The Role of Midbrain to Prelimbic Cortex Glutamatergic projections in Stress-induced Drug Seeking

中脑到前边缘皮层谷氨酸能投射在压力诱导的药物寻求中的作用

• 批准号: 10560233
• 负责人: Richard J. Noel
• 金额: $ 7.84万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-25 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10560233
• 关键词: Adherence; Affect; Amygdaloid structure; Area; Behavior; Behavioral; Brain; Cells; Cocaine; Cocaine Dependence; Communication; Cues; Data; Development; Disease; Dopamine; Drug Addiction; Exhibits; Exposure to; Female; Gender; Glutamates; Goals; Hippocampus (Brain); Individual; Investigation; Lead; Measures; Medial; Midbrain structure; Modeling; N-Methylaspartate; Neuronal Plasticity; Neurons; Nucleus Accumbens; Optics; Outcome; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Probability; Public Health; Publishing; Rattus; Relapse; Research; Research Priority; Rewards; Risk; Role; Stress; Stressful Event; Structure; Substance Use Disorder; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic Intervention; Ventral Tegmental Area; Withdrawal; addiction; cocaine exposure; cocaine self-administration; comorbidity; conditioned fear; design; disorder later incidence prevention; drug seeking behavior; experience; experimental study; fear memory; male; memory retrieval; neurophysiology; patch clamp; pre-clinical research; psychological trauma; sex; substance use; therapeutically effective; trauma exposure; traumatic event

SUMMARY Despite the recognized correlation between post-traumatic stress disorder (PTSD) and substance use disorder (SUD), it is unknown how trauma exposure and substance use may interact to alter the probability of an individual to develop either of these two disorders. Although some studies have revealed participation of the ventral tegmental area (VTA) and the medial prefrontal cortex (mPFC) in both PTSD and SUD, it is not yet known if the experience of a traumatic event alters the communication between these two structures in a way that may increase the risk of acquiring SUD. VTA projections to the mPFC are known to play an important role in the development of cocaine addiction; and other studies have shown that PTSD pathogenesis induces neurophysiological changes in the interaction between the amygdala, (VTA), mPFC, and hippocampus. Recently, studies showed that VTA glutamatergic neurons that co-release dopamine project towards the nucleus accumbens (NAc) and the prelimbic cortex (PL). Interestingly, VTA-NAc glutamatergic projections are involved in reward-seeking behavior; but the role of the VTA-PL glutamatergic projections in reward-seeking is still unknown. The overall goal of this investigation is to understand the mechanisms and adaptations of the brain when exposed to a traumatic event that leads to increased susceptibility of SUD acquisition. More specifically, the objective is to elucidate how the VTA glutamatergic projections into the PL are affected by stress and how this influences cocaine-seeking behavior in male and female rats. Our preliminary behavioral data show that stress prior to cocaine self-administration increases cocaine acquisition and cocaine-induced reinstatement, compared with the no-stress group in male rats. Our central hypothesis is that stress will strengthen synaptic transmission in the VTA-PL glutamatergic synapses, thus enhancing sensitivity to the reinforcing effects of cocaine and leading to increased cocaine-seeking behavior. To test this hypothesis, we will first evaluate the behavioral effects of fear conditioning prior to cocaine exposure on acquisition and reinstatement of cocaine- seeking (Aim 1a). Secondly, we will assess the neurophysiological changes of glutamatergic projections from the VTA to the PL using optical stimulation with whole cell patch-clamp recordings (ex-vivo) to measure synaptic changes (AMPA to NMDA ratio) in the VTA-PL glutamatergic synapses from cocaine-exposed rats with or without prior stress (Aim 1b). These experiments shall reveal how VTA modulates the PL neurons in the presence of stress and how this in turn, influences the drug seeking behavior.

摘要 尽管创伤后应激障碍(PTSD)与物质使用障碍之间存在着公认的相关性 (SUD)，尚不清楚创伤暴露和物质使用如何相互作用来改变个体发生 患上这两种疾病中的任何一种。尽管一些研究表明腹侧的参与 被盖区(VTA)和内侧前额叶皮质(MPFC)在PTSD和SUD中是否存在，目前尚不清楚。 创伤性事件的经历改变了这两个结构之间的沟通方式，可能 增加感染SUD的风险。众所周知，VTA对mPFC的预测在 可卡因成瘾的发展；其他研究表明，创伤后应激障碍的发病机制导致 杏仁核(VTA)、mPFC和海马区相互作用中的神经生理学变化。 最近的研究表明，共同释放多巴胺的VTA谷氨酸能神经元向细胞核投射。 伏隔核(NAC)和前脑皮质(PL)。有趣的是，VTA-NAC谷氨酸能投射与 但VTA-PL谷氨酸能投射在寻找奖赏行为中的作用仍然是 未知。这项研究的总体目标是了解大脑的机制和适应 当暴露在创伤性事件中时，会增加获得SUD的易感性。更确切地说， 目的是阐明应激是如何影响VTA谷氨酸能投射到PL的，以及如何影响VTA谷氨酸能投射到PL 这会影响雄性和雌性大鼠的可卡因寻找行为。我们的初步行为数据显示 自我注射可卡因之前的压力会增加可卡因的获得性和可卡因诱导的恢复， 雄性大鼠与非应激组比较。我们的中心假设是压力会加强突触 在VTA-PL谷氨酸能突触中的传递，从而增强对VTA-PL增强效应的敏感性 可卡因并导致寻求可卡因的行为增加。为了检验这一假设，我们将首先评估 可卡因暴露前恐惧条件作用对可卡因习得和恢复的行为影响-- 寻求(目标1a)。其次，我们将评估谷氨酸能投射的神经生理变化。 用全细胞膜片钳记录(体外)光刺激测量突触的VTA至PL 可卡因暴露大鼠VTA-PL谷氨酸能突触的变化(AMPA/NMDA比值) 先前的压力(目标1b)。这些实验将揭示VTA如何在存在的情况下调制PL神经元 压力以及这又是如何影响寻求毒品的行为的。