CN1771929A - 苯环利啶成瘾及苯环利啶成瘾相关行为的治疗 - Google Patents
苯环利啶成瘾及苯环利啶成瘾相关行为的治疗 Download PDFInfo
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- CN1771929A CN1771929A CNA2005101232670A CN200510123267A CN1771929A CN 1771929 A CN1771929 A CN 1771929A CN A2005101232670 A CNA2005101232670 A CN A2005101232670A CN 200510123267 A CN200510123267 A CN 200510123267A CN 1771929 A CN1771929 A CN 1771929A
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Abstract
本发明提供了一种方法,用来改变哺乳动物对致幻剂,尤其是对苯环利啶(PCP)成瘾而引发的与成瘾有关的行为。该方法包括:给予哺乳动物有效剂量的γ-乙烯基-γ氨基丁酸(GVG)、或其药用盐、或其对映结构体、或其外消旋混合物,其有效剂量足以减弱、抑制、或消除与对PCP的渴求或使用相关的行为。
Description
本申请是2001年3月7日提交的名称为“苯环利啶成瘾及苯环利啶成瘾相关行为的治疗”的第01819228.9号发明专利申请的分案申请。
本发明由美国政府资助,合同号为DEAC02-98CH10886,由美国能源部鉴定。美国政府拥有本发明的一定权利。
背景技术
本发明涉及使用一种不可逆的γ-氨基丁酸氨基转移酶抑制剂,用于治疗药物成瘾,以及减轻与药物成瘾有关的行为。更确切地说,本发明涉及与苯环利啶成瘾有关的治疗,以及与苯环利啶成瘾有关的行为的减轻。
苯环利啶,常称为PCP,是一种非法的合成药品。与可卡因和四氢大麻酚(THC)这些从天然物质中提取的药品不同,PCP是由工业化学品制成的。
PCP作为一种静脉麻醉剂是研制于20世纪50年代。PCP在人体的使用于1965年停止,因为发现病人从麻醉中苏醒时常常变得激动、妄想和无理性。PCP在实验室内非法生产在街头销售,常称为“天使粉末”,“新鲜空气”,“怪人”,和“火箭燃料”。“杀手翦”和“水晶极品”则指的是与大麻结合的PCP合剂。各种各样的PCP俗名反映了PCP的奇怪和多变的效应。
PCP是一种结晶白色粉末,易溶于水和酒精。它有一种独特的化学药品的苦味。PCP容易与染料混合并且以各种各样的片剂、胶囊、和有色粉末形式出现在毒品市场上。它通常采用三种方式服用:鼻吸、吸烟、或口服。以吸烟的方式服用时,PCP通常被涂于叶状物,如薄荷、欧芹、牛至、或大麻的表面。
PCP干扰新皮层的功能,新皮层是大脑的一部分,控制着思维能力,并保持受控制的本能。因为此毒品阻断痛觉受体,所以强烈的PCP毒瘾发作可能会导致自残。PCP的效应很多,但服药者常常主述距离感和陌生感,他们感到时间和躯体动作变慢,肌肉协调性变差,感觉变得迟钝。他们的言语受到影响,变得不连贯。在长期服药的后期阶段,服药者常常表现得多疑,有暴力行为,并出现幻觉。大剂量使用会导致惊厥(抽搐)和昏迷,及心肺功能衰竭。
PCP具有成瘾性。有证据表明PCP可引起躯体依赖和心理依赖。PCP的使用通常会导致心理依赖、对药物的渴求、和强迫的寻找PCP的行为。
许多PCP的使用者被送到急诊室是由于PCP导致的有害的心理效应或者药物过量。在医院或收容所里,PCP服用者常常变得有暴力和自杀倾向,给其自身和他人带来危险。
从小剂量到中度剂量,PCP的生理效应包括呼吸轻度增快和血压及脉率明显的上升及增加。服用者呼吸变浅,并出现面部潮红和大汗。四肢普遍麻木和肌肉运动不协调也会出现。心理效应包括躯体知觉的明显改变,与酒精中毒引起的症状类似。青少年服用PCP会扰乱与正常生长发育有关的激素并干扰学习过程。
大剂量服用PCP,会出现血压、脉率、和呼吸的下降和减慢。这些症状可能伴随着恶心、呕吐、视物模糊、不停地眨眼、流涎、失去平衡和头晕。大剂量的PCP还可引起癫痫发作、昏迷和死亡。大剂量PCP的心理效应包括错觉和幻觉。PCP可引起与所有精神分裂症的症状相似的效应,如妄想、偏执、思维混乱、对所在环境的遥远感、和紧张症候群。言语常常是贫乏和混乱的。
长期服用PCP的人主述记忆缺失、言语和思维困难、抑郁和体重下降。这些症状在连续服用PCP后可持续存在一年,情绪障碍也有报道。PCP有镇静效应,与其它的中枢神经系统抑制剂如乙醇和苯并二氮类相互作用,会导致昏迷和事故性药物过量。
已发现致瘾性药物如尼古丁、可卡因和PCP增强前脑的中脑报偿/强化通路中的多巴胺(DA)水平,很可能由此促进了大脑的报偿作用,进而产生了使用者所谓的“高潮状态”。这些多巴胺系统功能的改变已经在对毒品的渴求和正在戒毒的吸毒者吸毒习惯的复发中得到体现。例如,可卡因可以通过与DA载体(DAT)结合,阻碍DA向突触前末梢的再摄取而作用于DA系统。已有足够的证据证明,成瘾药物的致瘾性,是与中枢神经系统报偿/强化通路的再摄取过程被阻断相联系的。
