Neuroadaptation produced by acute PTSD-like stress create vulnerability for cannabis addiction
急性创伤后应激障碍(PTSD)样压力产生的神经适应导致大麻成瘾的脆弱性
基本信息
- 批准号:10266093
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylcysteineAcuteAcute Post Traumatic Stress DisorderAnimal ModelBehavioralBrainCannabidiolCannabisCharacteristicsClinicalCuesDSM-VDataDendritic SpinesDiagnosisDiseaseDrug Delivery SystemsDrug usageExtinction (Psychology)Extracellular MatrixFutureGeneral PopulationGlutamate TransporterGlutamatesIncidenceInterventionInvestigationLifeMatrix MetalloproteinasesMeasurementMeasuresMediatingMetalloproteasesModelingMorphologyN-MethylaspartateNeurologicNucleus AccumbensOdorsOutcomePatient-Focused OutcomesPatientsPatternPharmaceutical PreparationsPost-Traumatic Stress DisordersPrefrontal CortexProcessProteinsPublishingRattusRelapseResearchSelf AdministrationSeveritiesSignal TransductionSiteStimulusStressSubstance Use DisorderSymptomsSynapsesSynaptic CleftSynaptic TransmissionSynaptic plasticityTestingTetrahydrocannabinolTrainingTreatment outcomeVeteransaddictionbiological adaptation to stressbrain circuitrycombatcombat veterancomorbidityconditioningdensitydrug cravingexperienceimprovedinnovationmarijuana useneuroadaptationneurobiological mechanismnovelpostsynapticpre-clinical researchpreclinical evaluationpreventprotein expressionrestraint stressstressor
项目摘要
The incidence of post-traumatic stress disorder (PTSD) among combat-experienced Veterans is ~20%,
which is substantially larger than in the general population (~3.5%). Moreover, 40-50% of Veterans suffering
PTSD are also diagnosed with substance use disorders (SUDs). Patients with comorbid PTSD and SUDs have
greater drug use severity and show poorer treatment outcomes than patients diagnosed with either PTSD or
SUDs alone. This special need of returning combat Veterans is largely unaddressed by preclinical research.
PTSD and SUDs share in common the DSM-V characteristic that environmental stimuli associated with a
stressor or drug use can precipitate symptoms of the disorder. Conditioned drug cravings involve activation of
a circuit containing the prefrontal cortex and nucleus accumbens, and repeated drug use produces enduring
changes in synaptic plasticity in the accumbens. Also, drug-conditioned cues elicit drug seeking in animal
models of relapse by inducing transient synaptic plasticity at these synapses. We recently published and
present further new data that a single episode of acute restraint stress in rats produces long-lasting (>3 weeks)
changes in accumbens synapses that parallel the changes produced by addictive drugs. The overarching
hypothesis in our proposal is that cues predicting stress or drug delivery employ the same cortico-accumbens
mechanisms to elicit drug seeking and conditioned stress responding, and that these mechanisms underlie
comorbid PTSD and SUDs.
Cannabis is among the addictive drugs most widely abused by Veterans. We recently developed a model of
cannabis self-administration and cue-induced drug seeking in rats that uses a combination of two constituents
of cannabis, 9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We propose to use THC+CBD self-
administration and reinstated drug seeking in combination with acute restraint stress to evaluate how cannabis
use and conditioned stress interact through accumbens synaptic plasticity to promote stress-induced drug
seeking. Our investigation will utilize recent discoveries showing that quantifying synaptic changes in the
canonical pre- and postsynapse is insufficient to understand the transient plasticity produced by drug cues.
Accordingly, we will also quantify signaling in the protein-rich extracellular matrix (ECM) that surrounds the
synapse, and changes in perisynaptic astroglial processes that regulate synaptic transmission through the
patterned expression of proteins adjacent to the synaptic cleft. Together, these four synaptic compartments are
referred to as the tetrapartite synapse.
