Peptide Regulation of the Neurocircuitry Underlying Drug Relapse

描述（由申请人提供）：吸毒成瘾是一种毁灭性的疾病，对吸毒者和社会。不幸的是，几乎没有治疗方案可以防止戒断一段时间后重新吸毒。因此，这项建议的首要目标是扩大我们的理解的神经回路的基础上复发的行为，使用体内微透析和可卡因复吸模型的复发。本建议是基于可卡因引发的恢复至少部分介导的腹侧苍白球（VP）中的GABA的减少，并且GABA的减少是由μ阿片受体的激活介导的这一发现。注入VP的μ拮抗剂CTAP阻断了可卡因引发注射后GABA的减少和恢复行为。因此，该建议的主要假设是，戒断后可卡因引发需要减少VP中的GABA释放以产生恢复，并且增加VP中的GABA的干预措施将防止恢复。因此，将通过反向透析输注作用于VP中肽受体的几种化合物，并使用微透析和电化学检测来测量GABA浓度。发现增加GABA的化合物将在可卡因引发的药物复发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VP中注射阿片类拮抗剂阻断恢复的发现表明，慢性可卡因和禁欲改变了内源性阿片类肽从延髓核释放到VP的方式。为了更好地了解肽释放是如何改变后，慢性可卡因在大脑区域，如VP，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，该方法最终将用于检验可卡因引发导致VP中肽（特别是内源性阿片类药物）释放以产生复发行为的假设。最终，当快速作用的神经递质和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吸的最佳靶点。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了解，这些变化导致吸毒成瘾者复发的强烈倾向。将确定和核实预防复吸的具体目标，从而开发预防吸毒成瘾者复吸的潜在药物疗法。

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.