Oxytocin Induces Retrograde Metaplasticity to Attenuate CocainePreference Behavior

催产素诱导逆行可塑性以减弱可卡因偏好行为

• 批准号: 10810613
• 负责人: Kah Chung Leong
• 金额: $ 19.91万
• 依托单位: TRINITY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10810613
• 关键词: Affect; Attenuated; Behavior; Behavioral; CNR1 gene; Cocaine; Cocaine-Related Disorders; Cues; Data; Dopamine; Endocannabinoids; Female; Frequencies; Glutamates; Knock-in; Locomotion; Mediating; Neurons; Neuropeptides; Oxytocin; Oxytocin Receptor; Peripheral; Pharmaceutical Preparations; Phase; Process; Production; Rat Transgene; Rattus; Recombinant adeno-associated virus (rAAV); Research Project Grants; Rodent; Role; Structure; Synapses; Testing; Time; Training; Transgenic Organisms; Ventral Tegmental Area; Viral; attenuation; cannabinoid receptor; cocaine related behaviors; cocaine reward; cocaine seeking; conditioned place preference; dopaminergic neuron; gamma-Aminobutyric Acid; insight; knock-down; male; neuromechanism; neurotransmission; novel; preference; preservation; presynaptic; receptor expression; reward circuitry; small hairpin RNA; therapeutic target; tool

PROJECT SUMMARY/ABSTRACT A growing number of studies have demonstrated that oxytocin (OXT) provides an attenuating effect on cocaine reward behaviors in rodents and therefore may be investigated as a potential modulator of cocaine reward processes. Despite this, the specific mechanism through which OXT exerts this modulatory effect on cocaine- related behaviors remains unclear. The present research project proposes that OXT attenuates cocaine- associated preference via a two-fold mechanism on dopamine (DA) neurons within the ventral tegmental area (VTA). Recent evidence suggests that OXT receptors (OXTRs) on VTA DA neurons both increase tonic firing of the DA neuron and decreases excitatory inputs, likely affecting phasic activation of the DA neuron. This decrease in excitatory inputs has been shown to be mediated by an OXT interaction with presynaptic CB1 receptors (CB1Rs) on glutamatergic terminals. This project investigates the functional relevance of this effect using a novel combination of transgenic rat and virally-delivered shRNA to silence VTA DA OXTRs or presynaptic glutamatergic CB1Rs. First, OXTRs on DA VTA neurons will be silenced in male and female rats using a transgenic Cre rat and Cre-dependent knockdown of OXTRs to determine the effect of OXT-mediated DA firing rate. Behaviorally, OXT attenuates cocaine preference behaviors, and it is expected that silencing of OXTRs on VTA DA neurons will diminish this effect. Second, to further elucidate the specific mechanism through which OXT attenuates cocaine preference via VTA DA neurons, CB1Rs on VTA glutamatergic inputs will be silenced using a combination of transgenic Cre rat and shRNA silencing of CB1R in the absence of Cre expression. OXT is known to reduce neuronal excitation through production of endocannabinioids (eCB) that retrogradely reduce presynaptic input via CB1 receptors. Through this, the effect of glutamatergic CB1R silencing will be assessed on OXT-mediated VTA DA phasic neuronal firing. Behaviorally, this demonstrates that OXT-mediated reduction of VTA DA phasic firing underlies OXT-mediated attenuation of cocaine-associated preference. Overall, this project will utilize a novel combination of tools to investigate the specific neural mechanism through which OXT attenuates cocaine reward and offer insight into the use of OXT as a therapeutic target for cocaine-related disorders in males and females.

项目摘要/摘要 越来越多的研究表明，催产素（OXT）对可卡因产生了衰减作用 啮齿动物的奖励行为，因此可以作为可卡因奖励的潜在调节剂进行研究 过程。尽管如此，OXT对可卡因的调节作用的特定机制 - 相关行为尚不清楚。本研究项目提出，OXT会减轻可卡因 - 通过在腹侧对段区域内多巴胺（DA）神经元的两倍机制的相关偏好 （VTA）。最近的证据表明，VTA DA神经元上的OXT受体（OXTRS）都增加了滋补的滋补。 DA神经元并减少兴奋性输入，可能影响DA神经元的阶段激活。这种减少 在兴奋性输入中，已证明与突触前CB1受体的oxt相互作用介导 （CB1R）在谷氨酸能末端。该项目使用小说研究了这种效果的功能相关性 转基因大鼠和病毒传递的shRNA与沉默的VTA DA OXTRS或突触前的结合 谷氨酸能CB1RS。首先，使用A的雄性和雌性大鼠将在DA VTA神经元上的oxttrs沉默 转基因CRE大鼠和OXTR的CRE依赖性敲低，以确定OXT介导的DA发射的效果 速度。在行为上，OXT会减轻可卡因的偏好行为，预计Oxtrs的沉默 VTA DA神经元会减少这种效果。第二，进一步阐明了特定机制 OXT通过VTA DA神经元减弱可卡因的偏好，VTA谷氨酸能输入的CB1R将被沉默 在没有CRE表达的情况下，结合了CB1R的转基因CRE大鼠和shRNA沉默。牛 已知可以通过产生内源性大麻蛋白（ECB）来减少神经元激发 通过CB1受体的突触前输入。通过此，将评估谷氨酸能CB1R沉默的影响 OXT介导的VTA DA PHASIC神经元射击。在行为上，这表明OXT介导的减少 VTA DA PHASIC发射基础OXT介导的可卡因相关偏好的衰减。总体而言，这个项目 将利用一种新型工具组合来研究特定的神经机制 减轻可卡因的奖励，并深入了解使用OXT作为可卡因有关的治疗靶标 男性和女性的疾病。