Carpenter Colleen, Zestos Alexander G, Altshuler Rachel, Sorenson Roderick J, Guptaroy Bipasha, Showalter Hollis D, Kennedy Robert T, Jutkiewicz Emily, Gnegy Margaret E
Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.
Neuropsychopharmacology. 2017 Sep;42(10):1940-1949. doi: 10.1038/npp.2017.95. Epub 2017 May 11.
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]dopamine uptake through the dopamine transporter (DAT). The compound did not compete with [H]WIN 35,428 binding or affect surface DAT levels. Using microdialysis, direct accumbal administration of 1 μM 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.
苯丙胺类药物（AMPHs）在全球范围内被滥用。由于迄今为止尚无针对AMPH成瘾的有效治疗方法，因此迫切需要确定介导这类兴奋剂强化作用的可成药靶点。蛋白激酶C（PKC）激活可调节AMPH刺激的多巴胺外流。抑制PKC可减少AMPH刺激的多巴胺外流和运动活性。唯一已知的可透过中枢神经系统的PKC抑制剂是选择性雌激素受体调节剂他莫昔芬。在本研究中，我们证明了一种他莫昔芬类似物6c，其抑制PKC的能力比他莫昔芬更强，但对雌激素受体缺乏亲和力，可减少AMPH刺激引起的细胞外多巴胺增加和与强化相关的行为。在大鼠纹状体突触体中，6c抑制AMPH刺激的多巴胺外流的效力几乎是通过多巴胺转运体（DAT）摄取[H]多巴胺的五倍。该化合物不与[H]WIN 35,428结合竞争，也不影响表面DAT水平。使用微透析技术，向伏隔核直接注射1μM 6c可减少自由活动大鼠的多巴胺溢出。使用液相色谱-质谱联用技术，我们证明6c可透过中枢神经系统。在全身给予AMPH的同时或之前18小时，用6mg/kg 6c对大鼠进行全身治疗，可减少AMPH刺激的多巴胺溢出和AMPH诱导的运动效应。最后，皮下注射6mg/kg 6c对大鼠进行18小时预处理可减少AMPH自我给药，但不影响食物自我给药。这些结果证明了他莫昔芬类似物在减少AMPH对多巴胺和与强化相关行为的影响方面的效用，并为减少AMPH滥用的治疗方法开辟了一条新的发展途径。
