Chemokine CXCL12/CXCR4 system and synthetic cathinones

项目摘要 我们打算研究趋化因子CXCL 12（SDF-1α）及其主要受体CXCR 4如何与趋化因子之间的相互作用。 受暴露于合成卡西酮MDPV（亚甲二氧基吡咯戊酮）的影响，反过来，如何 CXCL 12/CXCR 4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。浴盐产品中含有不同的卡西酮，但MDPV及其下一代类似物 似乎更容易导致危及生命的医疗后果，包括高血压，心动过速， 攻击和自杀。MDPV的部分问题，以及更传统的非法精神兴奋剂 如可卡因，是一种高度成瘾表型，使持续吸毒和吸毒复发永久化 拿。MDPV类似于可卡因，可阻断细胞单胺再摄取，但在DAT时效力增强， 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 并有助于其成瘾效果。由于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，新的方法或两者兼而有之将导致第一个 批准的药物治疗。我们提出的靶点是趋化因子，特别是CXCL 12， CXCR 4。CXL 12是在大脑中发现的少数趋化因子之一。它也有一个FDA批准的，商业上- 可用的拮抗剂（AMD 3100）研究CXCR 4受体机制。值得注意的是，在所有趋化因子中， CXCL 12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显示出 CXCL 12的血浆水平。在人类可卡因滥用者中，CXCL 12是唯一与历史相关的趋化因子。 病理性可卡因使用和严重程度的依赖。最近，我们采取了关键的下一步， CXCL 12/CXCR 4系统在具有精神兴奋剂奖励的中边缘多巴胺回路中表明， 重复可卡因暴露增加中脑腹侧被盖区（VTA）CXLC 12基因表达 并在大鼠中产生位置偏好，其被CXCR 4拮抗剂（AMD 3100）降低。的疗效 CXCR 4拮抗作用扩展到MDPV诱导的行为，因为我们的数据显示AMD 3100可降低MDPV 大鼠的位置偏爱、自发激活和获得（自我给药）。我们建议行为， 细胞和神经化学实验来检验CXCL 12和CXCR 4在中脑边缘DA中的假设， MDPV暴露和戒断导致回路失调， VTA中的CXCR 4受体通过减少中脑边缘细胞减少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脑边缘系统之间如何相互作用的信息， 奖励系统影响精神兴奋剂成瘾，我们希望将CXCL 12/CXCR 4鉴定为趋化因子- 基于治疗靶点，以对抗新的和已建立的精神兴奋剂药物的不良反应。

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.