Glutamergic Mechanisms in Opioid and Cocaine Co-Use
阿片类药物和可卡因共同使用的谷氨酸机制
基本信息
- 批准号:9978489
- 负责人:
- 金额:$ 21.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-30 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylcysteineAnimalsAttenuatedBiological MarkersBrainChemosensitizationChronicClinicalCocaineCuesDendritic SpinesDependenceDevelopmentDiseaseDoseDrug ControlsDrug Use DisorderDrug usageFoodGlutamate TransporterGlutamatesHeroinHomosynaptic DepressionHumanIndividualIntakeInterventionIntravenousKnowledgeLaboratoriesMagnetic Resonance SpectroscopyMaintenanceMeasuresMethodsModelingMotivationN-MethylaspartateNeuronsNucleus AccumbensOpioidOpioid agonistOralOxycodonePatternPharmaceutical PreparationsPharmacotherapyPhasePhased Innovation AwardsPhysical DependencePhysiologicalPlacebosProteinsProtocols documentationProxyPublic HealthRandomizedReportingSelf AdministrationSpecific qualifier valueStimulusSynapsesSynaptic plasticitySystemTimeUnited StatesUp-RegulationWithdrawalWorkcocaine exposurecocaine usecomorbiditycomparison groupexperienceglutamatergic signalingimproved outcomeincentive saliencemeetingsmotivated behaviormultiple drug useneurobiological mechanismneuromechanismnovelnovel therapeuticsopioid useopioid use disorderopioid withdrawaloverdose riskpolysubstance abusepre-clinicalprotein expressionrelating to nervous systemsex
项目摘要
Opioid use disorder (OUD) is a leading public health crisis in the United States. Individuals with opioid use
disorder frequently use other substances, including cocaine. Past year opioid withdrawal was associated with 4
times greater odds of current cocaine use, which may represent an attempt to ameliorate opioid withdrawal
effects but also increases overdose risk, as evidenced by preclinical and clinical findings. Approved OUD
pharmacotherapies are modestly effective, but these medications are not indicated for treating cocaine co-use,
highlighting the need for a novel intervention approach to improve outcomes in co-morbid OUD and cocaine use
disorder. Mechanistically, drug-motivated behaviors are regulated by glutamate signaling within corticostriatal
circuitry. Both opioid and cocaine self-administration (SA) down-regulate the glial glutamate transporter (GLT-
1), and alter synaptic plasticity measured as changes in dendritic spines and AMPA-to-NMDA current ratios
(A/N) within the nucleus accumbens core (NAcore). Thus, glutamatergic plasticity is a conserved neural
mechanism underlying drug motivation in both opioid and cocaine use. The combined effects of opioid and
cocaine co-use on glutamatergic systems, however, are unknown. n-Acetylcysteine (NAC) has shown
translational promise for treating multiple drug use disorders, including cocaine and opioids. NAC is capable of
restoring glutamatergic alterations induced by either drug alone, likely by increasing glutamate clearance from
the synapse following drug use through upregulation of GLT-1. Clinically, we have shown that NAC reduces the
incentive salience of cocaine-related stimuli, which controls drug seeking. As well, others have shown that NAC
normalizes glutamate function in cocaine-dependent individuals. Whether NAC reduces drug intake and reverses
glutamatergic alterations induced by co-use of opioids and cocaine is unknown. The work proposed here will
begin to fill those crucial knowledge gaps. Our overarching hypotheses are that (1) persistent brain glutamate
changes induced by chronic opioid use will exacerbate use of cocaine during opioid physical dependence and
withdrawal and (2) that NAC will ameliorate glutamatergic dysregulation, and thus will reduce both oxycodone
and cocaine use. We propose a two phase, translational project supported by the R21/R33 mechanism. In the
first phase (R21), we will characterize NAcore glutamatergic signaling in opioid and cocaine co-use as a neural
biomarker for pharmacotherapeutic targeting with NAC using preclinical laboratory methods. Upon meeting the
milestones set forth for the R21, we will conduct the second phase (R33), in which we will determine the influence
of NAC on glutamate function and reinforcing effects of cocaine in co-morbid opioid and cocaine use disorder
using human laboratory methods. The milestones completed during this translational project will elucidate
glutamatergic dysregulation underlying opioid and cocaine co-use, laying the groundwork for effective
pharmacotherapeutic treatment for this pattern of polysubstance abuse through targeting glutamate signaling.
