Chemokine CXCL12/CXCR4 system and synthetic cathinones

趋化因子CXCL12/CXCR4系统和合成卡西酮

• 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
• 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

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 （虐待。浴盐产品中含有不同的卡西酮，但 MDPV 及其下一代类似物 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、 攻击和自杀。 MDPV 以及更传统的非法精神兴奋剂的部分问题 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 服用。 MDPV 与可卡因类似，可阻断细胞单胺再摄取，但在 DAT 和 网。关于大脑奖赏通路中的非单胺系统如何受到 MDPV 的影响，人们知之甚少 并有助于其成瘾作用。由于仍然没有批准的药物可用于治疗可卡因滥用， 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 批准的药物治疗。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。它还拥有 FDA 批准的商业化 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关系最密切的一种。暴露于急性可卡因的小鼠表现增加 CXCL12 的血浆水平。在人类可卡因滥用者中，CXCL12 是唯一与历史相关的趋化因子 病理性可卡因使用和依赖性严重程度。最近，我们采取了关键的下一步，将 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。功效 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 大鼠的位置偏好、运动激活和获取（自我给药）。我们建议行为， 细胞和神经化学实验来检验中脑边缘 DA 中 CXCL12 和 CXCR4 的假设 MDPV 暴露和戒断导致回路失调，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 多巴胺（DA）输出。通过提供有关趋化因子和中边缘脑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。