Pathway-specific Intervention in Prelimbic Cortical Circuitry Decreases Cocaine-seeking
对前额皮质回路进行特定通路干预可减少可卡因寻求
基本信息
- 批准号:10268963
- 负责人:
- 金额:$ 33.87万
- 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 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AbstinenceAnxietyBrain-Derived Neurotrophic FactorCREB1 geneCaliberCocaineCocaine DependenceCoupledCuesCyclic AMPCyclic AMP-Dependent Protein KinasesDataDendritic SpinesDrug abuseEarly InterventionElectrophysiology (science)EnvironmentExtracellular Signal Regulated KinasesFemaleFunctional disorderFutureGlutamatesHeadImageIndividualInfusion proceduresInterventionMediatingNatureNeurobiologyNeuronsPathway interactionsPerformancePharmaceutical PreparationsPhasePhosphorylationPre-Clinical ModelPrefrontal CortexProtein DephosphorylationProtein Kinase A InhibitorProteinsRattusRegulationRelapseResearchRewardsRoleSignal TransductionSliceStructureStructure of paraventricular nucleus of thalamusSubstance Use DisorderSynaptic plasticityTestingTimeViral VectorWithdrawalWomanaddictionanxiety-related behaviorcocaine self-administrationcombinatorialdesigner receptors exclusively activated by designer drugseffective therapyinsightmalemenneuroadaptationnew therapeutic targetnovelpre-clinicalpreventrelating to nervous systemretrograde transporttransmission processwithdrawal-induced anxiety
项目摘要
Specific Aims
A major challenge for individuals suffering from substance use disorders (SUDs) is the lack of effective
treatments that reduce relapse vulnerability. Drug predictive cues in the environment are powerful triggers for
relapse and understanding how these persistent associations are formed and maintained is a critical focus of
preclinical SUD research. In this proposal, we have built on our discovery that immediately after the end of
cocaine self administration (SA), an infusion of brain-derived neurotrophic factor (BDNF) into the prelimbic (PL)
prefrontal cortex prevents the cocaine SA-induced dephosphorylation of key glutamatergic-related plasticity-
related proteins (PRPs), including GluN2A, GluN2B, ERK MAP kinase, and CREB32,96. This early intervention
with BDNF also prevents prolonged cocaine-induced deficits in PL-NA core glutamatergic transmission that
promote subsequent cocaine seeking9. In contrast, by the end of the first week of abstinence, protein kinase A
(PKA)-dependent augmentation of GluA1 and CREB phosphorylation emerges. At that time, intra-PL BDNF
has no effect on relapse8 but intra-PL infusion of a PKA inhibitor, Rp-cAMPs, reverses the
hyperphosphorylation and decreases relapse70,92. More recently, we have shown that the biphasic changes in
GluA1 and pCREB within the first week of abstinence are associated with similar biphasic changes in the head
diameters (dH) of dendritic spines of PL–NA core neurons89. These data have spurred the overall hypothesis
that interventions to decrease drug seeking must be tailored to the dynamic changes in neuroadaptations that
emerge during different phases of the addiction cycle.
In chemogenetic studies to investigate the contribution of specific pathways originating in PL cortex to drug
seeking, we discovered that PL-NA core and PL-posterior paraventricular thalamic nucleus (pPVT) pathways
oppose each others’ effects during early withdrawal. Selective cre-dependent DREADD inhibition of PL-NA
core neurons infected with a retrogradely transported cre-AAV immediately after cocaine SA has no effect by
itself, but reverses the suppressive effect of intra-PL BDNF on subsequent drug seeking31. In contrast,
selective inhibition of the PL-pPVT pathway immediately after cocaine SA decreases subsequent cocaine-
seeking, an effect that is prevented by intra-PL BDNF31. Interestingly, we also found that selective inhibition of
the PL-pPVT pathway reduces anxiety-related behavior in rats withdrawing from cocaine and inactivation of
pPVT decreases conditioned aversion to cocaine, suggesting that cocaine’s engagement of anxiety- and
aversion-related circuitry that contributes to drug seeking includes pPVT.
Taken together, our new findings suggest the novel hypothesis that cocaine SA produces differential
regulation of PL-NA core and PL-pPVT pathways and that these two distinct circuits conspire to support future
drug seeking. In this proposal, we will use pathway-specific, combinatorial chemogenetic approaches, slice
electrophysiology, and state-of-the-art dendritic spine and PRP imaging in PL-NA core and PL-pPVT circuitry
to explore the time-dependent plasticity occurring in this network that influences cocaine seeking and aversion.
We will use these approaches in the following aims that will be performed in male and female rats.
Aim 1. BDNF regulation of PRPs and structural and synaptic plasticity in PL-NA core vs. PL-pPVT
neurons during early withdrawal. Using viral vector approaches, we will investigate the effects of intra-PL
BDNF infusion on (A) dendritic spine plasticity and PRP changes and (B) synaptic plasticity in PL-NA core vs.
PL-PVT neurons during early withdrawal.
Aim 2. PKA regulation of PRPs and structural and synaptic plasticity in PL-NA core vs. PL-pPVT
neurons after 7 and 30 days of abstinence. (A) We will investigate the effects of inhibiting cAMP/PKA
signaling on (A) dendritic spine plasticity and PRP changes and (B) synaptic plasticity in PL-NA core vs. PL-
PVT neurons after 7 or 30 days of abstinence with or without relapse testing.
