Potentiation of 5-methoxy-N,N-dimethyltryptamine-induced hyperthermia by harmaline and the involvement of activation of 5-HT1A and 5-HT2A receptors.
Potentiation of 5-methoxy-N,N-dimethyltryptamine-induced hyperthermia by harmaline and the involvement of activation of 5-HT1A and 5-HT2A receptors.
复制标题
通过Harmaline和5-HT1A和5-HT2A受体的激活参与5-甲氧基-N，N-甲基N-二甲基丁胺诱导的高温。
DOI：
10.1016/j.neuropharm.2014.10.013
复制
发表时间：
2015-02
影响因子：
4.7
通讯作者：
Yu AM
中科院分区：
文献类型：
--
作者：
Jiang XL;Shen HW;Yu AM
5-甲氧基-N，N-二甲基色胺（5-MeO-DMT）和harmonic是5-羟色胺（5-HT）类似物，经常一起滥用，这改变了体温调节，可能表明5-羟色胺毒性的严重程度。我们最近的研究表明，与单胺氧化酶抑制剂哈托伐他汀联合给药导致5-HT激动剂5-MeO-DMT暴露量增加和延长，这可能受到细胞色素P450 2D6（CYP2D6）状态的影响。本研究旨在确定骆驼蓬碱和5-MeO-DMT对野生型和CYP 2D 6人源化（Tg-CYP 2D 6）小鼠体温调节的影响，以及5-HT受体的参与。植入遥测发射器和给药后，在饲养笼中无创监测动物核心体温。Harmaline（5和15 mg/kg，i.p.）单独使用可诱导体温过低，而体温过低受CYP2D6状态的显著影响。相比之下，单独使用较高剂量的5-MeO-DMT（10和20 mg/kg）会导致体温过高。同时给予2、5或15 mg/kg的肝素可显著增强5-MeO-DMT（2或10 mg/kg）引起的体温升高，在一定剂量组合下，这种作用可能受CYP2D6状态的影响。有趣的是，骆驼蓬碱诱导的体温降低仅被5-HT 1A受体拮抗剂WAY-100635减弱，而5-MeO-DMT和骆驼蓬碱-5-MeO-DMT诱导的体温升高可被WAY-100635或5-HT 2A受体拮抗剂（MDL-100907和酮色林）抑制。此外，在饲养笼条件下应激诱导的体温过高不受WAY-100635的影响，但令人惊讶地被MDL-100907和酮色林减弱。我们的研究结果表明，共同管理的单胺氧化酶抑制剂在很大程度上加强5-MeO-DMT诱导的体温过高，涉及5-HT1A和5-HT2A受体的激活。这些发现将为抗焦虑药物的开发和减轻5-羟色胺毒性致死性高热的新策略提供见解。
5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are serotonin (5-HT) analogs often abused together, which alters thermoregulation that may indicate the severity of serotonin toxicity. Our recent studies have revealed that co-administration of monoamine oxidase inhibitor harmaline leads to greater and prolonged exposure to 5-HT agonist 5-MeO-DMT that might be influenced by cytochrome P450 2D6 (CYP2D6) status. This study was to define the effects of harmaline and 5-MeO-DMT on thermoregulation in wild-type and CYP2D6-humanized (Tg-CYP2D6) mice, as well as the involvement of 5-HT receptors. Animal core body temperatures were monitored noninvasively in the home cages after implantation of telemetry transmitters and administration of drugs. Harmaline (5 and 15 mg/kg, i.p.) alone was shown to induce hypothermia that was significantly affected by CYP2D6 status. In contrast, higher doses of 5-MeO-DMT (10 and 20 mg/kg) alone caused hyperthermia. Co-administration of harmaline (2, 5 or 15 mg/kg) remarkably potentiated the hyperthermia elicited by 5-MeO-DMT (2 or 10 mg/kg), which might be influenced by CYP2D6 status at certain dose combination. Interestingly, harmaline-induced hypothermia was only attenuated by 5-HT1A receptor antagonist WAY-100635, whereas 5-MeO-DMT- and harmaline-5-MeO-DMT-induced hyperthermia could be suppressed by either WAY-100635 or 5-HT2A receptor antagonists (MDL-100907 and ketanserin). Moreover, stress-induced hyperthermia under home cage conditions was not affected by WAY-100635 but surprisingly attenuated by MDL-100907 and ketanserin. Our results indicate that co-administration of monoamine oxidase inhibitor largely potentiates 5-MeO-DMT-induced hyperthermia that involves the activation of both 5-HT1A and 5-HT2A receptors. These findings shall provide insights into development of anxiolytic drugs and new strategies to relieve the lethal hyperthermia in serotonin toxicity.
登录
查看更多内容
影响因子：
4.2
作者：
Bruno, Raimondo;Matthews, Allison J.;Sindicich, Natasha
通讯作者：
Sindicich, Natasha
影响因子：
2.2
作者：
Cooper, Brad E.;Sejnowski, Celeste A.
通讯作者：
Sejnowski, Celeste A.
影响因子：
3.4
作者：
Halberstadt, Adam L.;Buell, Mahalah R.;Masten, Virginia L.;Risbrough, Victoria B.;Geyer, Mark A.
通讯作者：
Geyer, Mark A.
影响因子：
3.4
作者：
Halberstadt, Adam L.;Nichols, David E.;Geyer, Mark A.
通讯作者：
Geyer, Mark A.
影响因子：
3.9
作者：
Kim, H;Sablin, SO;Ramsay, RR
通讯作者：
Ramsay, RR