Chemokine CXCL12/CXCR4 system and synthetic cathinones

趋化因子CXCL12/CXCR4系统和合成卡西酮

基本信息

批准号：
10392410
负责人：
SCOTT M. RAWLS
金额：
$ 36.85万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10392410
关键词：
AMD3100 Abstinence Acute Adverse effects Affect Affective Aggressive behavior Anatomy Behavior Behavioral Biological Assay Brain CXCL12 gene CXCR4 Receptors CXCR4 gene Chronic Cocaine Cocaine Abuse Corpus striatum structure Cues Data Dependence Dopamine Exposure to FDA approved Female Gene Expression Genetic Human Hypertension Immunity Intake Knowledge Life Link Medical Messenger RNA Midbrain structure Mus Nucleus Accumbens Output Pathologic Pathway interactions Pharmaceutical Preparations Pharmacology Pharmacotherapy Phenotype Plasma Proteins Psychological reinforcement Rattus Recording of previous events Reinforcement Schedule Relapse Rewards Self Administration Severities Source Substantia nigra structure Suicide System Tachycardia Testing Ultrasonics Ventral Tegmental Area Viral abuse liability analog antagonist base bath salts behavior influence brain behavior cathinone chemokine chemokine receptor cocaine exposure cocaine use drug seeking behavior experimental study extracellular interest knock-down male monoamine neurochemistry next generation novel strategies pre-clinical preference psychostimulant receptor reuptake stimulant abuse stimulant dependence stimulant exposure therapeutic target transmission process vocalization

项目摘要

PROJECT SUMMARY We propose to investigate how the chemokine CXCL12 (SDF-1α), and its main receptor, CXCR4, are influenced by exposure to the synthetic cathinone MDPV (methylenedioxypyrovalerone), and, in turn, how CXCL12/CXCR4 antagonism influences behavioral and neurochemical correlates of synthetic cathinone (ab)use. Different cathinones are found in bath salts products, but MDPV and its next-generation analogs appear more apt to cause life-threatening medical consequences including hypertension, tachycardia, aggression and suicide. Part of the problem with MDPV, as well as more traditional illicit psychostimulants such as cocaine, is a highly-addictive phenotype that perpetuates ongoing drug taking and relapse to drug taking. MDPV, similar to cocaine, blocks cellular monoamine reuptake but with enhanced potency at DAT and NET. Little is known about how non-monoamine systems in the brain reward pathway are affected by MDPV and contribute to its addictive effects. Since there is still no approved medication available for cocaine abuse, let alone for synthetic cathinones, it is anticipated that a new target, a new approach or both will lead to the first approved pharmacotherapy. Our proposed target is a chemokine, specifically CXCL12, and its receptor CXCR4. CXL12 is one of the few chemokines found in the brain. It also has a FDA-approved, commercially- available antagonist (AMD3100) to investigate a CXCR4-receptor mechanism. Notably, of all the chemokines, CXCL12 is the one most linked to psychostimulant addiction. Mice exposed to acute cocaine display increased plasma levels of CXCL12. In human cocaine abusers, CXCL12 is the only chemokine correlated to the history of pathological cocaine use and severity of dependence. Recently, we took the critical next step of linking the CXCL12/CXCR4 system in the mesolimbic dopamine circuit with psychostimulant reward by showing that repeated cocaine exposure increases CXLC12 gene expression in the midbrain ventral tegmental area (VTA) and produces place preference in rats that is reduced by a CXCR4 antagonist (AMD3100). The efficacy of CXCR4 antagonism extends to MDPV-induced behaviors, as our data show that AMD3100 reduces MDPV place preference, locomotor activation, and acquisition (self-administration) in rats. We propose behavioral, cellular and neurochemical experiments to test the hypotheses that CXCL12 and CXCR4 in the mesolimbic DA circuit are dysregulated by MDPV exposure and abstinence and that genetic or pharmacological antagonism of CXCR4 receptors in the VTA reduces MDPV acquisition, reinforcement and relapse by decreasing mesolimbic dopamine (DA) output. By providing information about how interplay between chemokine and mesolimbic brain reward systems impact psychostimulant addiction, we expect to identify CXCL12/CXCR4 as a chemokine- based therapeutic target for countering adverse effects of both new and established psychostimulant drugs.

项目概要我们建议研究趋化因子 CXCL12 (SDF-1α) 及其主要受体 CXCR4 是如何作用的受到接触合成卡西酮 MDPV（亚甲二氧基吡咯戊酮）的影响，以及反过来如何影响 CXCL12/CXCR4 拮抗作用影响合成卡西酮的行为和神经化学相关性 (ab) 使用不同的卡西酮，但 MDPV 及其下一代类似物除外。似乎更容易引起危及生命的医疗后果，包括高血压、心动过速、攻击性和自杀是 MDPV 以及更传统的非法精神兴奋剂问题的一部分。例如可卡因，是一种高度成瘾的表型，会使持续吸毒和吸毒复发 MDPV 与可卡因类似，可阻断细胞单胺再摄取，但在 DAT 和 DAT 时的效力增强。 NET。人们对 MDPV 如何影响大脑奖赏通路中的非单胺系统知之甚少。并导致其成瘾作用，因为仍然没有批准的药物可用于可卡因滥用，更不用说合成卡西酮了，预计新的目标、新的方法或两者都将导致第一个我们提出的目标是趋化因子，特别是 CXCL12 及其受体。 CXCR4.CXL12 是大脑中发现的少数趋化因子之一，它还具有 FDA 批准的商业化作用。可用拮抗剂 (AMD3100) 来研究 CXCR4 受体机制值得注意的是，在所有趋化因子中， CXCL12 是与精神兴奋剂成瘾最相关的一种，暴露于急性可卡因的小鼠表现出增加。在人类可卡因滥用者中，CXCL12 的血浆水平是唯一与历史相关的趋化因子。最近，我们采取了关键的下一步，将可卡因的使用与依赖的严重程度联系起来。中脑边缘多巴胺回路中的 CXCL12/CXCR4 系统具有精神兴奋奖励，表明反复接触可卡因会增加中脑腹侧被盖区 (VTA) 的 CXLC12 基因表达并在大鼠中产生位置偏好，这种偏好可被 CXCR4 拮抗剂 (AMD3100) 降低。 CXCR4 拮抗作用延伸到 MDPV 诱导的行为，因为我们的数据显示 AMD3100 减少 MDPV 我们建议对大鼠进行位置偏好、运动激活和习得（自我管理）。细胞和神经化学实验来检验中脑边缘 DA 中 CXCL12 和 CXCR4 的假设神经回路因 MDPV 暴露和戒断而失调，并且 MDPV 的遗传或药理学拮抗作用 VTA 中的 CXCR4 受体通过减少中脑边缘来减少 MDPV 的获得、强化和复发通过提供有关趋化因子和中脑边缘之间如何相互作用的信息。奖励系统影响精神兴奋剂成瘾，我们期望将 CXCL12/CXCR4 识别为趋化因子 - 对抗新的和现有的精神兴奋药物的不良反应的治疗目标。