Role of Extinction in Circuit-Specific Modulation of Motivation and Mood in Cocaine Addiction

消退在可卡因成瘾的动机和情绪的电路特异性调节中的作用

• 批准号: 9238093
• 负责人: David W Self
• 金额: $ 36.45万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238093
• 关键词: AMPA Receptors; Abstinence; Amygdaloid structure; Anhedonia; Attenuated; Behavior; Behavioral; Biochemical; Biological; Brain; Chronic; Cocaine; Cocaine Dependence; Data; Data Set; Disease; Drug Addiction; Drug user; Electrophysiology (science); Environment; Extinction (Psychology); Frequencies; Glutamate Receptor; Goals; Hippocampus (Brain); Homosynaptic Depression; Individual; Lateral Hypothalamic Nucleus; Lead; Learned Helplessness; Measures; Medial; Mediating; Mental disorders; Methods; Modeling; Modification; Moods; Motivation; Neurobiology; Neuronal Plasticity; Neurons; Nucleus Accumbens; Output; Pharmaceutical Preparations; Play; Prefrontal Cortex; Rattus; Relapse; Research; Role; Self Administration; Societies; Source; Sucrose; Swimming; Synapses; Testing; Therapeutic; Therapeutic Intervention; Training; Up-Regulation; Withdrawal; Work; addiction; attenuation; cocaine use; depressive symptoms; disturbance in affect; drug craving; drug relapse; dysphoria; economic cost; experimental study; negative mood; neural circuit; neurophysiology; optogenetics; preference; receptor; research study; response; severe mental illness; social; trafficking

PROJECT SUMMARY Drug addiction is a serious and prolific mental illness involving persistent relapse despite sincere efforts to abstain. Extinction training has been used as a therapeutic method to reduce drug craving and relapse, although with limited efficacy due to an inability to fully capture contextual aspects unique to individual drug users. The identification of extinction-induced modifications in distinct brain circuits could lead to better neurostimulation approaches to treat drug addiction. This research studies modification of specific neural circuits by the extinction of self-administration behavior in a rat model of cocaine addiction. Our previous data indicate that extinction training enhances excitatory synaptic input to nucleus accumbens (NAc) shell neurons, and this effect attenuates psychomotor sensitization and relapse to cocaine-seeking behavior. The primary excitatory inputs to the NAc shell originate in the medial prefrontal cortex (PfC), basolateral amygdala (BlA) and ventral hippocampus (VH). Using an optogenetic low frequency stimulation approach to selectively depotentiate excitatory synaptic input emanating from these regions, this research will identify the specific source(s) of extinction-induced neuroplasticity in the NAc shell (Aim I), and study the role of this circuit-specific neuroplasticity in extinction-induced attenuation of sensitization and relapse behaviors (Aim II). Previous data also suggest that extinction of cocaine self-administration may reverse negative mood effects produced by chronic cocaine use. Thus, studies will determine the role of circuit-specific neuroplasticity in extinction- induced antidepressive efficacy (Aim III). Studies in Aim 1 will employ optogenetics to study the extinction circuits responsible for 1) extinction- induced synaptic trafficking of AMPA GluA receptor subunits, 2) extinction-induced enhancement in excitatory synaptic currents and 3) determine the direct and/or indirect NAc output neurons modified by extinction. Experiments in Aim II will determine the role of extinction-potentiated circuits in 4) extinction-induced reversal of locomotor sensitization and 5) extinction-induced attenuation of context- and cocaine-primed reinstatement of cocaine-seeking behavior. Experiments in Aim III will investigate the role of extinction-specific neuroplasticity in reversing negative mood effects in tests of 6) dysphoria in cocaine-conditioned place aversion, 7) learned helplessness/behavioral despair in forced swim tests and 8) anhedonia in sucrose preference tests. The integration of these neurobiological and behavioral datasets will determine the significant role that circuit-specific neuroplasticity plays in the beneficial effects of extinction on motivational and mood disturbances that contribute to cocaine addiction. A clear delineation of limbic circuits that mediate such beneficial effects could lead to better behavioral and targeted neurostimulation approaches in the treatment of cocaine and other addictions.

项目摘要 吸毒是一种严重和多产的精神疾病，尽管我们真诚地努力， 弃权。灭绝训练已被用作一种治疗方法，以减少药物渴望和复发， 尽管由于不能完全捕获个体药物特有的背景方面而具有有限的功效 用户.在不同的大脑回路中识别预防引起的修改可能会导致更好的 神经刺激疗法来治疗毒瘾。本研究研究的是对特定神经元的修饰， 在可卡因成瘾的大鼠模型中，通过消除自我给药行为来观察回路。我们以前的数据 表明消退训练增强了对延髓核（NAc）壳神经元兴奋性突触输入， 这种作用会减弱精神运动敏感性和寻求可卡因行为的复发。主 对NAc壳的兴奋性输入起源于内侧前额叶皮层（PfC）、基底外侧杏仁核（BlA） 和腹侧海马（VH）。使用光遗传学低频刺激方法选择性地 去增强兴奋性突触输入从这些地区发出，这项研究将确定具体的 来源（S）的抑制诱导的神经可塑性的NAc壳（目的I），并研究这种回路特异性的作用， 神经可塑性在预防诱导的致敏和复发行为的衰减中的作用（目的II）。先前数据 还表明，消除可卡因自我管理可能会逆转负面情绪的影响所产生的 长期吸食可卡因因此，研究将确定电路特定的神经可塑性在灭绝中的作用- 诱导抗抑郁疗效（Aim III）。 目标1的研究将采用光遗传学来研究负责1）灭绝的灭绝电路- 诱导的AMPA GluA受体亚单位的突触运输，2）抑制诱导的兴奋性增强 突触电流和3）决定直接和/或间接NAc输出神经元的灭绝修改。 目标二的实验将确定在极化诱发的反转中，极化增强回路的作用 运动敏感化和5）背景和可卡因引发的恢复的抑制诱导的衰减 寻找可卡因的行为目标III中的实验将研究预防特异性 可卡因条件下烦躁试验中逆转负面情绪效应的神经可塑性 厌恶，7）强迫游泳测试中的习得性无助/行为绝望和8）蔗糖中的快感缺失 偏好测试这些神经生物学和行为数据集的整合将决定 电路特异性神经可塑性在灭绝对动机的有益影响中发挥的重要作用 和情绪紊乱导致可卡因成瘾边缘系统回路的清晰描绘 这种有益的效果可以导致更好的行为和有针对性的神经刺激方法， 治疗可卡因和其他成瘾。