TOLERANCE AND SENSITIZATION

该项目的总体目标是研究对药物反应性变化的现象学和生物学基础。这些发现被用来提出对抗惊厥情绪稳定剂临床反应丧失的假设，并测试显示或逆转耐受过程的可能方法。所研究的模型还具有依赖于药物管理的偶然性或背景的独特特征。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对药物与疾病状态相互作用的适应。在点燃范式中，我们测量了抗惊厥药物疗效的丧失和恢复，在致敏模型中，我们研究了药物反应的环境因素。我们已经证明卡马西平、丙戊酸和地西泮的抗惊厥疗效可以被与药物给药和癫痫发作有关的时间因素所操纵。生理反应性、基因表达和受体调节的偶然变化已被证明与耐受性的发展相一致。为了研究可卡因致敏，我们开发了一种快速行为范式，该范式对可卡因产生条件或情境依赖的增强行为反应；与此相关的神经生物学研究仍在继续，因为它们与我们对环境线索如何与行为变化（即学习）联系在一起的理解有关。迄今为止的重要发现包括以下论证。1)对卡马西平和其他抗惊厥药物的偶然性无效和耐受性，即在点燃刺激之前而不是在点燃刺激之后偶然出现药物，导致在点燃进化的各个阶段对药物的反应减弱。2)偶然耐受性的可逆性，可通过暂停治疗甚至继续使用点燃性发作后给予的药物（即不停止给药，仅改变偶然耐受性）或单独由点燃性发作引起。3)卡马西平与拉莫三嗪、丙戊酸和PK-11195（外周型苯二氮卓受体拮抗剂）的选择性交叉耐受性，但对地西泮、氯硝西泮或苯妥英没有选择性交叉耐受性。4)癫痫发作阈值的改变反映了对卡马西平反应性的变化。5)减缓偶然容忍度发展的程序；例如，非偶然给药或在较低的刺激电流下点燃大鼠，但不同时给药NMDA拮抗剂MK-801或钙通道阻滞剂尼莫地平。6)偶然耐受性的一些神经化学相关物质，代表了GABA-A系统中癫痫诱导的适应性子集的丧失，以及肽mrna、营养因子和直接早期基因。7)在卡马西平耐受动物中，TRH mRNA未能显示癫痫诱导的增加与耐受性有更密切的机制联系，观察到双侧海马注射TRH具有抗惊厥作用，也增加了卡马西平耐受动物的有效性。8)地西泮偶然耐受性的神经化学相关因素与卡马西平耐受性的神经化学相关因素高度相似，尽管这两种抗惊厥药的作用机制不同。9)卡马西平和地西泮的耐受性与癫痫发作失败有关，无法增加GABA受体α -4亚基的mRNA特异性。10)卡马西平（15 mg/kg）和丙戊酸盐（低剂量[150 mg/kg]）联合治疗的耐受性发展较单用较慢。11)卡马西平和丙戊酸在重复给药和点火刺激（即最低有效剂量或较低刺激强度）的特定情况下药物反应性的振荡模式。12)开发一种新的一天可卡因致敏模式，该模式完全依赖于条件或情境，依赖于完整的杏仁核和伏隔核。13)完整的多巴胺功能对情境依赖性敏化的发展，而不是表达的要求。14)可卡因与NMDA拮抗剂MK-801之间、可卡因与普鲁卡因（灵长类动物也自行使用的一种局部麻醉剂）之间存在交叉致敏，但可卡因与利多卡因（非自行使用）或可卡因与咖啡因之间没有交叉致敏。15) MK-801、锂、尼莫地平、可乐定和地西泮可阻断致敏发展，但卡马西平、丙脲（CCK拮抗剂）或α -螺旋CRF （CRF拮抗剂）不能阻断致敏发展。16)可乐定、地西泮和尼莫地平对条件致敏表达的阻断。

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.