Long Term THC Elicits Distinct Changes in Adolescent Brain Dopamine Signaling

长期使用 THC 会引起青少年大脑多巴胺信号的明显变化

• 批准号: 9308499
• 负责人: Bertha K Madras
• 金额: $ 51.7万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308499
• 关键词: Acute; Adolescence; Adolescent; Adolescent Behavior; Adolescent marijuana use; Adult; Adverse effects; Affect; Age; Agonist; Animals; Anxiety; Attenuated; Behavior; Behavioral; Biological; Biological Assay; Brain; Brain region; Cognition; Complex; Corpus striatum structure; DCC gene; Development; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Dynorphins; Euphoria; Female; Fluorescence Resonance Energy Transfer; Future; Gene Expression; High Prevalence; Human; Hypersensitivity; Impaired cognition; In Situ; Laboratories; Link; Marijuana; Measures; Mediator of activation protein; Mental Depression; Methods; Microscopy; Molecular; Monkeys; Neurobehavioral Manifestations; Neurons; Nucleus Accumbens; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Population; Predisposition; Prefrontal Cortex; Primates; Proteins; Psychotic Disorders; Psychotropic Drugs; Rattus; Regulation; Relaxation; Research; Resolution; Rewards; Risk; Rodent; Schizophrenia; Sex Characteristics; Signal Transduction; Substance Use Disorder; THC exposure; Testing; Three-Dimensional Imaging; addiction; age difference; behavioral response; cohort; density; dopamine D5 receptor; dopamine transporter; gender difference; hedonic; in vitro testing; insight; male; marijuana use; marijuana use disorder; marijuana user; new technology; novel; preference; protein expression; psychiatric symptom; response; sex; vulnerable adolescent

Adolescents are more susceptible to developing a marijuana use disorder and adverse cognitive and psychiatric symptoms. Females are more vulnerable to marijuana-induced anxiety. In animals as in humans, THC (the main psychoactive constituent of marijuana) can elicit both positive (reward) and negative effects (anxiety). Our research has revealed two novel mechanisms that conceivably contribute to adolescent and female responses to marijuana. (1) We discovered a dopamine D1-D2 receptor heteromer complex in nucleus accumbens which in pilot studies, engenders anxiogenic or rewarding effects, depending on its functional activity: (a) Adolescent nucleus accumbens (NAc) expressed lower density of the D1-D2 heteromer, and disruption of its bimolecular association enhanced reward more in adolescents than adults. (b) D1-D2 heteromer density was higher in female NAc and activation promoted higher anxiogenic effects in female rather than male rats. This novel discovery of a unique molecular entity linked to rewarding or anxiogenic effects, provides exciting leads to investigate the relevance of D1-D2 heteromer to THC-induced behavior in adolescents or females. (2) We discovered that repeated THC administration to adolescent rats increased dcc gene expression subsequently in their mature prefrontal cortex. Implicated in schizophrenia, DCC protein guides the development of prefrontal cortical dopamine circuitry, specifically during adolescence. To pursue these leads: Aim 1 will quantify age- and sex-dependent expression of D1-D2 heteromer and whether modulation of heteromer activity is reflected in rewarding or aversive behaviors. Aim 2 will measure THC effects on D1-D2 heteromer expression, on behaviors, on plausible downstream mediators of behaviors, as a function of age and sex, and whether modulation of D1-D2 heteromer activity affects THC-induced behaviors. Aim 3 will manipulate D1-D2 heteromer expressing neurons in NAc and consequences to THC-induced behaviors. Aim 4 will determine if THC alters DCC expression in adolescent primate prefrontal cortex and dopamine prefrontal cortex circuitry. These novel biological substrates of THC will yield insights into heightened THC (or marijuana) reward in adolescents, or increased anxiety in females, and a possible mechanism by which adolescent marijuana use can elevate the risk for psychosis and cognitive impairment. Conceivably, novel targets for medications development may emerge from these newly identified biological substrates.

青少年更容易出现大麻使用障碍和不良认知和不良行为 精神症状。女性更容易受到大麻引起的焦虑的影响。在动物中，如 对于人类来说，THC（大麻的主要精神活性成分）可以引起积极（奖励）和 负面影响（焦虑）。我们的研究揭示了两种新的机制，可以认为它们有助于 青少年和女性对大麻的反应。 (1)我们发现了多巴胺D1-D2受体 伏隔核中的异聚体复合物在初步研究中产生焦虑或奖励 影响，取决于其功能活性： (a) 青少年伏隔核 (NAc) 表达较低 D1-D2 异聚体的密度及其双分子缔合的破坏更多地增强了奖励 青少年比成人多。 (b) 女性 NAc 中的 D1-D2 异聚体密度较高，并且促进激活 雌性大鼠比雄性大鼠有更高的致焦虑作用。这一独特分子的新发现 与奖励或焦虑效应相关的实体，提供了令人兴奋的线索来调查相关性 D1-D2 异聚体对 THC 诱导的青少年或女性行为的影响。 (2)我们发现重复 给青春期大鼠施用 THC 会增加成年大鼠的 dcc 基因表达 前额皮质。 DCC 蛋白与精神分裂症有关，可引导前额皮质的发育 多巴胺回路，特别是在青春期。为了追求这些线索：目标 1 将量化年龄和 D1-D2 异聚体的性别依赖性表达以及是否反映了异聚体活性的调节 奖励或厌恶行为。目标 2 将测量 THC 对 D1-D2 异聚体表达的影响， 行为，关于行为的合理下游中介，作为年龄和性别的函数，以及是否 D1-D2 异聚体活性的调节会影响 THC 诱导的行为。目标 3 将操纵 D1-D2 NAc 中异聚体表达神经元及其对 THC 诱导行为的影响。目标4将 确定 THC 是否会改变青少年灵长类动物前额皮质和多巴胺前额叶的 DCC 表达 皮层电路。 THC 的这些新型生物底物将深入了解 THC 的升高（或 大麻）奖励青少年，或增加女性焦虑，以及一种可能的机制 青少年吸食大麻会增加精神病和认知障碍的风险。可以想象，新颖 药物开发的目标可能会从这些新发现的生物底物中出现。