背景:通常认为甲基苯丙胺(METH)的奖励作用在METH使用障碍中起重要作用。多巴胺D1受体(D1R)的表达改变已被认为对METH的奖励作用至关重要。值得注意的是,D1R可以通过形成H3R-D1R异聚体(H3R-D1R)与组胺H3受体(H3R)相互作用。
目的:本研究旨在专门研究H3R-D1R参与METH的奖励效应。
方法:C57BL/6小鼠用选择性H3R拮抗剂(硫脲,THIO;20mg/kg),一种H1N1拮抗剂(Pyrilamine,PYRI;10mg/kg),或将巨细胞病毒(CMV)-跨膜结构域5(TM5)显微注射到伏隔核(NAc)中。应用条件放置偏好(CPP)的动物模型来确定H3R-D1R对METH的奖励效应的影响。
结果:METH导致对药物相关室的明显偏好,与NAc和腹侧被盖区(VTA)中H3R增加和D1R表达减少有关。THIO显著减弱METH的奖励效应,伴有H3R降低和D1R表达增加。相比之下,吡喃胺未能产生类似的效果。此外,Thio对METH诱导的CPP的抑制作用被D1R激动剂SKF38393逆转.此外,SCH23390,一种D1R拮抗剂,抵消了SKF38393对THIO的改善作用。免疫共沉淀(CO-IP)实验进一步证明了METHCPP小鼠中H3R和D1R之间的特异性相互作用。METH的奖励效应也被CMV跨膜结构域5(TM5)的中断显著阻断,但不是NAc中的CMV跨膜结构域7(TM7)。
结论:这些结果表明,调节H3R-D1R复合物的活性有望调节METH使用障碍,并可作为其治疗的潜在药物靶标。
BACKGROUND: The rewarding effect of Methamphetamine (METH) is commonly believed to play an important role in METH use disorder. The altered expression of dopamine D1 receptor (D1R) has been suggested to be essential to the rewarding effect of METH. Notably, D1R could interact with histamine H3 receptors (H3R) by forming a H3R-D1R heteromer (H3R-D1R).
OBJECTIVE: This study was designed to specifically investigate the involvement of H3R-D1R in the rewarding effect of METH.
METHODS: C57BL/6 mice were treated with intraperitoneal injections of a selective H3R antagonist (Thioperamide, THIO; 20 mg/kg), an H1R antagonist (Pyrilamine, PYRI; 10 mg/kg), or microinjections of cytomegalovirus (CMV)-transmembrane domain 5 (TM5) into the nucleus accumbens (NAc). The animal model of Conditioned Place Preference (CPP) was applied to determine the impact of H3R-D1R on the rewarding effect of METH.
RESULTS: METH resulted in a significant preference for the drug-associated chamber, in conjunction with increased H3R and decreased D1R expression in both NAc and the ventral tegmental area (VTA). THIO significantly attenuated the rewarding effect of METH, accompanied by decreased H3R and increased D1R expression. In contrast, pyrilamine failed to produce the similar effects. Moreover, the inhibitory effect of THIO on METH-induced CPP was reversed by SKF38393, a D1R agonist. Furthermore, SCH23390, a D1R antagonist, counteracted the ameliorative effect of SKF38393 on THIO. Co-immunoprecipitation (CO-IP) experiments further demonstrated the specific interaction between H3R and D1R in METH CPP mice. The rewarding effect of METH was also significantly blocked by the interruption of CMV-transmembrane domain 5 (TM5), but not CMV-transmembrane domain 7 (TM7) in NAc.
CONCLUSIONS: These results suggest that modulating the activity of H3R-D1R complex holds promise for regulating METH use disorder and serves as a potential drug target for its treatment.