Endocannabinoid system modulates relapse to methamphetamine seeking: Possible mediation by the arachidonic acid cascade
Endocannabinoid system modulates relapse to methamphetamine seeking: Possible mediation by the arachidonic acid cascade
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DOI：
10.1038/sj.npp.1300454
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发表时间：
2004-08-01
影响因子：
7.6
通讯作者：
Yamamoto, T
中科院分区：
文献类型：
--
作者：
Anggadiredja, K;Nakamichi, M;Yamamoto, T
我们澄清了内源性大麻素系统的调节作用，其可能的调解花生四烯酸级联反应，恢复甲基苯丙胺（METH）寻求行为，使用大鼠静脉自我管理模式。在METH自我给药12天后，用生理盐水替代METH导致杠杆按压反应逐渐降低（消退）。在消退条件下，METH引发或重新暴露于先前与METH输注配对的线索显着增加了反应（恢复药物寻求）。大麻素CB I受体拮抗剂SR 14171 6A阻断了这种行为。虽然大麻素激动剂Delta（8）-四氢大麻酚（THC）本身没有影响，但小剂量的激动剂和METH共同给药恢复了药物寻求行为。四氢大麻酚减弱了恢复诱导剂量的METH的作用，但增强了线索的作用。无论是在灭绝过程中重复或单独给予，在第一次METH启动或线索挑战前24小时，THC抑制了恢复。在另一组实验中，我们发现双氯芬酸，一种环氧合酶抑制剂，也减弱了暴露于线索或药物引发引起的复效。这些结果表明，内源性大麻素系统，通过可能的调解花生四烯酸级联，作为一个调制器的恢复作用的甲基引发和线索，扩展目前的观点对药物依赖的治疗，这些结果表明，内源性大麻素激活物质以及环氧合酶抑制剂可能是有前途的抗复发剂。
We clarified the modulating action of the endocannabinoid system, and its possible mediation by the arachidonic acid cascade, on the reinstatement of methamphetamine (METH)-seeking behavior, using the intravenous self-administration paradigm in rats. Following 12 days of self-administration of METH, the replacement of METH with saline resulted in a gradual decrease in lever press responses (extinction). Under extinction conditions, METH-priming or re-exposure to cues previously paired with METH infusion markedly increased the responses (reinstatement of drug-seeking). The cannabinoid CB I receptor antagonist, SR 14171 6A, blocked this behavior. Although the cannabinoid agonist, Delta(8)-tetrahydrocannabinol (THC), had no effects by itself, coadministration of the agonist and METH at small doses reinstated the drug-seeking behavior. THC attenuated the effects of the reinstatement-inducing dose of METH, but enhanced the effect of cues. Either given repeatedly during the extinction or singly, 24 h before the first METH-priming or cues challenge, THC suppressed the reinstatement. In another set of experiments, we found that diclofenac, a cyclooxygenase inhibitor, also attenuated the reinstatement induced by exposure to cues or drug-priming. These results suggest that the endocannabinoid system, through possible mediation by the arachidonic acid cascade, serves as a modulator of the reinstating effects of METH-priming and cues, Extending the current view on the treatment of drug dependence, these results indicate that endocannabinoid-activating substances as well as cyclooxygenase inhibitors may be promising as antirelapse agents.