The three proposed Specific Aims will be sequentially engaged. Aim 1 characterizes the behavioral and
synaptic effects of conditioned stress using the defensive burying model of stress responding that will allow
correlations to be evaluated between stress responding and measures of tetrapartite synaptic plasticity. Aim 2
uses the information garnered in Aim 1 to investigate the interactions between conditioned stress and
THC+CBD use and seeking. Conditioned stress will be used to reinstate THC+CBD seeking and we will
compare the intensity of drug seeking with measures of tetrapartite synaptic plasticity. Finally, in Aim 3 we
endeavor to prevent the interactions between conditioned stress and cannabis use by manipulating key
proteins regulating tetrapartite synaptic plasticity, including the astroglial glutamate transporter (GLT-1) and
specific matrix metalloproteases that catalytically signal synaptic plasticity. Through completion of these
Specific Aims, we expect to identify overlapping brain circuitry and cellular mechanisms between conditioned
stress and cannabis seeking that can be explored in future studies as sites of pharmacotherapeutic
intervention for treating the high incidence of PTSD and comorbid SUDs in our returning combat Veterans.
有战斗经验的退伍军人中创伤后应激障碍(PTSD)的发病率约为20%,
这一比例远远高于一般人群(约3.5%)。此外,40-50%的退伍军人遭受
PTSD也被诊断为物质使用障碍(SUD)。患有PTSD和SUD的患者
更大的药物使用严重程度,并显示出比诊断为PTSD或
只有SUD。这种特殊的需要返回战斗退伍军人在很大程度上是未解决的临床前研究。
PTSD和SUD都有一个共同的DSM-V特征,即环境刺激与
紧张性刺激或药物的使用可以加速紊乱的症状。条件性药物渴望涉及激活
一个包含前额叶皮层和丘脑核的回路,反复使用药物会产生持久的
突触可塑性的变化。此外,药物条件化线索在动物中引起药物寻求
通过在这些突触处诱导瞬时突触可塑性来建立复发模型。我们最近出版了
提出了进一步的新数据,即大鼠单次急性束缚应激可产生长期(>3周)
与成瘾药物产生的变化相平行的突触变化。总体
我们的假设是,预测压力或药物输送的线索使用相同的皮质类固醇
引起药物寻求和条件性应激反应的机制,这些机制是
合并创伤后应激障碍和SUD
大麻是退伍军人最广泛滥用的成瘾药物之一。我们最近开发了一个
使用两种成分的组合在大鼠中进行大麻自我给药和线索诱导的药物寻找
大麻、四氢大麻酚(THC)和大麻二酚(CBD)。我们建议使用THC+CBD自-
管理和恢复药物寻求与急性约束压力相结合,以评估大麻
使用和条件应激相互作用,通过突触可塑性,促进应激诱导的药物
寻找我们的研究将利用最近的发现,表明量化突触的变化,
典型的突触前和突触后不足以理解药物线索产生的瞬时可塑性。
因此,我们还将量化围绕细胞的富含蛋白质的细胞外基质(ECM)中的信号传导。
突触,以及突触周围星形胶质细胞过程的变化,这些过程通过突触传递调节突触传递。
邻近突触间隙的蛋白质的模式化表达。这四个突触区室合在一起
称为四分突触。
三个拟议的具体目标将按顺序进行。目标1描述了行为和
条件应激的突触效应,使用应激反应的防御性埋藏模型,
应激反应和四分突触可塑性测量之间的相关性有待评估。目的2
使用目标1中收集的信息来研究条件应激与
THC+CBD的使用和寻求。条件压力将用于恢复THC+CBD寻求,我们将
将药物寻求的强度与四分突触可塑性的测量进行比较。最后,在目标3中,
奋进防止条件压力和大麻使用之间的相互作用,通过操纵关键
调节四方突触可塑性的蛋白质,包括星形胶质细胞谷氨酸转运蛋白(GLT-1)和
催化突触可塑性信号的特定基质金属蛋白酶。通过完成这些
具体的目的,我们希望确定重叠的大脑回路和细胞机制之间的条件
压力和大麻寻求,可以在未来的研究中探索作为药物治疗的网站
干预治疗高发病率的创伤后应激障碍和共病SUDs在我们返回的战斗退伍军人。
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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Peter W Kalivas其他文献
Why D-neuron?
