-Meynell AA, Rawson NE, Levin BE. Distribution and phenotype of neurons containing the ATP-sensitive K~+ channel in rat brain. Brain Res 1998; 814: 41-54.
40.Levin BE, Dunn-Meynell AA, Routh VH. Brain glucose sending and body energy homeostasis: role in obesity and diabetes. American Journal of Physiology 1999; 276: R1223-31.
41.Schulaz R, Rose J, Heusch G. Involvement of activation of ATP-dependent potassium channel in ischemic preconditioning in swine. Am J Physiol. 1994:; 267: H1341-52.
42.Kalivas PW. Neurotransmitter regulation ofdopamine neurons in the ventral tegmental area. Brain Res. Brain Res. Rev. 1993; 18: 75-113.
43.Zhang Y, Loonam TM, Noailles PA, Angulo JA. Comparison of cocaine- and methamphetamine-evoked dopamine and glutamate overflow in somatodendritic and terminal field regions of the rat brain
during acute, chronic, and early withdrawal conditions. Ann N Y Acad Sci 2001; 937: 93-120.
44.Heidbreder CA, Thompson AC, Shippenberg TS. Role of extracellular dopamine in the initiation and long term expression of behavioral sensitization to cocaine. J. Pharmacol. Exp. Ther. 1996; 278: 490-502.
45.Pierce RC, Kalivas PW. Amphetamine produces sensitized locomotion and dopamine release preferentially in the nucleus accumbens shell of rats administered repeated cocaine. J. Pharmacol. Exp. Ther. 1996; 275: 1019-29.
46.Williams JEG, Wieczore W, Willner P. Parametric analysis of the effects of cocaine and cocaine pretreatment on dopamine release in the nucleus accumbens measured by fast cyclic voltammetry. Brain Res. 1995; 678: 225-32.
47.Masserano JM, Baker I, Natsukari N. Chronic cocaine administration increases tyrosine hydroxylase activity in the ventral tegmental area through glutaminergic- and dopaminergic D2-receptor mechanisms. Neurosci. Lett. 1996; 217: 73-6.
48.Kuhar MJ, Pilotte NS. Neurochemical changes in cocaine withdrawal. Trends Pharmacol. Sci. 1996; 17: 260-4.
49.Wellman GC, Quayle JM, Standen NB. ATP-sensitive K+ channel activation by calcitonin gene-related peptide and protein kinase A in pig coronary arterial smooth muscle. J Physiol 1998; 507: 117-29.
50.Robinson SE, Maher JR, Mcdowell KP et al. Effects of cocaine and the cocaine analog CFT on glutamatergic neurons. Pharmacol. Biochem. Behav. 1995; 50: 627-33.
51.Reid MS, Hsu K Jr, Berger SP. Cocaine and amphetamine preferentially stimulate glutamate release in the limbic system: study on the involment of dopamine. Synapse, 1997; 27: 95-105.
52.Reid MS, Berger SP. Evidence for sensitization of cocaine-induced nucleus accumbens glutamate release. Neuroreport, 1996; 7:
1325-9.
53.Pierce RC, Bell K, Duffy P et al. Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behaviral sensitization. J. Neurosci, 1996; 16:1550-60.
54.Cha XY, Pierce RC, Zuckerman JB et al. Cocaine alters mRNA levels for the Na/K ATPase pump in vivo and in vitro. Soc. Neurosci. Abstr. 1996; 22: 1880.
55.Meyer M, Chudziak F, Schwanstecher C et al. Structural requirements of sulphonylureas and analogues for interaction with sulphonylurea receptor subtypes. Br J Pharmacol, 1999; 128(1):27-34.
56.Nestler EJ, Aghajanian GK. Molecular and cellular basis of addiction. Science 1997; 278: 58-63.
57.Lane-Ladd SB, Pineda J, Boundy V et al. CREB (cAMP response element binding protein) in the locus coeruleus: biochemical, physiological, and behavioral evidence for a role in opiate dependence. J Neurosci 1997; 17:7890-901.
58.Kelz MB, Chen JS, Carlezon WA et al. Expression of the transcr IP Tion factor σ FosB in the brain controls sensitivity to cocaine. Nature 1999; 401:272-76.
59.Kelz MB, Nestler EJ. ∑ FosB: a molecular switch underlying long-term neural plasticity. Curr Opin Neurol 2000; 13: 715-20.
60.Nakao N, Nakai K, Itakura T. Metabolic inhibition enhances selective toxicity of L-DOPA toward mesencephalic dopamine neurons in vitro. Brain Res 1997; 777:202-9.