TOLERANCE AND SENSITIZATION

耐受性和致敏性

• 批准号: 6290593
• 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/6290593
• 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不断变化的药物反应性的现象学和生物底物。这些发现用于提出有关临床对抗惊厥情绪稳定器反应的临床丧失的假设，并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依赖药物服用的突发事件或背景的独特特征。因此，它们不涉及药代动力学的主要变化，而是依赖于神经系统中的适应性在与疾病状态相互作用时响应药物的适应。在点燃范式中，我们测量了抗惊厥药功效的损失和恢复，在致敏模型中，我们研究了药物反应的环境环境的决定因素。我们已经证明，可以通过与药物给药和癫痫发作有关的时间因素来操纵卡马西平，丙戊酸和地西epam的抗惊厥功效。与耐受性的发展一起，已经证明了生理反应，基因表达和受体调节的一定变化。为了研究可卡因的敏感性，我们开发了一种快速的行为范式，产生了有条件或上下文依赖的可卡因行为反应。神经生物学的相关性继续进行研究，因为它们与我们对环境线索如何与行为变化相关的理解（即学习）。迄今为止的重大发现包括以下示范。 1）偶然的效率低下和对卡马西平和其他抗惊厥药的耐受性，从而以前的偶然表现出来，但并非此后，点燃刺激会导致对药物的反应下降。 2）通过休假时间或什至对点燃癫痫发作后给药的药物进行治疗的可逆性（即不停止药物给药，仅偶然性发生）或单独使用点燃的癫痫发作。 3）卡马西平和拉莫三嗪，丙戊酸和PK-11195（外围型苯并二氮卓受体的拮抗剂）之间的选择性交叉耐受性，但不是地西epa，氯硝西epam或苯二甲酸。 4）癫痫发作阈值的改变，反映了对卡马西平的反应性的变化。 5）缓慢偶然性耐受性发展的程序；例如，在较低的刺激电流下进行非转化性药物表现或点燃大鼠，而不是对NMDA拮抗剂MK-801或钙通道阻滞剂Nimodipine的共同给药。 6）许多偶然耐受性的神经化学相关性，代表了GABA-A系统中癫痫发作诱导的适应的子集以及肽mRNA，营养因子和早期基因的丧失。 7）TRH mRNA未能显示出癫痫发作的含氨基丙氨酸耐受性动物的癫痫发作诱导的增加，与耐受性更紧密地联系在一起，观察到，TRH将双侧注射到海马中是抗惊厥药，并且还增加了甲壳虫在耐受动物中的有效性。 8）与地西ep抗性的神经化学相关性，尽管两种抗惊厥药的作用机理不同，但与地西ep剂的耐受性相似，这与在卡马西平耐受性中观察到的神经化学相关性。 9）对卡马西平和地西epa的耐受性与癫痫发作未能增加GABA受体α-4亚基的mRNA特异性有关。 10）与单独使用任何一种相比，与卡马西平（15 mg/kg）和丙丙酸酯（低剂量[150 mg/kg]）相结合的耐受性发展较慢。 11）在反复给药和点燃刺激的某些情况下，药物对卡马西平和丙丙酸酯的振荡模式（即，最小有效剂量或较低的刺激强度）。 12）开发一种新型的一日可卡因敏化范式，该范式完全依赖或依赖于上下文，并取决于完整的杏仁核和伏隔核。 13）完整多巴胺功能的需求对上下文依赖性敏化的发展而不是表达。 14）可卡因与NMDA拮抗剂MK-801之间以及可卡因和普罗caine（一种局部麻醉剂）之间的交叉敏化，但在可卡因和利多卡因（不是自我管理）或可卡因之间的局部麻醉剂（一种局部麻醉剂）或不是自我管理）或可卡因和可卡因和可卡因和可卡因。 15）封闭MK-801，锂，nimodipine，Clonidine和Wizepam的敏化开发，而不是卡马西平，proglumide（CCK拮抗剂）或α-螺旋甲基CRF（CRF拮抗剂）。 16）封锁可乐定，地西ep和尼莫地平的条件敏化表达。