美国食品和药物管理局(FDA)证明目前尚无治疗PCP成瘾的药品。但有治疗由于服用PCP引起的损害健康效应的药物。通常有两类用于治疗PCP成瘾的药物。它们是抗焦虑药如苯甲二氮(diazepam),多称为Valium。抗焦虑药用于PCP服用者出现妄想、幻觉、或偏执症状时。但是,这些药物只治疗症状而不是成瘾本身。
因此,目前需要一种方法以治疗PCP成瘾,它应能通过改变PCP在中枢神经系统的药理作用来减轻病人对药物的渴求。
发明简述
针对所述在先技术的需要,本发明提供了一种方法,用于治疗成瘾,并改变与成瘾有关的行为。对象为患有苯环利啶(PCP)成瘾的哺乳类动物,如灵长类。方法为给予该动物一有效剂量的药物组合物或药剂,包括γ-乙烯基-γ-氨基丁酸(GVG)。GVG的量约为15mg/kg至2g/kg不等,较佳剂量约为100mg/kg至600mg/kg,优选剂量约为150mg/kg至300mg/kg。
在另一实施例中,本发明可提供一种方法,改变对PCP成瘾的哺乳动物与成瘾有关的行为,该方法包括:给予该哺乳动物一有效剂量的GVG、或其药用盐、其有效剂量可削弱PCP所引起的报偿/激励效应,实验是在该动物体内不存在由食物引起的报偿/激励效应的情况下进行的。
GVG的剂量约为15mg/kg至2g/kg,较佳剂量约为15mg/kg至600mg/kg,优选剂量约为150mg/kg至600mg/kg。
作为本发明的结果之一,减少PCP成瘾和改变与成瘾有关的行为的方法基于一种药物组合物或药剂,其本身并不致瘾,却是在改善病人的成瘾和成瘾行为方面极其有效。本发明所使用的药物组合物或药剂有利于抑制或消除PCP成瘾者对PCP的强烈渴望。而且,对与PCP成瘾有关行为的消除是在没有由GVG引起的厌恶或欲望反应的条件下发生的。此外,对与PCP依赖有关的行为特征的减少或消除是在灵长类的运动功能不发生改变的条件下发生的。
在另一实施例中,本发明可提供一种方法,改变对PCP成瘾的哺乳动物的与成瘾有关的行为。该方法包括:给予该哺乳动物一有效剂量的GVG,或其药用盐,或其对映结构体,或其外消旋混合物,其有效剂量足以减少、抑制、或者消除对PCP的渴求或PCP的使用。
在本发明的另一有代表性的实施例中,该方法包括改变对PCP成瘾的哺乳动物的与成瘾有关的行为。该方法包含给予该哺乳动物一有效剂量的药物组合物或药剂,可提高中枢神经系统γ-氨基丁酸(GABA)水平,其有效剂量足以减弱、抑制、或消除与对PCP的渴求或使用相关的行为。
本发明对现有技术的其它改进,通过下文对本发明的优选实施例的描述可以更为明了。以下说明不是对本发明的限定,而是仅为提供本发明的优选实施方案。本发明的范围由所附的权利要求提出。
附图简要描述
图1图表说明,GVG对PCP诱导的伏隔核(Nacc)和额叶前部皮质(PFC)的DA释放的影响。
发明详述
本发明提供了一种很有效的方法,用于治疗PCP成瘾以及改变对PCP成瘾的如灵长类等哺乳类动物与成瘾有关的行为。
在此,与成瘾有关的行为指的是由于强迫性的PCP使用而导致的行为,其特征为对该药物明显的依赖。此行为的症候为:(i)无法抵抗地参与到PCP使用中,(ii)对PCP来源的保护,(iii)停药后复发的可能性很高。
此处定义的PCP成瘾包括PCP和其它毒品共同引起的成瘾。毒品包括(但不限于)神经兴奋剂、麻醉性镇痛剂、酒精、以及可致瘾的生物碱,例如尼古丁或其混合物。毒品还包括中枢神经系统镇静剂,如巴比妥酸盐、利眠宁,以及醇类,如乙醇、甲醇、异丙醇等。
强迫性毒品使用包括三个独立成分:耐受、心理依赖、以及躯体依赖。耐受会产生一种需求:在几次施用毒品后,需要增加毒品剂量,才能达到和以前同样强度的效果。躯体依赖是反复使用毒品0后产生的适应状态,表现为吸毒中断时强烈的身体不适。心理依赖的特征为对毒品强烈的欲望、渴望或使用,而吸毒者感觉毒品对他保持良好状态是必需的。参见Feldman,R.S.与Quenzer,L.F.所著《神经心理药理学基础》(Fundamentals ofNeuropsychopharmocology)418-422页(Sinaur Associates,Inc(1984)),全文结合于此作为参考。根据前述定义,在此所述的“依赖特征”包括所有与强迫性毒品使用有关、能够被宿主的生化成分、生理和心理特性所影响的特征。
在此所述的PCP的“报偿/激励效应”指的是:任何能够产生心理快感缺乏或者提高后天学会的反应的可能性的刺激(在此为一种毒品)。这与“加强”是同义的。对实验动物来说,通过使用据信可测量报偿的方法,能够认为一种刺激是否具有报偿性。所用方法为测量一种刺激能否产生接近反应,又称欲望反应,还是撤退反应,即动物对刺激进行躲避,又叫厌恶反应。条件性位置偏爱(CPP)是一测量接近(欲望)反应或撤退(厌恶)反应的参量。人们可以推断,报偿刺激可以导致接近行为。事实上,报偿的定义之一即为可引发接近行为的刺激。此外,报偿的结果是增加与报偿有关的刺激的激励特性。
报偿也可以通过确定一种报偿的获得是否与一特殊反应相一致而测量,进而增加该反应在相似条件下重复出现的可能,即强化参量。例如,一只老鼠以一固定次数击压一小棒以获取毒品注射,这便是一个强化效应的例子。另一种测量报偿效应的方法是,通过与中性环境刺激的多重配对,确定一种刺激(如一种毒品)是否能使以前为中性的环境刺激引发原来只与毒品有关的行为效应,这便是条件强化。CPP可被视为条件强化的一种形式。
