Development Of New Approaches To Neuroimaging with PET and SPECT
开发 PET 和 SPECT 神经影像新方法
基本信息
- 批准号:7733785
- 负责人:
- 金额:$ 123.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AdolescentAdultAffectAffinityAgeAgreementAmphetaminesAnimal ExperimentationAnimalsAnteriorAnxietyAnxiety DisordersAreaArtsAutopsyBehaviorBehavioralBindingBiological AssayBloodBlood specimenBolus InfusionBrainBrain imagingBrain regionCerebellar vermis structureCerebellumChildChildhoodChronicClinical ResearchConditionCorpus CallosumDataDevelopmentDiseaseDisease ProgressionDissociationDopamine ReceptorDorsalDoseDrug usageExhibitsExposure toFemaleGated Ion ChannelGenderHippocampus (Brain)HormonalHumanHuman VolunteersIllicit DrugsImageIn VitroInfantInfusion proceduresInjection of therapeutic agentInvasiveLifeLife StressLigandsLinkLiteratureMacacaMacaca mulattaMeasurementMeasuresMedialMediatingMental DepressionMethodologyMethodsMidbrain structureModelingMonkeysMoodsMothersMotivationMusMuscleNeurobiologyNicotineNicotinic AntagonistsNicotinic ReceptorsNumbersOnset of illnessOpioidParkinson DiseasePatternPerinatalPharmaceutical PreparationsPhenotypePlayPontine structurePositron-Emission TomographyPredisposing FactorPrefrontal CortexPropertyProsencephalonPubertyPumpRadioactivityRattusReproducibilityRewardsRiskRoleSaimiriSamplingScanningScheduleSelf AdministrationSelf-AdministeredSerotoninSerotonin Receptor 5-HT1ASex CharacteristicsSmokerSmokingSmoking BehaviorStressSubstance abuse problemTestingThalamic structureThinkingTimeTobacco smokeToxic effectUp-RegulationVenousbasebrain tissuecingulate cortexdaydensityearly childhoodexperiencefrontal lobehuman datain vivomalemethod developmentneuroimagingneuropsychiatrynicotine abusenon-smokernonhuman primatenovelnovel strategiespeerpreferencepsychostimulantputamenradioligandreceptorreceptor densityreceptor expressionresearch studyresponsesexsingle photon emission computed tomographysmoking cessationstress related disordervolunteer
项目摘要
Part of this project determined if differences in nAChR density between smokers and non-smokers could be shown in vivo with PET and to determine the neuroanatomical extent of the difference. We used dynamic PET imaging with 2F-18F-A-85380 (2FA) to measure total volume of distribution (VT) in non-smokers and heavy smokers. Values for VT obtained by several modeling methods using a metabolite-corrected arterial input function for 2FA yielded similar results. The thalamus (TH), midbrain (MB), pons (P), cerebellum (CB), frontal cortex (FC), putamen (PUT) and corpus callosum (CC) were sampled. VT was significantly higher in smokers than in nonsmokers in CB, FC, MB, P and PUT. PET imaging of nAChRs suggests that it can be used to study the role of nicotine-induced upregulation of nAChRs in smoking behaviors and in smoking cessation. Quantifying nAChRs in this study required arterial blood sampling and dynamic scanning as the 2FA was administered as a bolus injection. A second part of this project evaluated the less invasive bolus plus constant infusion (B/I) paradigm for quantifying nAChRs. Volunteers underwent a bolus injection study and a study in which the 2FA was administered by B/I to evaluate the feasibility of using shorter scan times and data from venous blood. VT values from the B/I studies were very similar to those calculated from bolus studies. Test/retest showed a high reproducibility of VT measurements. We conclude that B/I methodology will be useful for clinical and research studies of human brain nAChRs.
Male squirrel monkeys underwent quantitative studies of nAChRs with 2FA. Non-displaceable volumes of distribution (VDnd) were determined following blockade of 2FA specific binding by nicotine infusion. Binding potential (BP*) values, estimated using CB and muscle as reference regions, were compared for reproducibility of measurements. Administration of 2 mg/kg/day nicotine via osmotic pump nearly completely saturated specific binding to nAChRs and led to a very small changes in VT in CB and muscle (-9.4% and 0.6%, respectively), suggesting limited specific binding of 2FA in these areas. VT measured in muscle in 15 monkeys was reasonably constant but VDnd in studied brain regions exceeded VT in muscles by a factor of 1.3. Applying this factor and using muscle as a reference region, BP* values were in a good agreement with those obtained using CB as a reference region, suggesting that nAChRs can be accurately quantified using muscle as a reference region.
