TOLERANCE AND SENSITIZATION

耐受性和致敏性

• 批准号: 6111225
• 负责人: ROBERT M POST
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6111225
• 关键词: amygdala; anticonvulsants; behavioral /social science research tag; behavioral habituation /sensitization; benzodiazepine receptor; carbamazepine; clonazepam; cocaine; conditioning; diazepam; dopamine; drug administration rate /duration; drug habituation; drug tolerance; electrostimulus; epilepsy; kindling; laboratory rat; neurochemistry; neuropharmacology; nucleus accumbens; phenytoin; regulatory gene; valproate

The overall objectives of this project are to study the phenomenology and biological substrates of changing responsivity to drugs. These findings are used to develop hypotheses about clinical loss of response to the anticonvulsant mood stabilizers and to test possible ways of showing or reversing the tolerance process. The models under study also have the unique feature of being dependent on the contingencies or context of drug administration. As such, they do not involve primary changes in pharmacokinetics, but instead depend upon adaptations in the nervous system in response to the drugs as they interact with illness state. In the kindling paradigm, we measure the loss and reinstatement of anticonvulsant drug efficacy, and in the sensitization model, we study the environmental context determinants of drug response. We have demonstrated that the anticonvulsant efficacy of carbamazepine, valproate, and diazepam can be manipulated by temporal factors relating to drug administration and seizure presentation. Contingent changes in physiological responsivity, gene expression, and receptor regulation have been demonstrated in concert with the development of tolerance. For studying cocaine sensitization,we have developed a rapid behavioral paradigm that produces a conditioned or context-dependent enhanced behavioral response to cocaine; the neurobiological correlates of this continue to be investigated as they relate to our understanding of how environmental cues can be associated with changes in behavior (i.e., learning). Significant findings to date include demonstration of the following. 1) Contingent inefficacy and tolerance to carbamazepine and other anticonvulsants, whereby the contingent presentation of the drug before, but not after, kindling stimulation results in a diminished response to the drug in various stages of kindling evolution. 2) Reversibility of contingent tolerance by time off treatment or even continued treatment with the drugs given after the kindled seizures (i.e., drug administration is not discontinued, only the contingencies are changed) or by kindled seizures alone. 3) Selective cross tolerance between carbamazepine and lamotrigine, valproate, and PK-11195 (an antagonist at the peripheral-type benzodiazepine receptor), but not diazepam, clonazepam, or phenytoin. 4) Alterations in seizure threshold which mirror the changes in responsivity to carbamazepine. 5) Procedures to slow contingent tolerance development; e.g., noncontingent drug presentation or kindling the rats at lower stimulation currents, but not co-administration of the NMDA antagonist MK-801 or the calcium channel blocker nimodipine. 6) A number of neurochemical correlates of contingent tolerance that represent a loss of a subset of seizure-induced adaptations in the GABA-A system, as well as in peptide mRNAs, trophic factors, and immediate early genes. 7) The failure of TRH mRNA to show seizure-induced increases in carbamazepine-tolerant animals has been more closely mechanistically linked to tolerance, with the observation that TRH injected bilaterally into the hippocampus is anticonvulsant and also increases the effectiveness of carbamazepine in tolerant animals. 8) Neurochemical correlates of contingent tolerance to diazepam which are highly similar to those observed in carbamazepine tolerance despite the differential mechanisms of action of the two anticonvulsants. 9) Tolerance to both carbamazepine and diazepam has been associated with failure of seizures to increase the mRNA specificity for the alpha-4 subunit of the GABA receptor. 10) Slower tolerance development to combined treatment with carbamazepine (15 mg/kg) and valproate (low dose [150 mg/kg]) compared with either one alone. 11) Oscillatory patterns of drug responsivity to carbamazepine and valproate under certain circumstances of repeated drug administration and kindling stimulation (i.e., minimally effective doses or lower stimulation intensities). 12) Development of a novel one-day cocaine sensitization paradigm that is entirely conditioned or context-dependent and dependent on an intact amygdala and nucleus accumbens. 13) The requirement of intact dopamine function for the development, but not expression, of context-dependent sensitization. 14) Cross sensitization between cocaine and the NMDA antagonist MK-801, and between cocaine and procaine (a local anesthetic that is also self-administered by primates), but not between cocaine and lidocaine (which is not self-administered) or cocaine and caffeine. 15) Blockade of the development of sensitization by MK-801, lithium, nimodipine, clonidine, and diazepam, but not by carbamazepine, proglumide (CCK antagonist), or alpha-helical CRF (CRF antagonist). 16) Blockade of the expression of conditioned sensitization by clonidine, diazepam, and nimodipine.