一种毒品的激励动机值可以用条件性位置偏爱(CPP)来估算。动物在一种没有毒品的状态下接受测试,以决定与从前曾接受盐水的环境比较,它们是否更倾向于从前曾接受毒品的环境。在CPP模式中,动物在一截然不同的环境下接受一毒品,而在另一环境下接受合适的载体。CPP模式在评价实验动物对毒品的激励动机效应时被广泛使用(Van Der Kooy,1995)。进行条件化或与毒品配对之后,如果该动物,在无毒品的情况下,持续选择从前与毒品相关的环境,那么我们可以推论说:毒品的欲望值已经被编码入大脑,而且在无毒品存在时仍可被取得。CPP反映在,相对于注射载体对照的动物,动物在有与毒品有关的刺激存在的环境中花费的时间更长。
有人假定,由于人类对毒品的渴求通常是由从前与吸毒有关的感觉刺激所引起的,类似CPP这样的条件化模式可以用作实验动物渴求反应的模型。
在此所述的对某一毒品或联合毒品的渴求,指的是强烈希望主动使用曾经被哺乳动物使用过的毒品。哺乳动物不一定需要用毒品来防止戒断症状。
PCP的致瘾性与它对中枢神经系统(CNS)的中脑多巴胺(DA)强化/报偿通路的药理学作用相联系。这些通路中的多巴胺能传导系统是受γ-氨基丁酸(GABA)调节的。
PCP可抑制单胺类的突触前再摄取。中皮质边缘系DA系统中的多巴胺能神经元,其细胞体存在于腹侧被盖区(VTA),主要向伏隔核(NAcc)处投射,据认为该神经元参与PCP的强化效应。对腹侧被盖区(VTA)报偿中枢进行电刺激,可提高NAcc中细胞外DA水平,而NAcc中6-羟-多巴胺的损害可消除PCP的主动使用。体内微透析研究证实,PCP可增加NAcc中细胞外的多巴胺水平。
NAcc和腹苍白球处的γ-氨基丁酸(GABA)能神经元向腹侧被盖区(VTA)的DA神经元投射。药理学和电生理学研究显示,这些投射是抑制性的。腹侧被盖区DA神经元的抑制与GABAB受体刺激的结果类似。此外,向腹侧被盖区显微注射氯苯氨丁酸(baclofen),通过这些受体亚型的作用,能够减少NAcc中DA的浓度。总而言之,很明显,GABA的药理学使用可以通过调节腹侧被盖区DA神经元而影响NAcc处DA水平。
γ-乙烯基-γ-氨基丁酸
γ-乙烯基-γ-氨基丁酸(GVG)是一种选择性的、不可逆的GABA转氨酶(GABA-T)抑制剂,而后者已知可以增强GABA能的抑制。GVG成分为C6H11NO2,或4-氨基-5-己酸,商品名为VIGABATRIN,由Hoechst Marion Roussel生产,可自美国俄亥俄州辛西那提市Marion Merell Dow购得。GVG不与任何受体或再摄取复合物结合,但可通过选择性地、不可逆地抑制GABA转氨酶(GABA-T,通常对GABA进行分解代谢的酶类)的活性而提高内源性细胞内GABA水平。
此处所指的GVG包括外消旋化合物或混合物,其中包括等量的S(+)-γ-乙烯基-γ-氨基丁酸,和R(-)-γ-乙烯基-γ-氨基丁酸。GVG的这一外消旋化合物商品名为SABRIL,由Aventis PharmaAG生产。
GVG含有不对称的碳原子,因此能够以对映结构体的形式存在。本发明包含GVG的任何对映结构体形式,包括GVG的外消旋酸盐或外消旋混合物。在某些情况下,使用某一对映结构体,可能比使用其它对映结构体或外消旋酸盐或外消旋混合物,在即刻发明的方法中具有更大的优势(即功效更好)。这种优势可由本领域熟练的技术人员很快确定。例如,对映结构体S(+)-γ-乙烯基-γ-氨基丁酸在提高内源性细胞内GABA水平方面比R(-)-γ-乙烯基-γ-氨基丁酸更有效。
不同对映结构体可由手性起始材料合成,外消旋酸盐也可通过在化学上早已成熟的传统方法加以解决,方法包括非对映异构盐的手性层析、分馏结晶以及类似方法等等。
γ-乙烯基-γ-氨基丁酸的使用
在活体(in vivo)哺乳类动物中,GVG或其药用盐可以系统地经胃肠外或肠道途径给入,其中也包括经控制的释放给药系统。例如,GVG可以很容易地经静脉或经腹腔给入,而后者是较好的给药途径。静脉内或腹腔给药可以通过将GVG与一适宜的药物载体或赋形剂相混合而完成,本领域技术人员对此是应知的。
曾尝试过经口或肠道给药。片剂、胶囊、药丸、锭剂、酏剂、悬液、糖浆、薄饼、口香糖、及其它的配方形式都能够用来给予GVG或其药用盐。
在此,药用盐包括那些可形成盐的酸和碱,它们本身并不显著提高化合物的毒性。适宜的盐的例子包括矿物酸盐,如盐酸、碘氢、氢溴酸、磷酸、偏磷酸、硝酸、硫酸盐,以及有机酸盐,如酒石酸、醋酸、柠檬酸、苹果酸、安息香酸、乙醇酸、葡萄糖酸、古洛糖酸、琥珀酸、芳基磺酸如对-甲苯磺酸等有机酸的盐。
在此,有效剂量指的是能够达到改变哺乳动物成瘾相关行为的特定效果的有效剂量。这一剂量能够减少或缓解一种或多种由于终止或停用此毒品而导致的症状或体征。然而,应该强调的是,本发明并不限于任一特定剂量。
哺乳动物包括,如:人、狒狒及其它灵长类、以及宠物动物(如狗和猫)、实验动物(如大鼠和小鼠)及家畜(如马、羊、母牛)等。
GVG的使用剂量最好只有很少、或者根本没有副作用。例如,在治疗PCP成瘾时,GVG的使用量约为15mg/kg至2g/kg,较佳剂量约为100mg/kg至300mg/kg,或从约15mg/kg至约600mg/kg,而优选剂量约为150mg/kg至300mg/kg,或从约75mg/kg至约150mg/kg。
