Chemokine CXCL12/CXCR4 system and synthetic cathinones

项目总结 我们建议研究趋化因子CXCL12(SDF-1α)及其主要受体CXCR4是如何 受合成卡西酮MDPV(亚甲基二氧吡咯丙酮)的影响，反过来又是如何 CXCL12/CXCR4拮抗对合成卡西酮行为和神经化学相关性的影响 (Ab)使用。在浴盐产品中发现了不同的卡西酮，但MDPV及其下一代类似物 似乎更容易导致危及生命的医学后果，包括高血压，心动过速， 攻击性和自杀。MDPV问题的一部分，以及更传统的非法精神刺激剂 如可卡因，是一种高度上瘾的表型，使持续吸毒和复发成为可能。 夺取。MDPV类似于可卡因，可阻止细胞内单胺的再摄取，但在DAT和 Net.关于MDPV如何影响大脑奖赏通路中的非单胺系统，我们知之甚少。 并促成了它的成瘾效应。由于仍然没有批准的治疗可卡因滥用的药物， 更不用说合成卡西诺酮了，预计新的目标、新的方法或两者都将导致第一个目标 批准的药物疗法。我们建议的靶点是一种趋化因子，特别是CXCL12及其受体 CXCR4。CXL12是大脑中发现的为数不多的趋化因子之一。它还有一种FDA批准的商用- 可用的拮抗剂(AMD3100)来研究CXCR4受体的机制。值得注意的是，在所有的趋化因子中， CXCL12是与精神刺激性成瘾联系最密切的一种。暴露于急性可卡因的小鼠表现出更强的 血浆CXCL12水平。在人类可卡因滥用者中，CXCL12是唯一与病史相关的趋化因子 病理性可卡因的使用和依赖的严重程度。最近，我们采取了关键的下一步，将 CXCL12/CXCR4系统在中脑边缘多巴胺环路中的作用 反复暴露可卡因使中脑腹侧被盖区CXLC12基因表达增加 并在大鼠中产生位置偏爱，这种偏爱被CXCR4拮抗剂(AMD3100)降低。的功效。 CXCR4拮抗作用延伸到MDPV诱导的行为，因为我们的数据显示AMD3100降低了MDPV 大鼠的位置偏好、运动激活和习得(自我给药)。我们建议， 细胞和神经化学实验验证CXCL12和CXCR4在中脑边缘DA中的假说 环路受到MDPV暴露和戒断的失调，以及 VTA中的CXCR4受体通过减少中脑边缘减少MDPV的获得性、强化和复发 多巴胺(DA)输出。通过提供关于趋化因子和边缘中脑之间如何相互作用的信息 奖赏系统影响心理刺激成瘾，我们希望将CXCL12/CXCR4确定为趋化因子- 基于治疗目标，用于对抗新的和已有的精神刺激药物的不良反应。

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.