Aim 3. The role of PL-NA core and PL-pPVT neurons in cocaine-induced anxiety and aversion in
relationship to cocaine seeking after abstinence. We will use a retro-Gi DREADD approach to test the
effects of inhibiting PL-NA core or PL-pPVT neurons (A) on withdrawal-induced anxiety immediately after the
end of cocaine SA and (B) on conditioned avoidance of cocaine in an operant runway task before or after
cocaine SA followed by cue-induced relapse testing.
Scientific Impact: These studies will expand our understanding of how to reverse critical neuroadaptations
underlying prefrontal dysfunctions during different phases of the addiction cycle that trigger relapse to drug-
seeking. By understanding temporally dynamic, differential neuroadaptations in the PL networks regulating
reward and aversion, we may be able to discover novel therapeutic targets to decrease drug-seeking.
特定的目标
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Jacqueline F. McGinty其他文献
Oxytocin decreases methamphetamine-seeking and gene expression changes in rats after traumatic stress
- DOI:
10.1016/j.drugalcdep.2016.08.382 - 发表时间:
2017-02-01 - 期刊:
- 影响因子:
- 作者:
Jacqueline F. McGinty - 通讯作者:
Jacqueline F. McGinty
Seizure-Induced Alterations of Opioid Peptide and Zinc Metabolism in the Hippocampus of Rats
癫痫发作引起的大鼠海马阿片肽和锌代谢的改变
- DOI:
10.1016/b978-0-12-506455-2.50027-7 - 发表时间:
1988 - 期刊:
- 影响因子:6.1
- 作者:
Jacqueline F. McGinty;Tomoyuki Kanamatsu;Jau;JOHN D. Morton;Christopher J. Frederickson - 通讯作者:
Christopher J. Frederickson
Will the promise of translational neuropsychopharmacology research ever deliver? The lion’s roar; the kitten’s purr
转化神经精神药理学研究的前景能否实现?
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Jacqueline F. McGinty;Victoria Arango;Kathleen T. Brady;Sandra D. Comer;Rita Z. Goldstein;E. Nestler;William W. Stoops;Michael A. Nader - 通讯作者:
Michael A. Nader
Erratum to: Short and long access to cocaine self-administration activates tyrosine phosphatase STEP and attenuates GluN expression but differentially regulates GluA expression in the prefrontal cortex
- DOI:
10.1007/s00213-013-3155-0 - 发表时间:
2013-06-05 - 期刊:
- 影响因子:3.300
- 作者:
Wei-Lun Sun;Agnieszka Zelek-Molik;Jacqueline F. McGinty - 通讯作者:
Jacqueline F. McGinty
Lennart Heimer: in memoriam (1930–2007)
- DOI:
10.1007/s00429-008-0194-0 - 发表时间:
2008-08-08 - 期刊:
- 影响因子:2.900
- 作者:
Suzanne N. Haber;Jacqueline F. McGinty;Enrico Mugnaini;Laszlo Zaborszky - 通讯作者:
Laszlo Zaborszky
Jacqueline F. McGinty的其他文献
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{{ truncateString('Jacqueline F. McGinty', 18)}}的其他基金
Pathway-specific Intervention in Prelimbic Cortical Circuitry Decreases Cocaine-seeking
对前额皮质回路进行特定通路干预可减少可卡因寻求
- 批准号:
10674953 - 财政年份:2020
- 资助金额:
$ 33.87万 - 项目类别:
Pathway-specific Intervention in Prelimbic Cortical Circuitry Decreases Cocaine-seeking
对前额皮质回路进行特定通路干预可减少可卡因寻求
- 批准号:
10453594 - 财政年份:2020
- 资助金额:
$ 33.87万 - 项目类别:
COCA - Project 2 Preventing Drug-induced Neuroadaptations in Prelimbic Cortex
COCA - 项目 2 预防前边缘皮层药物诱导的神经适应
- 批准号:
10630231 - 财政年份:2019
- 资助金额:
$ 33.87万 - 项目类别:
COCA - Project 2 Preventing Drug-induced Neuroadaptations in Prelimbic Cortex
COCA - 项目 2 预防前边缘皮层药物诱导的神经适应
- 批准号:
10404585 - 财政年份:2019
- 资助金额:
$ 33.87万 - 项目类别:
Prevention of Cocaine-induced Prefrontal ERK Shutoff During Early Withdrawal
早期戒断期间预防可卡因引起的前额叶 ERK 关闭
- 批准号:
8787464 - 财政年份:2013
- 资助金额:
$ 33.87万 - 项目类别:
Prevention of Cocaine-induced Prefrontal ERK Shutoff During Early Withdrawal
早期戒断期间预防可卡因引起的前额叶 ERK 关闭
- 批准号:
9187444 - 财政年份:2013
- 资助金额:
$ 33.87万 - 项目类别:
Prevention of Cocaine-induced Prefrontal ERK Shutoff During Early Withdrawal
早期戒断期间预防可卡因引起的前额叶 ERK 关闭
- 批准号:
8439031 - 财政年份:2013
- 资助金额:
$ 33.87万 - 项目类别:
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