已知PCP可以增加NAcc中细胞外DA水平,而GABA可在同一核中抑制DA活性。据此,我们证实,γ-乙烯基-γ-氨基丁酸可削弱PCP诱导的细胞外DA变化。例如,正离子发散断层(PET)技术显示,灵长类动物(狒狒)脑中,γ-乙烯基-γ-氨基丁酸可显著削弱由PCP诱导的新纹状体突触DA水平增高。
这些发现提示,一种药理学策略可能对治疗PCP成瘾有效,该策略针对GABA能神经递质系统,该系统不同于中脑中的DA报偿/强化系统,但与其在功能上有关联。然而,这一新方法没有用一种直接的GABA激动剂来针对GABA受体复合物,而是使用了γ-乙烯基-γ-氨基丁酸,利用了可提高内源性GABA水平的不可逆酶抑制剂的长效作用,而避免了GABA激动剂由于直接作用于受体本身而带来的致瘾性。
尽管本例子中使用了γ-乙烯基-γ-氨基丁酸,但是对本领域熟练技术人员应该了解,已知的其它组合物或药剂也可以加强GABA能系统的活性,或者在中枢神经系统中提高细胞外内源性GABA水平。这些组合物或药剂包括那些可增强中枢神经系统GABA产生或释放的药物。这些药物包括(但不限于):加巴喷丁、丙戊酸、氟柳双胺、γ-羟基丁酸、酚加宾、十六烷基GABA、托吡脂(topiramate)、替加宾(tiagabine)、acamprosate(同型-钙-乙酰牛磺酸)或其药用盐、或其对映结构体、或其外消旋混合物。
本发明包括加巴喷丁、丙戊酸、氟柳双胺、γ-羟基丁酸、酚加宾、十六烷基GABA、托吡脂(topiramate)、替加宾(tiagabine)或acamprosate的任何对映结构体形式,包括其外消旋酸盐或外消旋混合物。
如前所述,在某些情况下,使用某一对映结构体,可能比使用其它对映结构体或外消旋酸盐或外消旋混合物,在即刻发明的方法中具有更大的优势(即功效更好)。这种优势可由本领域熟练技术人员很容易地确定。
本发明所采用的组合物或药剂包括GABA的前体药物,或者在化学结构中以GABA作为组分的药物。在中枢神经系统中,这些前体药物经代谢、酶解、或非酶解的途径生物转化成或切割成GABA,从而具有药理活性。GABA前体药物的例子之一便是氟柳双胺,它在通过血脑屏障后,可增加内源性中枢神经系统GABA水平。
如前所述,γ-乙烯基-γ-氨基丁酸(GVG)是一种选择性的、不可逆的GABA转氨酶(GABA-T)抑制剂,而后者可以增强GABA能的抑制。其它可抑制中枢神经系统GABA再摄取的组合物或药剂也包含在本发明中。GABA再摄取抑制剂的例子之一便是替加宾(tiagabine)。
本发明所使用的方法可用于增强GABA能系统的活性,或提高中枢神经系统细胞外内源性GABA的水平。在此,增强或提高内源性中枢神经系统GABA水平的定义为:在哺乳动物活体内,较之正常水平,能大幅提高或上调GABA水平。优选地,内源性中枢神经系统GABA水平能比正常水平升高至少约10%至600%。
如前所述,在此所述的有效剂量指的是能够达到改变哺乳动物与成瘾有关的行为的特异结果的有效剂量。这一剂量能够减少或者缓解由于终止或停用PCP而导致的一种或多种症状或体征。然而,应该强调的是,本发明并不限于任一特殊剂量。
例如,给予哺乳动物的有效加巴喷丁剂量约为500mg至2g/天。加巴喷丁的商品名为NEUROTONIN,可自美国Parke-Davis获得。
例如,给予哺乳动物的丙戊酸,优选有效剂量约为5mg/kg至100mg/kg/天。丙戊酸商品名为DEPAKENE,可自美国Abbott获得。
例如,给予哺乳动物的托吡脂(topiramate),优选有效剂量约为50mg至1g/天。托吡脂(Topiramate)商品名为TOPAMAX,可自美国McNeil获得。给予哺乳动物的氟柳双胺,优选有效剂量约为250mg至2g/天。氟柳双胺商品名为GABRENE,可自法国Synthelabo获得。氟柳双胺的化学式为C17H16N2O2。
给予哺乳动物的酚加宾,优选有效剂量约为250mg至4g/天。酚加宾的商品名为SL79229,可自法国Synthelabo获得。酚加宾的化学式为C17H17C12NO。
给予哺乳动物的γ-羟基丁酸,优选有效剂量约为5mg/kg至100mg/kg/天。γ-羟基丁酸可自Sigma化学试剂公司获得。γ-羟基丁酸的化学式为C4H7O3Na。
本发明的详细内容以下述实施例的方式得以充分阐明。发明的完整范围见所附的权利要求。
实施例1
我们在自由活动的大鼠中探查,内源性GABA活性增加对PCP诱导的额叶前部皮质(PFC)和伏隔核(NAcc)的细胞外多巴胺浓度的影响。
所有动物均使用IACUC认可的实验程序,并严格遵循NIH准则。成年雄性Sprague-Dawley大鼠(体重200-300g,Taconic农场)在12∶12的明/暗条件下,饲养在动物饲养设施中。动物分成6组(n=3-6),研究开始前至少4天,将动物麻醉,以趋实体的方式将硅化的指引套管植入右侧NAcc(位于前囟前方2.0mm、侧方1.0mm、皮质表面腹侧7.0mm)和额叶前部皮质(PFC)。将微透析探针(2.0mm,生物分析系统公司,BAS,West Lafayette,IN)置入引导套管内,使用CMA/100微灌流泵(BAS),以2.0μl/分钟的流速,将人工脑脊液(ACSF,155.0mM NA-,1.1mM Ca2-,2.9mM K-,132.76mM Cl-,和0.83mM Mg2-)注入探针。