Potential predisposing factors (e.g., presmoking density of nAChRs) for becoming addicted to nicotine are difficult to evaluate in humans for ethical reasons. We used five squirrel monkeys to determine whether the density of nAChRs before exposure to nicotine would predict an animal's motivation to self administer nicotine. Binding potential for 2FA prior to nicotine exposure was measured and this value negatively correlated with the animal's number of responses made under the progressive ratio schedule, suggesting that low nAChR density in people may be a predisposing factor for becoming a smoker. As nicotine use increases the density of nAChRs, smoking may be a way to "normalize" receptor density.
We used microPET to quantify nAChRs in the rat brain, measuring BP* in anesthetized rats that were imaged repeatedly over six months. Using a B/I paradigm, 2FA was administered intravenously over 8 to 9 h. Steady state conditions developed within 5 h. A 2-h nicotine infusion initiated 2 h before the end of scanning displaced specifically bound 2FA. BP* averages for TH, forebrain, and CB were consistent with nAChR distribution in rat brain measured in vitro. Studies of nAChR occupancy determined that 0.29 nmol/kg/h nicotine occupied 50% of the nAChRs.
A novel radioligand F-18 NIDA131 for imaging extrathalamic nAChRs was characterized in vitro and in vivo. The Kd and T1/2 off dissociation of NIDA131 measured in vitro were 4.9 pM and 81 min, respectively. The in vivo patterns of radioactivity distribution for F-18NIDA131 and 2FA were similar and matched the distribution of nAChRs. F-18NIDA131 exhibited better in vivo binding properties than 2FA, and accumulated in monkey brain to a substantially greater extent. VT and VDnd were substantially greater than those of 2FA. The toxicity of NIDA131 in mice was comparable to 2FA and was consistent with a 2300 fold higher affinity for alpha4beta2* nAChRs than for alpha3beta4* nAChRs. These results suggest that F-18 NIDA131 is promising for studying extrathalamic nAChR in humans.
Nicotine may function as a gateway drug to illicit drug use as it produces cross sensitization to opioids in rats in a conditioned place preference (CPP) paradigm. We utilized CPP to test the hypothesis that nicotine produces behavioral cross sensitization to stimulants and demonstrated that nicotine pretreatment enhances the rewarding effects of amphetamine for at least 3 to 5 days following the cessation of nicotine, with this effect dissipating within 19 days. The underlying mechanism involves alpha4beta2 nAChRs as a competitive alpha4beta2 antagonist effectively blocks development of nicotine-induced cross sensitization. An alpha7 nicotinic antagonist also blocked cross-sensitization at doses that do not block nicotine self-administration in rats. This study clearly demonstrated that nicotine produces cross-sensitization to the rewarding effects of both psychostimulants measured with CPP.
Traumatic experiences in early childhood are associated with increased risk for developing stress-related disorders (e.g., depression, anxiety, posttraumatic stress and substance abuse). Rearing infant macaques with same-aged peers (PR) is an established model of early adversity and induces high levels of anxiety-like behavior in monkeys. Chronic early stress affects expression and function of 5-HT1A receptors (5HTR) and human data suggest sex differences in 5HTR expression. Based on the hypothesis that PR animals would exhibit differences in 5HTR expression from mother reared (MR) animals and that this effect may be related to sex, we measured 5HTR density with F-18 FPWAY and PET in male and female monkeys. The results showed a significant rearing by sex interaction. In females, greater 5HTR density was observed in the dorsomedial prefrontal cortex in PR than in MR animals. In contrast, 5HTR density was lower in PR males in the medial cingulated cortex compared to MR males. These results suggest that early life stress affects the available density of 5HRT differently in males and females. Early life stress is also linked to structural brain abnormalities in adults and children. However, it is unclear if these volumetric brain changes are present before disease onset or if they reflect the consequences of the disease progression. To identify structural abnormalities that may predict increased risk for subsequent stress-related neuropsychiatric disorders, we acquired anatomical brain images in MR and PR juvenile rhesus monkeys. Compared to MR controls, we found an enlarged cerebellar vermis, medial prefrontal and dorsal anterior cingulate cortex. We propose that these enlargements are a structural phenotype for a high risk to stress-related neuropsychiatric disorders. Moreover, we found decreased hippocampus volume in females exposed to stress. Interestingly, this effect was evident before the gender-specific hormonal influences that occur during puberty, suggesting that an increased womens vulnerability to mood and anxiety disorders may be present during childhood.
