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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >The effects of sigma, PCP, and opiate receptor ligands in rats trained with ibogaine as a discriminative stimulus.
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The effects of sigma, PCP, and opiate receptor ligands in rats trained with ibogaine as a discriminative stimulus.

机译：σ，PCP和阿片受体配体对以ibogaine进行识别刺激的大鼠的影响。

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摘要

Although the mechanism of action of ibogaine, a hallucinogen that may be useful in the treatment of addiction, remains unknown, receptor binding studies suggest that ibogaine produces its effects via interactions with multiple receptor types. In addition to serotonergic receptors, which have been studied previously with respect to ibogaine, likely candidates include opiate, sigma (sigma), and phencyclidine (PCP) binding sites. In an attempt to determine which of these receptor interactions are involved in the in vivo effects of ibogaine, ligands for sigma, PCP, and opiate receptors were assessed for their ability to substitute for or to antagonize the ibogaine-induced discriminative stimulus (10 mg/kg I.P., 60 min presession) in Fischer-344 rats. Intermediate levels of generalization were observed with the subtype nonselective sigma ligands 3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine [(+)-3-PPP] (69.0%) and 1,3-di(2-tolyl)guanidine (DTG) (73.5%) but not with the sigma1-selective agents (+)-N-allylnormetazocine [(+)-SKF 10,047] and (+)-pentazocine. These findings, along with observations that ibogaine has appreciable affinity for sigma2 receptors, suggest that these receptors may be involved in the ibogaine discriminative stimulus. With regard to opiate receptors, neither morphine, the prototypic mu agonist, nor kappa selective agonists (bremazocine,and U-50488) substituted for ibogaine. However, intermediate levels of generalization were observed with the mixed action opiates (-)-SKF 10,047 (78.9%), (+/-)-pentazocine (73.9%), nalorphine (70.4%), and diprenorphine (75.0%) indicating a potential role for opiate receptors in the ibogaine stimulus. Partial substitution was also observed with naltrexone (55.6%) but not with naloxone or the selective kappa antagonist nor-binaltorphimine (nor-BNI). These agents were largely ineffective as antagonists of the ibogaine cue, although naloxone produced a moderate but statistically significant antagonism (69.8%). In addition, naloxone produced complete antagonism of the ibogaine-appropriate responding elicited by both (-)-SKF 10,047 (19.7%) and nalorphine (25.8%), whereas the ibogaine-appropriate responding produced by diprenorphine was only partially antagonized (44.4%). The latter observations taken together with the finding that both nalorphine (>100 microM) and diprenorphine (30 microM) have extremely low affinity for sigma2 receptors, suggest that the ibogaine-appropriate responding produced by these agents is not mediated by sigma2 receptors. These findings imply that opiate effects may be involved in the ibogaine stimulus. In contrast to sigma2 and opiate receptors, ibogaine's reported interactions with NMDA receptors do not appear to be involved in its discriminative stimulus, as neither PCP nor MK-801 produced a significant level of ibogaine-appropriate responding. Thus, the present study offers evidence that unlike NMDA receptors, both sigma2 and opiate receptors may be involved in the ibogaine discriminative stimulus.
机译：尽管依博加因（一种可能用于治疗成瘾的致幻剂）的作用机理仍然未知，但受体结合研究表明依博加因通过与多种受体类型的相互作用产生作用。除了先前已针对伊博加因进行过研究的血清素能受体外，可能的候选药物还包括鸦片，西格玛（sigma）和苯环利定（PCP）结合位点。为了确定这些受体相互作用中的哪些参与了ibogaine的体内作用，评估了sigma，PCP和阿片受体的配体替代或拮抗ibogaine诱导的歧视性刺激的能力（10 mg / kg IP，赛前60分钟）在Fischer-344大鼠中。中等水平的泛化观察到亚型非选择性西格玛配体3-（3-羟苯基）-N-（1-丙基）-哌啶[（+）-3-PPP]（69.0％）和1,3-di（2 -甲苯基）胍（DTG）（73.5％），但不与sigma1-选择剂（+）-N-allyinormetazocine [（+）-SKF 10,047]和（+）-pentazocine结合使用。这些发现以及有关伊博加因对sigma2受体具有明显亲和力的观察结果表明，这些受体可能参与了伊博加因的歧视性刺激。关于阿片受体，吗啡，原型mu激动剂或kappa选择性激动剂（溴咪唑胺和U-50488）都不能替代伊博加因。但是，观察到中等水平的泛化作用，其中混合作用的鸦片剂（-）-SKF为10,047（78.9％），（+/-）-喷他佐辛（73.9％），纳洛啡（70.4％）和二肾上腺素（75.0％），表明阿片受体在伊博加因刺激中的潜在作用。纳曲酮（55.6％）也观察到部分取代，但纳洛酮或选择性kappa拮抗剂nor-binaltorphimine（nor-BNI）没有观察到部分取代。尽管纳洛酮产生了中度但统计学上显着的拮抗作用（69.8％），但这些药物在很大程度上不能有效发挥伊博加因提示的拮抗剂作用。另外，纳洛酮对（-）-SKF 10,047（19.7％）和纳洛啡（25.8％）引起的与依博加宁适当的应答产生完全拮抗作用，而双肾上腺素对依波加因产生的宜博加宁适当应答则仅被部分拮抗（44.4％）。 。后一项观察结果与纳洛啡（> 100 microM）和二肾上腺素（30 microM）对sigma2受体的亲和力极低的发现一起，表明由这些药物产生的与ibogaine相适应的应答不是由sigma2受体介导的。这些发现暗示阿片效应可能与伊波加因刺激有关。与sigma2和阿片受体相反，由于PCP和MK-801均未产生明显水平的与ibogaine相适应的反应，因此ibogaine与NMDA受体的相互作用似乎并未参与其歧视性刺激。因此，本研究提供的证据表明，与NMDA受体不同，西格玛2和阿片受体均可能参与了伊博加因的判别刺激。

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