Circuitry Progression of Cocaine-induced Cellular Adaptation
Circuitry Progression of Cocaine-induced Cellular Adaptation
批准号:
9982846
负责人:
Yan Dong
金额:
$19.56万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-08-01 至 2022-07-31
关键词:
Action PotentialsAnatomyBackBehaviorBehavioralBrain regionCocaineComplexCorpus striatum structureDopamine D1 ReceptorDorsalDrug AddictionDrug ExposureDrug usageEnsureExhibitsExtinction (Psychology)Fire - disastersHumanKnowledgeLateralLeadMedialMediatingMembraneMolecularMonkeysMusNeuronsNucleus AccumbensOutputPharmaceutical PreparationsProceduresPublishingRattusRelapseReporterResistanceRodentRodent ModelRoleSelf AdministrationSubstantia nigra structureTestingTransgenic OrganismsVentral Tegmental AreaViralWithdrawalbasecocaine usedrug developmentdrug withdrawalexperienceexperimental studyhuman modelpreventrecruitresponsesuccess
中文摘要
摘要
毒瘾已经被概念化为从最初的自愿和
将药物使用限制为习惯性和不断升级的药物使用,并最终强制使用。来自大脑的结果
针对特定地区的研究得出了一个突出的假设,即最初使用可卡因的动机主要是
伏隔核(NAC)的强化作用,并通过以下方式转变为更持久或习惯性的药物使用
重新招募背侧纹状体(DS),导致可卡因使用升级和对灭绝的抵抗。而当
在人类和啮齿动物身上都观察到了从有限的可卡因使用到逐渐增加的可卡因使用的行为转变
模型,可卡因诱导的关键细胞适应从NAC进展到DS以促进这一点
行为转变仍然没有得到充分的研究。针对这一知识鸿沟,我们关注的是内在的膜
NAC和DS中棘神经元的兴奋性(IME)。IME决定神经元的放电能力
动作电位对兴奋性输入的反应,从而直接决定神经元的输出。
先前的结果表明,关键的IME适应-可卡因经历降低了NAC MSN的IME,并且
可卡因诱导的NAC的IME适应有助于可卡因、可卡因的精神运动效应
与戒断相关的NAC的一般低活动状态,以及戒毒后的可卡因寻找。这个
初步结果显示,在短期(5d)的可卡因自我注射过程中,小鼠表现出
有限的可卡因摄入,这种可卡因程序只诱导NAC MSN的IME适应,而不是DS
MSNS。在长时间(21d)给药后,小鼠表现出可卡因摄入量的增加,并出现了IME
在NAC和内侧/背侧DS MSN均观察到了适应。因此,可卡因诱导的IME适应
在长期服用可卡因后,从NAC进展到DS,与可卡因升级相关
夺取。此外,通过实验阻止可卡因诱导的NAC MSN中的IME适应,可以防止
在长期服用可卡因期间,对DS MSNS的IME适应进展,提示一个关键的
从NAC到DS的信息流。这一应用将探索NAC-to-NAC的解剖学基础。
可卡因诱导的IME适应的DS进展及其行为后果。这个
中心假说是可卡因诱导的IME适应在延长后从NAC到DS的进展
可卡因自身给药部分是由纹状体纹状体上升螺旋调节的,这是一种环路复合体
通过与腹侧被盖区和实质的相互投射连接NAC和DS
黑质,这种可卡因诱导的IME适应的NAC到DS的过程促进了行为转变
从有限的可卡因使用升级到逐步升级。拟议中的实验将表征一种关键形式的可卡因-
诱导细胞适应,在长期服用可卡因后,从NAC进展到DS。
预期的结果可能提供一种电路机制和具体的细胞衬底,
从有限的药物使用逐步升级到最终的强制药物使用。
英文摘要
Abstract
Drug addiction has been conceptualized as the endpoint of cascades of transitions from initial voluntary and
limited drug use to habitual and escalated drug use, and eventually to compulsive use. Results from brain
region-specific studies lead to a prominent hypothesis that the initial cocaine use is primarily motivated by the
nucleus accumbens (NAc)-based reinforcing effects, and transitions to more persistent or habitual drug use by
recruiting the dorsal striatum (DS), resulting in escalated cocaine use and resistance to extinction. While the
behavioral transition from limited to escalated cocaine use has been observed in both humans and rodent
models, the key cocaine-induced cellular adaptations that progress from the NAc to DS to promote this
behavioral transition remain underexplored. Targeting this knowledge gap, we focus on the intrinsic membrane
excitability (IME) of NAc and DS medium spiny neurons (MSNs). IME determines the ability of neurons to fire
action potentials in response to excitatory inputs, and thus directly determines the output of the neurons.
Previous results demonstrate a critical IME adaptation—cocaine experience decreases IME of NAc MSNs, and
this cocaine-induced IME adaptation in the NAc contributes to psychomotor effects of cocaine, cocaine
withdrawal-associated general hypoactive state of the NAc, and cocaine seeking after drug withdrawal. The
preliminary results show that during a short-term (5d) cocaine self-administration procedure, mice exhibited
limited cocaine taking, and this cocaine procedure only induced the IME adaptation in NAc MSNs, but not DS
MSNs. After prolonged (21d) cocaine self-administration, mice exhibited escalated cocaine taking, and the IME
adaptation was observed in both NAc and medial/dorsal DS MSNs. Thus, cocaine-induced IME adaptation
progresses from the NAc to DS after prolonged cocaine self-administration, correlated to escalated cocaine
taking. Furthermore, experimentally preventing cocaine-induced IME adaptation in NAc MSNs prevented the
progression of IME adaptation to DS MSNs during prolonged cocaine self-administration, suggesting a critical
informational flow from the NAc to DS. This application will explore the anatomical basis mediating the NAc-to-
DS progression of cocaine-induced IME adaptation and the behavioral consequence of this progression. The
central hypothesis is that the NAc-to-DS progression of cocaine-induced IME adaptation after prolonged
cocaine self-administration is mediated, in part, by the striatonigrostriatal ascending spiral, a circuit complex
connecting the NAc and DS through reciprocal projections with the ventral tegmental area and substantia
nigra, and this NAc-to-DS progression of cocaine-induced IME adaptation promotes the behavioral transition
from limited to escalated cocaine use. The proposed experiments will characterize a critical form of cocaine-
induced cellular adaptation that progresses from the NAc to DS after prolonged cocaine self-administration.
The expected results may provide a circuit mechanism and concrete cellular substrates that mediate the
progression of limited drug use toward escalated and eventually compulsive drug use.
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