Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides
Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides
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DOI：
10.1016/s0028-3908(02)00056-4
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发表时间：
2002-06-01
影响因子：
4.7
通讯作者：
Bowen, WD
中科院分区：
文献类型：
--
作者：
Matsumoto, RR;McCracken, KA;Bowen, WD
使用药理学和分子生物学工具来验证sigma受体参与可卡因的作用。放射配体结合研究表明，大脑和心脏中存在显著水平的sigma受体，其中可卡因优先与sigma(1)亚型相互作用。在小鼠行为药理学研究中，九种新型西格玛受体拮抗剂显著减轻可卡因引起的惊厥，而与西格玛受体弱相互作用的结构类似物无效。与拮抗剂提供的保护相反，经典的西格玛受体激动剂加重了可卡因的惊厥作用。拮抗剂还能减弱可卡因引起的致死率，最好的化合物即使在治疗后使用也能防止死亡。在拮抗剂对基线运动活动没有影响的剂量下，它们显著减弱了可卡因的运动刺激作用，这表明它们能够阻断可卡因的精神运动和毒性作用。为了进一步验证抗可卡因作用是通过干扰可卡因进入sigma受体而实现的，研究表明，针对sigma(1)受体的反义寡脱氧核苷酸可以减弱可卡因的惊厥和运动刺激作用。总之，这些研究支持了西格玛受体，特别是西格玛(1)亚型参与可卡因的行为影响。(C) 2002 Elsevier Science Ltd.版权所有。
Pharmacological and molecular biological tools were used to validate the involvement of sigma receptors in the actions of cocaine. Radioligand binding studies demonstrated significant levels of sigma receptors in the brain and heart, where cocaine interacts preferentially with the sigma(1) subtype. In behavioral pharmacological studies using mice, nine novel sigma receptor antagonists significantly attenuated cocaine-induced convulsions, while structural analogs with weak interactions with sigma receptors were ineffective. In contrast to the protection provided by the antagonists, a classical sigma receptor agonist exacerbated the convulsive effects of cocaine. The antagonists also attenuated cocaine-induced lethality, with the best compound protecting against death even when administered as a post-treatment. At doses where the antagonists had no effect on baseline locomotor activity, they significantly attenuated the locomotor stimulatory effects of cocaine, suggesting their ability to block the psychomotor as well as the toxic effects of cocaine. To further validate that the anti-cocaine effects were achieved by interfering with cocaine's access to sigma receptors, antisense oligodeoxynucleotides against sigma(1) receptors were shown to attenuate the convulsive and locomotor stimulatory effects of cocaine. Together, the studies support the involvement of sigma receptors, particularly the sigma(1), subtype, in the behavioral effects of cocaine. (C) 2002 Elsevier Science Ltd. All rights reserved.