School of Public Health, Health Science Center, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang, 315211, PR China.
School of Teaching and Education, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang, 315211, PR China.
Eur J Pharmacol. 2024 Oct 15;981:176866. doi: 10.1016/j.ejphar.2024.176866. Epub 2024 Jul 30.
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).
This study was designed to specifically investigate the involvement of H3R-D1R in the rewarding effect of METH.
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.
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.
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.
人们普遍认为，甲基苯丙胺（METH）的奖赏效应在 METH 使用障碍中起着重要作用。多巴胺 D1 受体（D1R）的表达改变被认为对 METH 的奖赏效应至关重要。值得注意的是，D1R 可以通过形成 H3R-D1R 异源二聚体（H3R-D1R）与组胺 H3 受体（H3R）相互作用。
本研究旨在专门研究 H3R-D1R 与 METH 的奖赏效应的关系。
C57BL/6 小鼠接受腹腔注射选择性 H3R 拮抗剂（噻哌酰胺，THIO；20mg/kg）、H1R 拮抗剂（吡拉明，PYRI；10mg/kg）或细胞巨化病毒（CMV）-跨膜结构域 5（TM5）微注射到伏隔核（NAc）。应用条件性位置偏爱（CPP）动物模型来确定 H3R-D1R 对 METH 奖赏效应的影响。
METH 导致对药物相关室的明显偏好，同时 NAc 和腹侧被盖区（VTA）中的 H3R 增加和 D1R 表达减少。THIO 显著减弱 METH 的奖赏效应，同时降低 H3R 和增加 D1R 表达。相比之下，吡拉明没有产生类似的效果。此外，D1R 激动剂 SKF38393 逆转了 THIO 对 METH 诱导的 CPP 的抑制作用。此外，D1R 拮抗剂 SCH23390 拮抗了 SKF38393 对 THIO 的改善作用。免疫共沉淀（CO-IP）实验进一步证明了 METH CPP 小鼠中 H3R 和 D1R 之间的特异性相互作用。NAc 中 CMV-跨膜结构域 5（TM5）而非 CMV-跨膜结构域 7（TM7）的中断也显著阻断了 METH 的奖赏效应。
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，并作为其治疗的潜在药物靶点。