将动物放在碗中,插入探针,用ACSF灌流过夜。在研究当天,最少要注射3个样品,以确定基线稳定性。收集样品20分钟,在线注射(CMA/160,BAS)。3个稳定样品的平均多巴胺浓度定为对照值(100%),所有随后处理值都换算成对照值的百分比。一旦建立起稳定的基线,便经腹腔(i.p.)注射PCP。高效液相层析(HPLC)系统由一个BAS反相柱(3.0μC-18)、一个BAS LC-4C电化学传感器(带有一个双/玻璃碳电极,电压设为650mV)、一台使用商业软件包(Chromograph生物分析系统公司)的计算机用于在线分析数据,以及一个双笔图表记录仪组成。动态相(流速1.0ml/分钟)组成如下:7.0%甲醇、50mM磷酸二氢钠(NaH2PO4)、1.0mM辛基硫酸钠、0.1mM EDNA,pH值4.0。多巴胺洗脱7.5分钟。
γ-乙烯基-γ-氨基丁酸(GVG)是一种不可逆的GABA转氨酶抑制剂,其在注射PCP(7mg/kg)之前2.5小时经腹腔注射。在所有研究中,进行实验的前一天晚上,都将动物放在微透析碗中,通过微透析探针,以2.0μl/分钟的流速,灌注人工脑脊液(ACSF)。每次研究完毕时,将动物杀死,取出大脑,并且进行切片,以检验探针位置。
通过以趋实体方式植入的探针对NAcc中细胞外DA水平进行连续取样。其结果显示于图1图表中(PCP对照组,n=6;150mg/kgGVG组,n=3;300mg/kgGVG组,n=4;500mg/kgGVG组,n=4)和PFC(PCP对照组,n=5;300mg/kgGVG组,n=5)。单独给以PCP提高PFC中DA浓度至基线以上407%以及NAcc中DA浓度至基线以上117%(p<0.01,T=3.79)。GVG剂量依赖地减弱NAcc中DA对PCP的反应,事先给以150mg/kgGVG处理后无明显抑制,事先给以300mg/kgGVG处理后减弱62%(p<0.01,T=4.97),事先给以500mg/kgGVG处理后减弱67%(p<0.001,T=6.02)。GVG预处理后PFC的活性减弱67%(p<0.01,T=3.54),其表明在NMDA-拮抗剂中相关的皮质GABA能系统的活性诱导DA释放。这些数据表明GABA能系统作为一个药物治疗的目标是针对病理生理学的NMDA拮抗剂模型。
实施例2
对在灵长类动物中,使用11C-奎丙灵(雷氯必利,(raclopride))、GVG、和PCP进行研究,实验设计的目标是提供出从细胞外DA浓度的变化(体内微透析)到通过正离子发散断层(PET)技术来检测的突触前DA浓度的变化的结果,PET实验是在四只papio anubis狒狒中进行的。在所有情况下,先静脉给以300mg/kgGVG,以防止给以PCP(1mg/kg)后结合的11C-奎丙灵(雷氯必利(raclopride))的减少,即防止了突触前DA的增高。本实施例的结果表明GVG有效地削弱了PCP应激后NAcc中DA的增高。
因此,选择性地作用于GABA能系统的药物有益于PCP成瘾的治疗。更确切地说,GVG诱导的GABA-T抑制,导致了脑内细胞外GABA水平的增高,表明了一种治疗PCP成瘾的有效药物及新的治疗策略。
尽管本发明已经参照优选实施例进行了说明,但是,对于本领域的技术人员来说,本发明可以有各种更改和变化。本发明的各种更改、变化、和等同物由所附的权利要求书的内容涵盖。
参考文献
Bardo.M.T.(1998)Neuropharmacological mechanism of drug reward:beyonddopamine in the nucleus accumbens.Crit.Rev.Neurobiol.,12:37-67.
Bolser、D.C.,Blythin,D.J.,Chapman,R.W.,Egan,R.W.,Hey,J.A.,Rizzo,C.,Kuo S.-C.,Kreutner,W.(1995)The pharmacology ofSCH 50911:A novel,orally-active GABA-B receptor antagonist.J.Pharmacol.Exp.Ther.,274:1393-1398.
Bowery,N.G.,Pratt,G.D.(1992)GABAB receptors as targets for drug actionArzneim.Forsch.,42:215-223.
Brazell,M.P.,Mitchell,S.N.,Joseph,M.H.,Gray,J.A.(1990)Acuteadministration of nicotine increases the in vivo extracellular levels of dopamine,3,4-dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbensof the rat:Comparison with caudateputamen.Neuropharmacology,29:1177-1185.
Chesselet,M.-F.(1984)Presynaptic regulation of neurotransmitter release in thebrain:Facts and hypothesis.Neuroscience,12:347-375.
