Peptide Regulation of the Neurocircuitry Underlying Drug Relapse

描述(申请人提供)：吸毒成瘾对吸毒者和社会来说都是一种毁灭性的疾病。不幸的是，在戒毒一段时间后，几乎没有可用的治疗选择来防止再次吸毒。因此，这项建议的主要目的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，即可卡因诱导的恢复至少部分是由腹侧苍白球(VP)中GABA的减少介导的，而GABA的减少是通过激活MU阿片受体来调节的。注射Mu拮抗剂CTAP可阻断注射可卡因后GABA的下降和行为的恢复。因此，这一建议的主要假设是，戒断后启动可卡因需要减少VP中GABA的释放以产生恢复，而干预增加VP中的GABA将阻止恢复。因此，几种作用于VP中的多肽受体的化合物将通过反向透析注入，并将使用微透析和电化学检测来测量GABA浓度。被发现增加GABA的化合物将在可卡因引发的药物复发恢复模型中进行测试，以确定是否增加VP中GABA的化合物也会阻止恢复。此外，在伏核注射阿片拮抗剂阻断恢复的发现表明，慢性可卡因和戒断改变了内源性阿片类药物等多肽从伏隔核释放到VP的方式。为了更好地了解慢性可卡因后脑区如VP区的多肽释放是如何改变的，需要开发一种可靠的方法来测量微透析样本中的神经肽。因此，这项建议的第二个目标是开发一种使用质谱学测量多肽的方法，最终将用于检验可卡因引发VP中的多肽释放，特别是内源性阿片类药物产生复发行为的假说。最终，当充分了解快速作用的神经递质和多肽之间的相互作用时，我们将能够找到预防吸毒者复发的最佳靶点。这项建议与公众健康有关，因为它将增加我们对长期接触药物滥用后大脑发生的变化的了解，这些药物滥用导致吸毒者有如此强烈的复发倾向。将确定和核实预防复发的具体目标，从而开发潜在的药物疗法，以防止吸毒成瘾的个人再次吸毒。

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.