Tolerance And Sensitization

该项目的总体目标是研究药物反应性变化的现象学和生物学基础。这些发现被用来发展关于对抗惊厥情绪稳定剂的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。所研究的模型也具有依赖于药物给药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，而是取决于神经系统对药物的适应，因为它们与疾病状态相互作用。在点燃范式中，我们测量抗惊厥药物疗效的丧失和恢复，在致敏模型中，我们研究药物反应的环境背景决定因素。我们已经证明，卡马西平、丙戊酸盐和地西泮的抗惊厥疗效可以通过与给药和癫痫发作表现相关的时间因素来控制。生理反应、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，该范式产生对可卡因的条件性或情境依赖性增强行为反应;其神经生物学相关性继续被研究，因为它们与我们对环境线索如何与行为变化相关的理解有关（即，学习）。迄今为止的重要调查结果包括以下方面的证明。1)对卡马西平和其他抗惊厥药的偶然无效和耐受性，即在点燃刺激之前而不是之后偶然出现药物，导致点燃演变的各个阶段对药物的反应减弱。2)通过停止治疗或甚至在点燃癫痫发作后继续使用药物治疗（即，药物给药不中断，只是偶然性改变）或单独点燃癫痫发作。3)卡马西平与拉莫三嗪、丙戊酸盐和PK-11195（外周型苯二氮卓类受体拮抗剂）之间存在选择性交叉耐受，但与地西泮、氯硝西泮或苯妥英之间不存在选择性交叉耐受。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)减缓偶发性耐受发展的程序;例如，非偶然的药物呈现或点燃大鼠在较低的刺激电流，但不共同管理的NMDA拮抗剂MK-801或钙通道阻滞剂尼莫地平。6)许多神经化学相关的偶然性耐受，代表了一个子集的损失，在GABA-A系统，以及肽mRNA，营养因子，和立即早期基因的神经诱导的适应。7)TRH mRNA在卡马西平耐受动物中未表现出惊厥诱导的增加，这在机制上与耐受性有更密切的联系，观察到TRH双侧注射到海马中具有抗惊厥作用，并且还增加了卡马西平在耐受动物中的有效性。8)尽管两种抗惊厥药的作用机制不同，但与卡马西平耐受性高度相似的地西泮偶然耐受性的神经化学相关性。9)对卡马西平和地西泮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)与任一单独给药相比，卡马西平（15 mg/kg）和丙戊酸盐（低剂量[150 mg/kg]）联合给药的耐受性发展较慢。11)在重复给药和点燃刺激的某些情况下，对卡马西平和丙戊酸盐的药物反应性的振荡模式（即，最低有效剂量或较低刺激强度）。12)一种新的一天可卡因致敏范式的发展，完全是条件性的或上下文依赖的，并依赖于完整的杏仁核和杏仁核。13)完整的多巴胺功能对于情境依赖性敏化的发展而非表达的要求。14)可卡因和NMDA拮抗剂MK-801之间以及可卡因和普鲁卡因（一种灵长类动物也自我给药的局部麻醉剂）之间存在交叉致敏作用，但可卡因和利多卡因（不能自我给药）或可卡因和咖啡因之间不存在交叉致敏作用。15)MK-801、锂、尼莫地平、可乐定和地西泮可阻断致敏作用，但卡马西平、丙谷胺（CCK拮抗剂）或α-螺旋CRF（CRF拮抗剂）不能阻断致敏作用。16)可乐定、地西泮和尼莫地平阻断条件性敏化的表达。

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.