Department of Pharmacology, Hyogo College of Medicine, Hyogo 663-8501, Japan.
Molecular Neurobiology Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, Maryland 21224, U.S.A.
Brain Res. 2012 Feb 23;1439:15-26. doi: 10.1016/j.brainres.2011.12.043. Epub 2011 Dec 31.
Nomifensine is a dopamine/norepinephrine reuptake inhibitor. Nomifensine and some of its structural analogues produce behavioral effects indicative of indirect dopaminergic agonist properties, such as hyperlocomotion. By contrast, the deaminated and demethylated nomifensine analogue 4-phenyl-1,2,3,4-tetrahydroisoquinoline (PTIQ) is reported to have amphetamine-antagonistic properties, as demonstrated by inhibition of methamphetamine (METH)-induced dopamine release in the nucleus accumbens and METH-induced hyperlocomotion in rats. In the present study, we examined the effect of PTIQ (10mg/kg, i.p.) and nomifensine (3mg/kg, i.p.) on METH (5 or 10mg/kg, i.p.)-induced stereotypical behavior in mice in order to determine whether PTIQ and nomifensine inhibit and augment, respectively, METH-induced stereotypical behavior. Unexpectedly, our observations demonstrated that both PTIQ and nomifensine significantly augmented METH-induced stereotypical behavior and locomotion in mice. This augmentation is likely the result of additive effects on dopaminergic function by METH in combination with PTIQ or nomifensine. These results suggest that, contrary to some reports, PTIQ may display dopaminergic agonist properties in mice.
去甲咪嗪是一种多巴胺/去甲肾上腺素再摄取抑制剂。去甲咪嗪及其一些结构类似物产生行为效应，表明具有间接多巴胺激动剂特性，如过度活跃。相比之下，去氨基和去甲基的去甲咪嗪类似物 4-苯基-1,2,3,4-四氢异喹啉（PTIQ）据报道具有安非他命拮抗特性，如在伏隔核中抑制安非他命（METH）诱导的多巴胺释放和大鼠中 METH 诱导的过度活跃。在本研究中，我们检查了 PTIQ（10mg/kg，ip）和去甲咪嗪（3mg/kg，ip）对 METH（5 或 10mg/kg，ip）诱导的小鼠刻板行为的影响，以确定 PTIQ 和去甲咪嗪是否分别抑制和增强 METH 诱导的刻板行为。出乎意料的是，我们的观察结果表明，PTIQ 和去甲咪嗪都显著增强了 METH 诱导的小鼠刻板行为和运动。这种增强可能是由于 METH 与 PTIQ 或去甲咪嗪联合作用对多巴胺能功能的相加效应所致。这些结果表明，与一些报道相反，PTIQ 可能在小鼠中显示出多巴胺激动剂特性。