Childress,A.R.,McLellan,A.T.,O′Brien,C.P.(1988)The role of conditioningfactors in the development of drug dependence.Psychiatr.Clin.North Amet.,9:413-426.
Childress,A.R.,McLellan、A.T.,Ehrmann,R.N.,O′Brien,C.P.(1986a)Extinction of conditioned responses in abstinent cocaine or opioid users.NIDA Res.Monogr.,76:189-195.
Childress,A.R.McLellan.A.T.,Ehrman.R.N.,O′Brien,C.P.(1986b)Classically conditioned resPonses in abstinent cocaine or opioid users.NIDA Res.Monogr.,76:24-43).
Clarke.P.B.S.,Fibiger,H.C.(1987)Apparent absence of nicotine-inducedconditioned place preference.Psychopharmacology,92:84-88.
Clarke,P.B.S.,Fu,D.S.,Jakubovic,A.,Fibiger,H.C.(1988)Evidence thatmesolimbic dopaminergic activation underlies the locomotor stimulant action ofnicotine in animals.J.Pharmacol.Exp.Ther..246:701-708.
Damsma,G.,Day,J.,Fibiger,H.C.(1989)Lack of toleranee to nicotine-induceddopamine release in the nucleus accumbens.Eur.J.Pharmacol.,168:363-368.
Dewey,S.L.,Chaurasia,C.S.,Chen,C.,Volkow,N.D.,Clarkson F.A.,Porter,S.P.,Straughter-Moore,R.M.,Alexoff,D.L.,Tedeschi,D.,Russo,N.B.,Fowler,J.S.and Brodie,J.D.GABAergic attenuation of cocaine-induced dopamine release andlocomotor activity.Synapse 25:393-398,1997.
Dewey,S.L.,Morgan,A.E.,Ashby,Jr.,C.R.,Horan,B.,Gardner,E.L.,Logan,J.,Volkow,.N.D.,Fowler,J.S.,Kushner,S.A.,Brodie,J.D.(1998)A novel strategy forthe treatment of cocaine addiction.Synapse,30:119-129.
Dewey,S.L.,Smith,G.S.,Logan,J.,Brodie,J.D.,Yu.D-W.,Ferrie ri,R.A.,King,P.T.,MacGregor,R.R.,Martin,T.P.,Wolf.A.P.,Volkow,N.D.,Fowler,J.S.GABAergic inhibition of endogenous dopamine release measured in vivo with11C-raclopride and positron emission tomography.J.Neuroscience 12,3773-3780,1992.
Dewey,S.L.,Smith,G.S.,Logan,J.,Brodie,J.D.,Fowler,J.S.,Wolf,A.P.Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modifysynaptic dopamine levels.Synapse 13,350-356,(1993).
Dewey,S.L.,Smith,G.S.,Logan,J.,Simkowitz.P.,Brodie,J.D.,Volkow,N.D.,Fowler,J.S.,Wolf, A.P.(1993)Effects of central choiinergic blockade on striataldopamine release measured with positron emission tomography(PET)in normal humansubjeets.Proc.Natl.Acad.Sci.,90:11816-11820.
Di Chiara,G.,Imperato,A.(1988)Drugs abused by humans preferentiallyincrease synaptic dopamine concentrations in the mesolimbic system of freely movinganimals.Proc.Natl.Acad.Sci.USA.85:5274-5278.
Ehrman,R.N.,Robbins,S.J.,Childress,A.R.,O Brien,C.P.(1992)Conditionedresponses to cocaine-related stimuli in cocaine abuse patients.Psychopharmacology,107:523-529.
Fudala,P.J.,Iwamoto,E.T.(1986)Further studies on nicotine-inducedconditioned place preference.Pharmacol.Biochem.Behav.,25:1041-1049.
Fudala,P.J.,Teoh,K.W.,Iwamoto,E.T.(1985)Pharmacologic characterizationof nicotine induced conditioned place preference.Pharmacol.Biochem.Behav.,22:237-241.
Gardner,E.L.(1997)Brain reward mechanisms in Substance Abuse:AComprehensive Textbook,3rd end.,eds.Lowinson,J.H.,Ruiz,P.,Millmna,R.B.&Langrod,J.G.,51-85(Williams and Wilkins,Baltimore,MD,1997).
Grant,S.M.and Heel,R.C.Vigabatrin:A review of its pharmacodynamic andpharmacokinetic properties,and therapeutic potential in epilepsy and disorders of motorcontrol.Drugs,41:889-926,1991.
Henningfield,J.E.(1995)Nicotine medications for smoking cessation.NewEng.J.Med.,333:1196-1203.26
Henningfield,J.E.,Goldberg.S.R.(1983)Control ofbehavior by intravenousnicotine injections in human subjects.Pharmacol.Biochem.Behav.,19:1021-1026.
Henningfield,J.E.,London,E.D.,Jaffe,J.H.(1987)nicotine reward:studies ofabuse liability and physical dependence potential.In:Brain Reward Systems andAbuse,ed.By J.Engel and L.Oreland,New York,Raven Press,pp.147-164.
Henningfield,J.E.,Miyasato,K.,D.R.Jasinski(1983)Cigarette smokers self-administer intravenous nicotine.Pharmacol.Biochem.Behav.,19:887-890.
Horan,P.,Smith,M.,Gardner,E.Lepore,M.,Ashby,Jr.C.R.(1997)(-)-nicotine produces conditioned place preference in Lewis,but not Fischer 344 animals.Synapse,26:93-94.
Hurd,Y.L.,McGregor,A.,Ponten,M.(1997)In vivo amygdala dopaminelevels modulate cocaine self-administration behavior in the rat:D1 dopamine receptorinvolvement.Eur.J.Neuroscience,12:2541-2548.