阿片类药物使用障碍(OUD)是美国的一个主要公共卫生危机。阿片类药物使用者
经常使用其他物质,包括可卡因。去年阿片类药物戒断与4
当前可卡因使用的可能性增加一倍,这可能代表着试图改善阿片类药物戒断
临床前和临床结果证明,这不仅会产生副作用,而且会增加用药过量的风险。批准的OUD
药物治疗是适度有效的,但这些药物不适用于治疗可卡因的共同使用,
强调需要一种新的干预方法,以改善OUD和可卡因使用共病的结局
disorder.从机制上讲,药物激发的行为是由皮质纹状体内的谷氨酸信号调节的。
电路阿片类药物和可卡因自我给药(SA)均下调神经胶质谷氨酸转运蛋白(GLT-1)。
1),并改变突触可塑性,测量树突棘和AMPA-NMDA电流比的变化
(A/N)在核内的神经节核心(NAcore)。因此,突触可塑性是一个保守的神经
阿片类药物和可卡因使用的潜在药物动机机制。阿片类药物和
然而,可卡因联合使用对谷氨酸能系统的影响尚不清楚。N-乙酰半胱氨酸(NAC)已显示
翻译的承诺,用于治疗多种药物使用障碍,包括可卡因和阿片类药物。NAC能够
恢复由任一药物单独诱导的谷氨酸能改变,可能是通过增加谷氨酸清除率,
通过GLT-1的上调来研究药物使用后的突触。临床上,我们已经证明NAC可以减少
可卡因相关刺激的激励显着性,控制药物寻求。此外,其他人也表明,NAC
使可卡因依赖者的谷氨酸功能正常化。NAC是否减少药物摄入并逆转
阿片类药物和可卡因联合使用诱导的多巴胺能改变尚不清楚。这里提出的工作将
开始填补这些关键的知识空白。我们的总体假设是:(1)持续的大脑谷氨酸
慢性阿片类药物使用引起的变化将加剧阿片类药物身体依赖期间可卡因的使用,
停药和(2)NAC将改善多巴胺能失调,因此将减少羟考酮
可卡因的使用。我们提出了一个由R21/R33机制支持的两阶段转化项目。在
第一阶段(R21),我们将描述阿片类药物和可卡因共同使用中的NAcore神经递质信号传导,
使用临床前实验室方法,使用NAC靶向药物的生物标志物。在会见
根据R21的里程碑,我们将进行第二阶段(R33),在该阶段,我们将确定
NAC对阿片类药物和可卡因共病患者谷氨酸功能的影响及可卡因的强化作用
使用人类实验室方法。在此翻译项目期间完成的里程碑将阐明
阿片类药物和可卡因共同使用的潜在代谢紊乱,为有效治疗奠定基础
通过靶向谷氨酸信号传导,对这种多物质滥用模式进行药物治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Cassandra D Gipson-Reichardt其他文献
Cassandra D Gipson-Reichardt的其他文献
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{{ truncateString('Cassandra D Gipson-Reichardt', 18)}}的其他基金
Neurobehavioral mechanisms underlying xylazine and fentanyl co-use and withdrawal
赛拉嗪和芬太尼共同使用和戒断的神经行为机制
- 批准号:
10737712 - 财政年份:2023
- 资助金额:
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Contributions of Progestins Independently and Interactively with Contraceptive Estrogen to Nicotine Use
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10710219 - 财政年份:2022
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Contributions of Progestins Independently and Interactively with Contraceptive Estrogen to Nicotine Use
孕激素独立和与避孕雌激素相互作用对尼古丁使用的贡献
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10592661 - 财政年份:2022
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Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
寻求尼古丁的神经炎症和谷氨酸机制
- 批准号:
10214266 - 财政年份:2020
- 资助金额:
$ 21.36万 - 项目类别:
Glutamergic Mechanisms in Opioid and Cocaine Co-Use
阿片类药物和可卡因共同使用的谷氨酸机制
- 批准号:
10669480 - 财政年份:2020
- 资助金额:
$ 21.36万 - 项目类别:
Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
寻求尼古丁的神经炎症和谷氨酸机制
- 批准号:
10231269 - 财政年份:2020
- 资助金额:
$ 21.36万 - 项目类别:
Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
寻求尼古丁的神经炎症和谷氨酸机制
- 批准号:
10684702 - 财政年份:2020
- 资助金额:
$ 21.36万 - 项目类别:
Glutamergic Mechanisms in Opioid and Cocaine Co-Use
阿片类药物和可卡因共同使用的谷氨酸机制
- 批准号:
10264811 - 财政年份:2020
- 资助金额:
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Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
寻求尼古丁的神经炎症和谷氨酸机制
- 批准号:
10684352 - 财政年份:2020
- 资助金额:
$ 21.36万 - 项目类别:
Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
寻求尼古丁的神经炎症和谷氨酸机制
- 批准号:
10899797 - 财政年份:2020
- 资助金额:
$ 21.36万 - 项目类别:
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