该项目的总体目标是研究 反应性不断变化的现象学和生物底物 吸毒。这些发现用于提出有关的假设 临床对抗惊厥情绪稳定器的反应丧失和 测试显示或逆转公差过程的可能方法。 所研究的模型还具有成为独特的特征 取决于药物管理的突发事件或背景。 因此，它们不涉及药代动力学的主要变化， 而是取决于神经系统中的适应 对药物与疾病状态相互作用时的反应。在 点燃范式，我们衡量 抗惊厥药功效，在致敏模型中，我们 研究药物反应的环境环境决定因素。我们 已经证明了抗惊厥的功效 卡马西平，丙丙酸酯和地西epa可以通过 与药物管理和癫痫发作有关的时间因素 推介会。生理反应性的一定变化， 基因表达和受体调节已在 与宽容的发展。用于研究可卡因 敏化，我们开发了一种快速的行为范式， 产生条件或上下文的增强行为 对可卡因的反应；神经生物学的相关性继续 在与我们的理解有关的情况下进行调查 环境提示可以与行为变化相关联（即 学习）。迄今为止的重大发现包括 下列的。 1）效率不足和对卡马西平的耐受性 和其他抗惊厥药，偶然的表现 以前的药物，但不是之后，点燃刺激导致 在点燃的各个阶段对药物的反应减少 进化。 2）按时间休息的偶然性公差的可逆性 治疗甚至继续治疗后给予的药物 点燃的癫痫发作（即，不终止药物管理局， 仅改变意外情况）或仅通过点燃的癫痫发作。 3） 卡马西平和拉莫三嗪之间的选择性交叉耐受性， 瓣膜酸盐和PK-11195（外围型的拮抗剂 苯二氮卓受体），但不是地西epa，氯硝西ep剂量或 苯托因。 4）癫痫发作阈值的改变 对卡马西平的反应性变化。 5）放慢的程序 宽容的发展；例如，非偶然药物 在较低的刺激电流中表现或点燃大鼠，但 NMDA拮抗剂MK-801或 钙通道阻滞剂nimodipine。 6）许多神经化学 代表子集的损失的偶然公差的相关性 GABA-A系统中的癫痫发作诱导的适应 肽mRNA，营养因子和立即的早期基因。 7） TRH mRNA未能显示癫痫发作诱导的增加 耐甲状动腺素的动物更加紧密 与耐受性相关的机械链接，观察到TRH 双侧注入海马是抗惊厥药，也是 提高卡马西平在耐受动物中的有效性。 8） 对地西ep的偶有耐受性的神经化学相关性 与在卡马西平中观察到的高度相似 尽管两者的作用机理不同，但容忍度 抗惊厥药。 9）对卡马西平和地西ep的耐受性 与癫痫发作未能增加mRNA有关 GABA受体的α-4亚基的特异性。 10） 耐受性的发展降低，将治疗与 卡马西平（15 mg/kg）和丙戊酸（低剂量[150 mg/kg]） 与一个单独的一个相比。 11）药物的振荡模式 在某些地方对卡马西平和丙丙酸酯的反应 反复的药物管理和点燃的情况 刺激（即，最小有效剂量或较低的刺激 强度）。 12）开发新颖的一日可卡因 完全条件或 与上下文有关，并依赖于完整的杏仁核和 伏隔核。 13）完整多巴胺的要求 开发的功能，但不表达 依赖上下文的灵敏度。 14）交叉敏化 可卡因和NMDA拮抗剂MK-801，以及可卡因之间 和Procaine（一种局部麻醉，也是由 灵长类动物），但不在可卡因和利多卡因之间（不是 自我管理）或可卡因和咖啡因。 15）封锁 MK-801，锂，nimodipine的敏化发展， 可乐定和地西epa，但不是卡马西平，proglumide （CCK拮抗剂）或α-螺旋CRF（CRF拮抗剂）。 16） 封锁条件敏化表达 可乐定，地西ep和nimodipine。