为什么是D-神经元?
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
Shieenobu Toda;Sakurako Kosugi;Haowei Shen;YoshioIguchi;Tetsu Hirosawa;Yoshio Minabe;Peter W Kalivas;戸田重誠;戸田重誠;池本桂子;Ikemoto K - 通讯作者:
Ikemoto K
Orexin: a gatekeeper of addiction
食欲素:成瘾的看门人
- DOI:
10.1038/nm0306-274 - 发表时间:
2006-03-01 - 期刊:
- 影响因子:50.000
- 作者:
David Carr;Peter W Kalivas - 通讯作者:
Peter W Kalivas
Cocaine-induced metaplasticity may be based on the altered balance betweenprotein translation and protein elimination in the rat nucleus accumbens : implications of glutamatergic tone for protein turnover.
可卡因诱导的化塑性可能是基于大鼠伏隔核中蛋白质翻译和蛋白质消除之间平衡的改变:谷氨酸能张力对蛋白质周转的影响。
- DOI:
- 发表时间:
2010 - 期刊:
- 影响因子:0
- 作者:
Shigenobu Toda;Sakurako Kosugi;Haowei Shen;Yoshio Iguchi;Tetsu Hirosawa;Yoshio Minabe;Peter W Kalivas - 通讯作者:
Peter W Kalivas
Role of PSD structure sustained by action and tonic dopamine in the ratnucleus accumbens of repeatedly cocaine administrated rats.
反复给予可卡因的大鼠伏隔核中作用和强直多巴胺维持的 PSD 结构的作用。
- DOI:
- 发表时间:
2010 - 期刊:
- 影响因子:0
- 作者:
Shieenobu Toda;Sakurako Kosugi;Haowei Shen;YoshioIguchi;Tetsu Hirosawa;Yoshio Minabe;Peter W Kalivas - 通讯作者:
Peter W Kalivas
「線条体と依存症」Brain and Nerve
《纹状体与成瘾》大脑与神经
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
Shieenobu Toda;Sakurako Kosugi;Haowei Shen;YoshioIguchi;Tetsu Hirosawa;Yoshio Minabe;Peter W Kalivas;戸田重誠 - 通讯作者:
戸田重誠
Peter W Kalivas的其他文献
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{{ truncateString('Peter W Kalivas', 18)}}的其他基金
Center for Opioid and Cocaine Addiction (COCA)
阿片类药物和可卡因成瘾中心 (COCA)
- 批准号:
10404580 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Center for Opioid and Cocaine Addiction (COCA)
阿片类药物和可卡因成瘾中心 (COCA)
- 批准号:
10914549 - 财政年份:2019
- 资助金额:
-- - 项目类别:
COCA - Project 3. Tetrapartite Synapses Regulate Cue-induced Drug Seeking
COCA - 项目 3。四方突触调节提示诱导的药物寻求
- 批准号:
10630234 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Center for Opioid and Cocaine Addiction (COCA)
阿片类药物和可卡因成瘾中心 (COCA)
- 批准号:
10630221 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Center for Opioid and Cocaine Addiction (COCA)
阿片类药物和可卡因成瘾中心 (COCA)
- 批准号:
9793193 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Center for Opioid and Cocaine Addiction (COCA)
阿片类药物和可卡因成瘾中心 (COCA)
- 批准号:
10017210 - 财政年份:2019
- 资助金额:
-- - 项目类别:
COCA - Project 3. Tetrapartite Synapses Regulate Cue-induced Drug Seeking
COCA - 项目 3。四方突触调节提示诱导的药物寻求
- 批准号:
10404586 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Neuroadaptation produced by acute PTSD-like stress create vulnerability for cannabis addiction
急性创伤后应激障碍(PTSD)样压力产生的神经适应导致大麻成瘾的脆弱性
- 批准号:
10477266 - 财政年份:2019
- 资助金额:
-- - 项目类别:
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