Hurt,R.D.,Sachs,D.P.,Glover,E.D.,Offord,K.P.,Johnston,J.A.,Dale,L.C.,Khayrallah,M.A.,Schroeder,D.R.,Glover,P.N.,Sullivan,C.R.,Croghan,I.T.,Sullivan,P.M.(1997)A comparison of sustained-release bupropion and placebo forsmoking cessation.N.Eng.J.Med.,237:1195-1202.
Imperato,A.,Mulas,A.,Di Chiara,G.(1986)Nicotine preferentially stimulatesdopamine release in the limbic system of the freely moving rat.Eur.J.Pharmacol.,132:337-338.
Jarvik,M.E.,Henningfield,J.E.(1988)Pharmacological treatment of tobaccodependence.Pharmacol.Biochem.Behav.,30:279-294.
Jung,M.J.,Lippert,B.,Metcalf,B.W.,Bohlen,P.,Schechter,P.J.(1977)Gamma-Vinyl GABA(4-amino-hex-5-enoic acid),a new selective irreversible inhibitorof GABA-T:effects on brain GABA metabolism in mice.J.Neurochem.,29:787-802.
Kerr,D.I.B.,Ong.J.,Prager,R.H.(1990)GABAB receptor agonists andantagonists.In:GABAB receptors in Mammalian Function,Bowery,N.G.,Bittiger,H.and Olpe.H.-R.(eds.)John Wiley and Sons,New York,pp.29-45.
Kushner.S.A.,Dewey.S.l.,Kornetsky,C.Comparison of the effects ofvigabatrin on cocaine self-administration and food reinforcement.Soc.Neuro.Abstr.23:1942(1997a).
Kushner,S.A.,Dewey,S.L.,Kornetsky,C.The effects of gamma-vinyl GABAon cocaine-induced lowering of brain-stimulation reward thresholds.
Psychopharmacology,133,383-388,(1997b).
Lacey,M.G.,Mercuri,N.B.and North,A.N.On the potassium conductanceincrease activated by GABAB and dopamine D2 receptors in rat substantia nigraneurones.J.Physiol.401:437-453,1988.
Logan,J.,Fowler,J.S.,Volkow,N.D.,Wolf,A.P.,Dewey,S.L.,Schlyer,D.J.,MacGregor,R.R.,Hitzemann,R.,Bendriem,B.,Gatley,S.J.,Christman,D.R.(1990)Graphical analysis of reversible radioligand binding from time activity measurementsapplied to[N-11C-methyl]-(-)-cocaine PET studies in human subjects.J.Cereb.BloodFlow and Metab.,10:740-747.
Marshall,D.L.,Redfern,P.H.,Wonnacott,S.(1997)Presynaptic nicotinicmodulation of dopamine release in the three ascending pathways studied by in vivomicrodialysis:Comparison of naive and chronic nicotine-treated rats.J.Neurochem.,68:1511-1519.
Morgan,A.E.,Dewey,S.L.Effects of pharmacologic increases in brain GABAlevels on cocaine-induced changes in extracellular dopamine.Synapse 28,60-65(1998).
Nisell,M.,Nomikos,G.G.,Svensson,T.H.(1994a)Systemic nicotine-induceddopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in theventral segmental area.Synapse,16:36-44.
Nisell.M.,Nomikos,G.G.,Svensson,T.H.(1994b)Infusion of nicotine in theventral segmenial area or the nucleus accumbens differentially affects accumbaldopamine release.Pharmacol.Toxicol.,75:348-352.
Nisell,M.,Nomikos,G.G.,Svensson,T.H.(1995)Nicotine dependence,midbrain dopamine systems and psychiatric disorders.Pharmacol.Toxicol.,76:157-162.
N.R.,Van der Kooy,G.F.&Wenger,J.R.Cholecystokinin producesconditioned place-aversion,not place-preferences,in food-deprived rats:evidenceagainst involvement in satiety.Life Sci.32,2087-2093,(1989).
O′Brien,C.P.,Childress,A.R.,McLellan,A.T.,Ehnnan,R.(1992)A learningmodel of addiction,.In:Addictive States,O′Brien,C.P.and Jaffe,J.H.,(eds),RavenPress,New York,pp.157177.
Pontieri,F.E.,Tanda,G.,Orzi,F.,Di Chiara,G.(1997)Effeets of nicotine onthe nucleus accumbens and similarity to those of addictive drugs.Nature,382:255-257.
Porter,R.J.,Meldrum,B.S.(1998)Antiepileptic drugs.In:Basic and ClinicalPharmacology,ed.by Katzung,B.G.,Appelton and Lange,Stamford,CT,pp.386-408.
Roberts,D.C.,Andrews,M.M.(1997)Baclofen suppression of cocaine self-administration:demonstration using a discrete trials procedure.Psychopharmacology,131:271-277.
Roberts,D.C.,Andrews,M.M.,Vickers,G.J.(1996)Baclofen attenuates thereinforcing effects of cocaine in animals.Neuropsychopharmacology,15:417-423.
Rocha,B.A.,Scearce-Levie,K.,Lucas,J.J.,Hiroi,N.,Castanon,N.,Crabbe,J.C.,Nestler,E.J.,Hen,R.(1998)Increased vulnerability to cocainein mice lacking the-serotonin-1B-receptor.Nature Neuroscience,393:175-178.
Seeman,P.,Guan,H.C.,Niznik,H.B.(1989)Endogenous dopamine lowers thedopamine D2 receptor density as measured by[3H]raclopride:implications for positronemission tomography of the human brain.Synapse,3:96-97.
Sora,I.,Wichems,S.I.,Takahashi,C.,Li,X.F.,Zeng,Z.,Revay,R.,Lesch,K.P.,Murphy,D.L.,Uhl,D.R.(1998)cocaine reward models:conditioned placepreference can be established in dopamine-and serotonin-transporter knockout mice.Proc.Natl.Acad.Sci.,U.S.A.,95:7699-7704.