该项目的一部分工作是确定吸烟者和非吸烟者之间的nAChR密度差异是否可以用PET在体内显示,并确定这种差异的神经解剖学程度。我们使用2F-18F-A-85380 (2FA)动态PET成像来测量非吸烟者和重度吸烟者的总分布容积(VT)。使用代谢物校正的2FA动脉输入函数的几种建模方法获得的VT值产生了类似的结果。采集丘脑(TH)、中脑(MB)、脑桥(P)、小脑(CB)、额叶皮质(FC)、壳核(PUT)和胼胝体(CC)。吸烟者的VT明显高于不吸烟者的CB、FC、MB、P和PUT。PET成像显示nAChRs可用于研究尼古丁诱导的nAChRs上调在吸烟行为和戒烟中的作用。在本研究中,定量nachr需要动脉采血和动态扫描,因为2FA是一种大剂量注射。本项目的第二部分评估了用于量化nachr的微创丸加持续输注(B/I)范式。志愿者进行了一项大剂量注射研究和一项通过B/I给药2FA的研究,以评估使用更短扫描时间和静脉血数据的可行性。B/I研究的VT值与大剂量研究计算的VT值非常相似。测试/重新测试显示VT测量的高再现性。我们得出结论,B/I方法将有助于人脑nachr的临床和研究。
项目成果
期刊论文数量(21)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
5-substituted derivatives of 6-halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with low picomolar affinity for alpha4beta2 nicotinic acetylcholine receptor and wide range of lipophilicity: potential pr
6-卤代-3-((2-(S)-氮杂环丁基)甲氧基)吡啶和6-卤代-3-((2-(S)-吡咯烷基)甲氧基)吡啶的5-取代衍生物,对 alpha4beta2 具有低皮摩尔亲和力
- DOI:10.1021/jm030432v
- 发表时间:2004
- 期刊:
- 影响因子:7.3
- 作者:Zhang,Yi;Pavlova,OlgaA;Chefer,SvetlanaI;Hall,AndrewW;Kurian,Varughese;Brown,LaVerneL;Kimes,AlaneS;Mukhin,AlexeyG;Horti,AndrewG
- 通讯作者:Horti,AndrewG
Estimation of D2-like receptor occupancy by dopamine in the putamen of hemiparkinsonian Monkeys.
半帕金森猴壳核中多巴胺对 D2 样受体占据的估计。
- DOI:10.1038/sj.npp.1301404
- 发表时间:2008
- 期刊:
- 影响因子:0
- 作者:Chefer,SvetlanaI;Kimes,AlaneS;Matochik,JohnA;Horti,AndrewG;Kurian,Varughese;Shumway,Dean;Domino,EdwardF;London,EdytheD;Mukhin,AlexeyG
- 通讯作者:Mukhin,AlexeyG
6-[18F]Fluoro-A-85380: an in vivo tracer for the nicotinic acetylcholine receptor.
6-[18F]Fluoro-A-85380:烟碱乙酰胆碱受体的体内示踪剂。
- DOI:10.1016/s0969-8051(99)00082-7
- 发表时间:2000
- 期刊:
- 影响因子:3.1
- 作者:Scheffel,U;Horti,AG;Koren,AO;Ravert,HT;Banta,JP;Finley,PA;London,ED;Dannals,RF
- 通讯作者:Dannals,RF
Radiosynthesis and preliminary evaluation of 5-[123/125I]iodo-3-(2(S)-azetidinylmethoxy)pyridine: a radioligand for nicotinic acetylcholine receptors.
