Direct and Systemic Administration of a CNS-Permeant Tamoxifen Analog Reduces Amphetamine-Induced Dopamine Release and Reinforcing Effects
Direct and Systemic Administration of a CNS-Permeant Tamoxifen Analog Reduces Amphetamine-Induced Dopamine Release and Reinforcing Effects
复制标题
DOI：
10.1038/npp.2017.95
复制
发表时间：
2017-09-01
影响因子：
7.6
通讯作者：
Gnegy, Margaret E.
中科院分区：
文献类型：
--
作者：
Carpenter, Colleen;Zestos, Alexander G.;Gnegy, Margaret E.
安非他明（AMPH）在全球范围内被滥用。由于迄今为止还没有有效的治疗AMPH成瘾的方法，因此迫切需要鉴定介导这种兴奋剂类的强化作用的可药物化靶点。AMPH刺激的多巴胺外排受蛋白激酶C（PKC）激活的调节。PKC的抑制减少AMPH刺激的多巴胺流出和运动活性。唯一已知的CNS渗透性PKC抑制剂是选择性雌激素受体调节剂他莫昔芬。在这项研究中，我们证明，他莫昔芬类似物，6c，更有力地抑制PKC比他莫昔芬，但缺乏亲和力的雌激素受体，减少AMPH刺激增加细胞外多巴胺和神经胶质相关的行为。在大鼠纹状体突触体中，6c通过多巴胺转运蛋白（DAT）抑制AMPH刺激的多巴胺外排的效力几乎是[H-3]多巴胺摄取的5倍。该化合物不与[H-3] WIN 35，428竞争结合或影响表面DAT水平。使用微透析，直接给药1 μ M的6c减少多巴胺溢出在自由活动的大鼠。使用LC-MS，我们证明6c是CNS渗透的。同时或18小时之前，系统性AMPH管理与6毫克/公斤的6C的大鼠全身治疗减少AMPH刺激的多巴胺溢出和AMPH诱导的运动效应。最后，用6 mg/kg 6c s.c.减少AMPH自身给药，但不减少食物自身给药。这些结果证明了他莫昔芬类似物在减少AMPH对多巴胺和神经行为的影响方面的效用，并提出了减少AMPH滥用的治疗方法的新途径。
Amphetamines (AMPHs) are globally abused. With no effective treatment for AMPH addiction to date, there is urgent need for the identification of druggable targets that mediate the reinforcing action of this stimulant class. AMPH-stimulated dopamine efflux is modulated by protein kinase C (PKC) activation. Inhibition of PKC reduces AMPH-stimulated dopamine efflux and locomotor activity. The only known CNS-permeant PKC inhibitor is the selective estrogen receptor modulator tamoxifen. In this study, we demonstrate that a tamoxifen analog, 6c, which more potently inhibits PKC than tamoxifen but lacks affinity for the estrogen receptor, reduces AMPH-stimulated increases in extracellular dopamine and reinforcement-related behavior. In rat striatal synaptosomes, 6c was almost fivefold more potent at inhibiting AMPH-stimulated dopamine efflux than [H-3] dopamine uptake through the dopamine transporter (DAT). The compound did not compete with [H-3] WIN 35,428 binding or affect surface DAT levels. Using microdialysis, direct accumbal administration of 1 mu M 6c reduced dopamine overflow in freely moving rats. Using LC-MS, we demonstrate that 6c is CNS-permeant. Systemic treatment of rats with 6 mg/kg 6c either simultaneously or 18 h prior to systemic AMPH administration reduced both AMPH-stimulated dopamine overflow and AMPH-induced locomotor effects. Finally, 18 h pretreatment of rats with 6 mg/kg 6c s.c. reduces AMPH-self administration but not food self-administration. These results demonstrate the utility of tamoxifen analogs in reducing AMPH effects on dopamine and reinforcement-related behaviors and suggest a new avenue of development for therapeutics to reduce AMPH abuse.