Takada,K.,Yanagita,T.(1997)Drug dependence study on vigabatrin in rhesusmonkeys and animals.Arzneim-Forsch Drug Res.47:1087-1095.
Tsuji M,Nakagawa Y,Ishibashi Y,Yoshii T,Takashima T,Shimada M,SuzukiT.(1995)Activation of ventral segmental GABA-B receptors inhibits morphine-induced place preference in animals.Eur.J.Phamacol.,313:169-173.
Valentine,J.D.,Hokanson,J.S.,Matta,S.G.,Sharp,B.M.(1997)Self-administration in animals allowed unlimited access to nicotine.Psychopharmacology,133:300-304.
Van Der Kooy,K.(1987).In Methods of Assessing the Properties of AbusedDrugs,M.A.Bozarth,Ed.,Springer-Verlag,New York,pp.229-241.
Volkow,N.D.,Wang,G.J.,Fowler,J.S.,Logan,J.,Schlyer,D.,Hitzemann,R.,Liberman,J.,Angrist,B.,Pappas,N.,MacGregor,R.,Burr,G.,Cooper,T.,Wolf,A.P.Imaging endogenous dopamine competition with[11C]raclopride in the human brain.Synapse,16,255-262(1994).
Wikler,A.(1965)Conditioning factors in opiate addiction and relapse.In:Narcotics,Kassenbaum,G.G.and Wilner,D.I.(eds),McGraw-Hill,New York,pp.85-100.
Claims (20)
1.加巴喷丁在制备用于减弱、抑制、或消除与对PCP的渴求或使用相关的行为的药物中的应用。
2.根据权利要求1所述的应用,其中所述加巴喷丁的使用剂量约为500mg至2g/天。
3.托吡脂在制备用于减弱、抑制、或消除与对PCP的渴求或使用相关的行为的药物中的应用。
4.根据权利要求3所述的应用,其中所述托吡脂的使用剂量约为50mg至1g/天。
5.氟柳双胺在制备用于减弱、抑制、或消除与对PCP的渴求或使用相关的行为的药物中的应用。
6.根据权利要求5所述的应用,其中所述氟柳双胺的使用剂量约为250mg至2g/天。
7.酚加宾在制备用于减弱、抑制、或消除与对PCP的渴求或使用相关的行为的药物中的应用。
8.根据权利要求7所述的应用,其中所述酚加宾的使用剂量约为250mg至4g/天。
9.γ-羟基丁酸在制备用于减弱、抑制、或消除与对PCP的渴求或使用相关的行为的药物中的应用。
10.根据权利要求9所述的应用,其中所述γ-羟基丁酸使用剂量约为5mg/kg至100mg/kg/天。
11.加巴喷丁在制备用于减低PCP依赖特性的药物中的应用。
12.根据权利要求11所述的应用,其中所述加巴喷丁的使用剂量约为500mg至2g/天。
13.托吡脂在制备用于减低PCP依赖特性的药物中的应用。
14.根据权利要求13所述的应用,其中所述托吡脂的使用剂量约为50mg至1g/天。
15.氟柳双胺在制备用于减低PCP依赖特性的药物中的应用。
16.根据权利要求15所述的应用,其中所述氟柳双胺的使用剂量约为250mg至2g/天。
17.酚加宾在制备用于减低PCP依赖特性的药物中的应用。
18.根据权利要求17所述的应用,其中所述酚加宾的使用剂量约为250mg至4g/天。
19.γ-羟基丁酸在制备用于减低PCP依赖特性的药物中的应用。
20.根据权利要求19所述的应用,其中所述γ-羟基丁酸的使用剂量约为5mg/kg至100mg/kg/天。
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CN114903006A (zh) * | 2021-02-09 | 2022-08-16 | 中国科学院脑科学与智能技术卓越创新中心 | 一种非人灵长类动物物质成瘾模型的构建方法与应用 |
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GB2133002B (en) | 1982-12-30 | 1986-01-29 | Merrell Toraude & Co | Process for preparing 4-amino-5-hexenoic acid |
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US5189064A (en) | 1985-07-22 | 1993-02-23 | Matrix Technologies, Inc. | Treatment of cocaine addiction |
ATE91891T1 (de) | 1987-10-07 | 1993-08-15 | Matrix Technologies Inc | Pharmazeutische zusammensetzung fuer die behandlung der kokainsucht. |
US5102913A (en) * | 1991-07-01 | 1992-04-07 | Halikas James A | Treatment for cocaine use employing valproic acid |
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CN1234352C (zh) | 2006-01-04 |
JP2004512301A (ja) | 2004-04-22 |
CA2426210C (en) | 2009-12-22 |
EP1335717A1 (en) | 2003-08-20 |
EP1335717A4 (en) | 2004-06-30 |
IL155574A0 (en) | 2003-11-23 |
AU4201101A (en) | 2002-05-06 |
IL155574A (en) | 2010-02-17 |
WO2002034249A1 (en) | 2002-05-02 |
KR20030074610A (ko) | 2003-09-19 |
AU2001242011B8 (en) | 2006-03-02 |
HRP20030322A2 (en) | 2005-02-28 |
BR0114898A (pt) | 2003-08-12 |
AU2001242011B2 (en) | 2005-11-03 |
NO20031814L (no) | 2003-06-19 |
HUP0301441A2 (hu) | 2003-11-28 |
MXPA03003589A (es) | 2005-08-16 |
NO20031814D0 (no) | 2003-04-23 |
NZ526072A (en) | 2004-08-27 |
CA2426210A1 (en) | 2002-05-02 |
HUP0301441A3 (en) | 2011-07-28 |
PL361028A1 (en) | 2004-09-20 |
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CN1476326A (zh) | 2004-02-18 |
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