5-[123/125I]碘-3-(2(S)-氮杂环丁基甲氧基)吡啶的放射合成和初步评价:烟碱乙酰胆碱受体的放射性配体。
- DOI:10.1016/s0969-8051(98)00086-9
- 发表时间:1999
- 期刊:
- 影响因子:3.1
- 作者:Horti,AG;Koren,AO;Lee,KS;Mukhin,AG;Vaupel,DB;Kimes,AS;Stratton,M;London,ED
- 通讯作者:London,ED
Aging and caloric restriction in nonhuman primates: behavioral and in vivo brain imaging studies.
非人类灵长类动物的衰老和热量限制:行为和体内脑成像研究。
- DOI:10.1111/j.1749-6632.2001.tb05661.x
- 发表时间:2001
- 期刊:
- 影响因子:5.2
- 作者:Ingram,DK;Chefer,S;Matochik,J;Moscrip,TD;Weed,J;Roth,GS;London,ED;Lane,MA
- 通讯作者:Lane,MA
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ELLIOT A STEIN其他文献
ELLIOT A STEIN的其他文献
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{{ truncateString('ELLIOT A STEIN', 18)}}的其他基金
EFFECTS OF INTRAVENOUS COCAINE ON REGIONAL CEREBRAL ACTIVITY MEASURED BY FMRI
通过 FMRI 测量静脉注射可卡因对区域大脑活动的影响
- 批准号:
6419457 - 财政年份:2000
- 资助金额:
$ 123.97万 - 项目类别:
EFFECTS OF CIGARETTE SMOKING AND NICOTINE ON REGIONAL CEREBRAL ACTIVITY VIA FMRI
通过 FMRI 研究吸烟和尼古丁对区域大脑活动的影响
- 批准号:
6419443 - 财政年份:2000
- 资助金额:
$ 123.97万 - 项目类别:
EFFECTS OF COCAINE WITHDRAWAL AND CRAVING ON REGIONAL CEREBRAL ACTIVITY
可卡因戒断和渴望对区域大脑活动的影响
- 批准号:
6419477 - 财政年份:2000
- 资助金额:
$ 123.97万 - 项目类别:
EFFECTS OF COCAINE WITHDRAWAL AND CRAVING ON CEREBRAL ACTIVITY MEASURED BY MRI
通过 MRI 测量可卡因戒断和渴望对大脑活动的影响
- 批准号:
6114685 - 财政年份:1998
- 资助金额:
$ 123.97万 - 项目类别:
EFFECTS OF INTRAVENOUS COCAINE ON REGIONAL CEREBRAL ACTIVITY MEASURED BY FMRI
通过 FMRI 测量静脉注射可卡因对区域大脑活动的影响
- 批准号:
6114657 - 财政年份:1998
- 资助金额:
$ 123.97万 - 项目类别:
EFFECTS OF COCAINE WITHDRAWAL AND CRAVING ON REGIONAL CEREBRAL ACTIVITY
可卡因戒断和渴望对区域大脑活动的影响
- 批准号:
6218394 - 财政年份:1998
- 资助金额:
$ 123.97万 - 项目类别:
EFFECTS OF CIGARETTE SMOKING AND NICOTINE ON REGIONAL CEREBRAL ACTIVITY VIA FMRI
通过 FMRI 研究吸烟和尼古丁对区域大脑活动的影响
- 批准号:
6218351 - 财政年份:1998
- 资助金额:
$ 123.97万 - 项目类别:
EFFECTS OF INTRAVENOUS COCAINE ON REGIONAL CEREBRAL ACTIVITY MEASURED BY FMRI
通过 FMRI 测量静脉注射可卡因对区域大脑活动的影响
- 批准号:
6218366 - 财政年份:1998
- 资助金额:
$ 123.97万 - 项目类别:
EFFECTS OF CIGARETTE SMOKING AND NICOTINE ON REGIONAL CEREBRAL ACTIVITY VIA FMRI
通过 FMRI 研究吸烟和尼古丁对区域大脑活动的影响
- 批准号:
6114642 - 财政年份:1998
- 资助金额:
$ 123.97万 - 项目类别:
EFFECTS OF CIGARETTE SMOKING AND NICOTINE ON REGIONAL CEREBRAL ACTIVITY VIA FMRI
通过 FMRI 研究吸烟和尼古丁对区域大脑活动的影响
- 批准号:
6245737 - 财政年份:1997
- 资助金额:
$ 123.97万 - 项目类别:
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