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)对可卡因有减毒作用。 啮齿类动物的奖赏行为，因此可能被研究为可卡因奖赏的潜在调节器 流程。尽管如此，OXT对可卡因产生这种调节作用的具体机制是- 相关行为仍不清楚。本研究项目提出OXT对可卡因的抑制作用。 腹侧被盖区多巴胺(DA)神经元的双重机制引起的相关偏爱 (VTA)。最近的证据表明，VTA DA神经元上的oxt受体(OXTRs)都能增加紧张性放电。 并减少兴奋性输入，可能影响DA神经元的时相激活。这一下降 在兴奋性输入中被证明是由OXT与突触前CB1受体相互作用所介导的 (CB1Rs)在谷氨酸能终末。该项目使用一种新颖的方法来研究这种效应的功能相关性。 转基因大鼠与病毒携带的shRNA联合沉默VTA、DA、OXTRs或突触前 谷氨酸能CB1Rs。首先，雄性和雌性大鼠DA VTA神经元上的OXTRs将被沉默，使用 转基因Cre大鼠及依赖Cre的OXTRs敲除对oxt介导的DA放电的影响 费率。在行为学上，OXT减弱了可卡因的偏好行为，预计OXTRs的沉默 VTA DA神经元将减弱这一效应。第二，进一步阐明通过什么机制 OXT通过VTA DA神经元减弱可卡因偏好，VTA谷氨酸能传入的CB1R将被沉默 使用转基因Cre大鼠和在没有Cre表达的情况下shRNA沉默CB1R的组合。OXT 已知通过产生内源性大麻素(ECB)来减少神经元兴奋，这种内源性大麻素 通过CB1受体的突触前输入。通过这一点，谷氨酸能CB1R沉默的效果将被评估 OXT介导的VTA DA时相神经元放电。在行为上，这表明OXT介导的减少 VTA DA时相放电是OXT介导的可卡因相关偏好减弱的基础。总体而言，这个项目 将利用一种新的工具组合来研究oxt 减弱可卡因奖赏，并提供对OXT作为可卡因相关治疗靶点的洞察力 男性和女性的精神障碍。