Glutamatergic plasticity that drives cannabinoid withdrawal and craving

谷氨酸可塑性导致大麻素戒断和渴望

• 批准号: 10743526
• 负责人: SADE MONIQUE SPENCER
• 金额: $ 53.75万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10743526
• 关键词: Abstinence; Address; Adolescence; Adolescent; Adolescent and Young Adult; Affect; Affective Symptoms; Amygdaloid structure; Anhedonia; Behavior; Behavioral; Brain; Brain region; Canis familiaris; Cannabinoids; Cannabis; Cerebral hemisphere; Chronic; Clinical; Communication; Coupling; Cues; DSM-V; Development; Electrophysiology (science); FOS gene; Female; Genetic; Glutamates; Hippocampus; Hour; Immediate-Early Genes; Immunohistochemistry; In Vitro; Incubated; Individual; Intravenous; Knowledge; Legal; Light; Link; Male Adolescents; Maps; Measures; Medial; Mediating; Microscopy; Modeling; Neurobiology; Neuronal Plasticity; Neurons; Nucleus Accumbens; Outcome; Output; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Prefrontal Cortex; Prevalence; Process; Psychotropic Drugs; Rattus; Relapse; Relaxation; Reporter; Research; Research Domain Criteria; Rewards; Self Administration; Severities; Slice; Structure; Substance Withdrawal Syndrome; Substance of Abuse; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Tetrahydrocannabinol; Thalamic structure; Time; Tissues; Treatment outcome; Tremor; Uncertainty; United States; Virus; Withdrawal; Withdrawal Symptom; cannabinoid withdrawal; cannabis seeking; cannabis withdrawal; cell type; clinically significant; comparison control; craving; critical period; cue reactivity; design; endophenotype; experience; genetic manipulation; illicit drug use; immunoreactivity; in vivo; marijuana use; marijuana use disorder; marijuana user; negative affect; neural; neuroadaptation; neurophysiology; neuroregulation; neurotransmission; novel therapeutics; optogenetics; pre-clinical; response; therapeutic target; transmission process

PROJECT SUMMARY/ABSTRACT Cannabis is the most frequently used illicit drug in the United States. Onset of cannabis use usually occurs during adolescence, which represents a vulnerable period in neurobiological development. Due to uncertainty surrounding the long-term consequences of adolescent cannabis exposure, there is mounting concern that relaxing legal restrictions will result in increased adolescent use. Approximately 30% of users develop cannabis use disorder (CUD), and nearly half of all regular cannabis users develop cannabis withdrawal syndrome which is marked by negative affective symptoms and craving that may drive relapse. During abstinence craving may increase over time or “incubate” resulting in a period of heightened vulnerability to relapse in response to drug-related cues. Withdrawal symptoms during abstinence are clinically significant because they may impact efforts to reduce cannabis use, promote use of other substances of abuse, and adversely influence treatment outcomes. Currently there are no approved pharmacotherapies for CUD. The primary objective of this proposal is to determine how chronic cannabinoid use in adolescence impacts glutamatergic transmission and plasticity in the nucleus accumbens (NAc), and the contribution of these adaptations to later relapse-like behavior and craving. Our central hypothesis is that cannabinoid self- administration and withdrawal induces changes in glutamate transmission and synaptic connectivity in the NAc that promote negative affective processes and ultimately trigger relapse. To test this hypothesis we will use behavior, whole mount immunohistochemistry and light sheet microscopy, optogenetic aided neurophysiology, and chemogenetic manipulation techniques to assess the involvement of pathway specific glutamatergic neuroplasticity in cannabis seeking. We will use a model of adolescent intravenous D9-tetrahydrocannabinol (THC) self-administration and withdrawal to confirm the presence of an incubation of drug seeking effect at an intermediate or protracted withdrawal time point. We will assess somatic and non-somatic symptoms of spontaneous withdrawal based on alignment with DSM-5 criteria and the Research Domain Criteria framework. Unbiased mapping of whole brain c-Fos immunoreactivity will be used to identify regional neural activation associated with cannabinoid withdrawal and cue-reactivity. We will examine input-specific cannabinoid withdrawal-induced plasticity at glutamatergic synapses in identified D1 and D2 medium spiny neurons in NAc core and shell coupling in vitro slice electrophysiology with optogenetically evoked EPSCs. Finally, we will utilize chemogenetic neuromodulation to test the importance of one of these circuits for regulating relapse-like behavior and endophenotypes of withdrawal. These studies will inform our understanding of the mechanisms underlying cannabis withdrawal syndrome, an important and understudied facet of CUD, and how glutamate transmission and synaptic plasticity is altered over the course of withdrawal. This may have important implications for identifying unique therapeutic targets.

项目概要/摘要 大麻是美国最常用的非法药物，通常会出现吸食大麻的情况。 由于不确定性，青春期是神经生物学发育的脆弱时期。 关于青少年接触大麻的长期后果，人们越来越担心 放宽法律限制将导致青少年使用量增加约 30%。 大麻使用障碍（CUD），近一半的常规大麻使用者出现大麻戒断症状 其特征是负面情感症状和渴望，可能会导致复发。 禁欲的渴望可能会随着时间的推移而增加或“潜伏”，导致胃肠道在一段时间内容易受到 戒断期间对药物相关线索的戒断症状复发具有临床意义。 因为它们可能会影响减少大麻使用、促进使用其他滥用物质的努力，以及 目前尚无批准的 CUD 药物疗法。 该提案的主要目标是确定青春期长期使用大麻素如何影响 伏核（NAc）中的谷氨酸传递和可塑性，以及这些的贡献 我们的中心假设是大麻素的自我调节。 给药和停药会引起 NAc 中谷氨酸传输和突触连接的变化 为了检验这个假设，我们将使用这些因素来促进负面情感过程并最终引发复发。 行为、整体免疫组织化学和光片显微镜、光遗传学辅助神经生理学、 和化学遗传学操作技术来评估途径特异性谷氨酸能的参与 我们将使用青少年静脉注射 D9-四氢大麻酚的模型。 (THC) 自我给药和停药，以确认是否存在潜伏的寻药效应 我们将评估中间或长期戒断时间点的躯体和非躯体症状。 基于与 DSM-5 标准和研究领域标准框架一致的自发退出。 全脑 c-Fos 免疫反应性的无偏图谱将用于识别区域神经激活 与大麻素戒断和提示反应性相关。我们将检查输入特异性大麻素。 NAc 中已鉴定的 D1 和 D2 中型多棘神经元中谷氨酸能突触的戒断诱导可塑性 最后，我们将体外切片电生理学与光遗传学诱发的 EPSC 耦合。 化学遗传学神经调节利用这些回路之一的重要性来调节复发样 这些研究将帮助我们了解戒断的机制。 潜在的大麻戒断综合症，CUD 的一个重要且未被充分研究的方面，以及谷氨酸如何 传递和突触可塑性是在退出过程中进行的。 对确定独特治疗靶点的影响。