Peptide Regulation of the Neurocircuitry Underlying Drug Relapse

描述（由申请人提供）：吸毒成瘾对吸毒者和社会都是一种毁灭性的疾病。不幸的是，在一段时间的戒断后，很少有治疗方案可以防止复发。因此，本研究的首要目标是利用体内微透析和可卡因复吸模型来扩展我们对复吸行为背后的神经回路的理解。目前的建议是基于这样的发现，可卡因引发的恢复至少部分是由腹侧苍白质（VP）中GABA的减少介导的，GABA的减少是由mu阿片受体的激活介导的。注入VP的mu拮抗剂CTAP阻断了注射可卡因后GABA的减少和恢复行为。因此，本提案的主要假设是，戒断后可卡因启动需要VP中GABA释放的减少来产生恢复，而增加VP中GABA的干预将阻止恢复。因此，将通过反透析注入几种作用于VP中肽受体的化合物，并使用微透析和电化学检测来测量GABA浓度。发现增加GABA的化合物将在药物复发的可卡因启动恢复模型中进行测试，以确定增加VP中GABA的化合物是否也会阻止恢复。此外，在副脑室注射阿片拮抗剂阻断恢复的发现表明，长期可卡因和戒断改变了内源性阿片样物质等多肽从伏隔核释放到副脑室的方式。为了更好地了解慢性可卡因后肽释放在脑区域（如VP）中的改变，需要开发一种可靠的方法来测量微透析样品中的神经肽。因此，本提案的第二个目的是开发一种使用质谱法测量肽的方法，该方法最终将用于验证可卡因启动导致VP中肽（特别是内源性阿片样物质）释放从而产生复发行为的假设。最终，当快速作用的神经递质和多肽之间的相互作用被完全理解时，我们将能够找到预防吸毒成瘾者复发的最佳目标。这一建议与公共卫生有关，因为它将增加我们对长期接触滥用药物后大脑发生的变化的理解，这些变化导致成瘾者如此强烈的复发倾向。预防复发的具体目标将被确定和验证，从而导致开发潜在的药物治疗方法来预防成瘾个体的药物复发。

DESCRIPTION (provided by applicant): Drug addiction is a devastating disease both for the addict and for society. Unfortunately there are few treatment options available that prevent relapse to drug use after a period of abstinence. Therefore, the overarching aim of this proposal is to extend our understanding of the neural circuitry underlying relapse behavior using in vivo microdialysis and the cocaine reinstatement model of relapse. The present proposal is based on the finding that cocaine-primed reinstatement is at least partially mediated by a decrease in GABA in the ventral pallidum (VP), and that the decrease in GABA is mediated by activation of mu opioid receptors. The mu antagonist CTAP infused into the VP blocked both the decrease in GABA and reinstatement behavior after a cocaine-priming injection. Therefore, the primary hypothesis of this proposal is that cocaine-priming after abstinence requires a decrease in GABA release in the VP to produce reinstatement, and interventions that increase GABA in the VP will prevent reinstatement. Therefore, several compounds that act on peptide receptors in the VP will be infused by reverse dialysis, and GABA concentrations will be measured using microdialysis and electrochemical detection. Compounds found to increase GABA will be tested in the cocaine-priming reinstatement model of drug relapse to determine if compounds that increase GABA in the VP will also block reinstatement. In addition, the finding that an opioid antagonist injected in the VP blocks reinstatement suggests that chronic cocaine and abstinence changes the way peptides like the endogenous opioids are released from the nucleus accumbens to the VP. In order to better understand how peptide release is altered after chronic cocaine in brain regions such as the VP, a reliable method needs to be developed to measure neuropeptides from microdialysis samples. Therefore, a second aim of this proposal is to develop a method for measuring peptides using mass spectrometry, which will ultimately be used to test the hypothesis that cocaine-priming causes a release of peptides, particularly the endogenous opioids, in the VP to produce relapse behavior. Ultimately, when the interactions between fast-acting neurotransmitters and peptides are fully understood, we will be able to find the best target for the prevention of relapse in drug addicts. This proposal is relevant to public health because it will increase our understanding of the changes that take place in the brain after chronic exposure to drugs of abuse that lead to such a strong propensity for an addict to relapse. Specific targets for the prevention of relapse will be determined and verified, leading to the development of potential pharmacotherapies for the prevention of drug relapse in addicted individuals.