Receptor mediation of the discriminative stimulus properties of phencyclidine and sigma-opioid agonists.
Receptor mediation of the discriminative stimulus properties of phencyclidine and sigma-opioid agonists.
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DOI：
10.1007/978-3-642-73223-2_10
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发表时间：
1988
期刊：
影响因子：
--
通讯作者：
R. Balster;J. Willetts
中科院分区：
文献类型：
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作者：
R. Balster;J. Willetts
越来越多的证据表明，苯环利定(PCP)的区别性刺激效应可能是通过哺乳动物大脑中的一种特定受体传递的。有两条主要的证据支持这一假设。其一是五氯酚的芳基环己胺类似物对五氯酚类区分作用和取代[~3H]五氯酚结合的构效关系。另一个更有力的证据是，一些非芳基环己胺类药物的代表既是五氯苯酚的泛化产物，又在五氯苯酚结合部位具有活性。这些药物包括(+)-N-烯丙基去甲氧嘧啶(NANM)、1，3-取代二氧杂环己烷地索沙德罗和埃托沙德罗以及一些苯环(F)异喹啉等类抗精神病药。早期证据表明，PCP和Sigma激动剂的区别效应和受体系统可能完全重叠，并且继续有证据支持这些药物组的共性。另一方面，与放射性标记的Sigma激动剂的结合研究揭示了一个非PCP位点。该位点在Sigma激动剂的行为行为中的作用目前尚不清楚。PCP类似物和其他PCP类药物也可以作为自我给药行为的增强剂，这表明相同的细胞机制可能对这些药物的区分和增强刺激作用负责。PCP已被证明可以阻断N-甲基-D-天冬氨酸(NMDA)的许多体外和体内效应，NMDA是一种可能的兴奋性氨基酸受体亚型的特异性激动剂。最近的证据表明，NMDA拮抗剂是由PCP在大鼠和鸽子体内推广而来的，这一证据表明，兴奋性氨基酸神经递质的改变可能是PCP受体的一种生理功能，并且这种受体复合体可能参与了PCP的区别性刺激效应。
Evidence has accumulated that the discriminative stimulus effects of phencyclidine (PCP) may be transduced by a specific receptor in mammalian brain. Two major lines of evidence support this hypothesis. One is the structure-activity correlation that arylcyclohexylamine analogs of PCP have for PCP-like discriminative effects and displacement of [3H]PCP binding. The other, even stronger, evidence is that representatives of some nonarylcyclohexylamine classes of drugs are both generalized from PCP and have activity at PCP-binding sites. These include the psychotomimetic sigma-agonist opioids such as (+)-N-allylnormetazocine (NANM), the 1,3-substituted dioxolanes dexoxadrol and etoxadrol and some benz(f)isoquinolines. Early evidence suggested that there may be a complete overlap in the discriminative effects and receptor systems for PCP and sigma-agonists, and there continues to be evidence to support the commonality of these drug groups. On the other hand, binding studies with radiolabeled sigma agonists have revealed a non-PCP site. The role of this site in the behavioral actions of sigma-agonists is at present unknown. PCP analogs and other PCP-like drugs also can function as reinforcers for self-administration behavior, suggesting that the same cellular mechanisms may be responsible for both discriminative and reinforcing stimulus effects of these drugs. PCP has been shown to block many of the in vitro and in vivo effects of N-methyl-D-aspartate (NMDA), a putative specific agonist for a subtype of excitatory amino acid receptor. Recent evidence that NMDA antagonists are generalized from PCP in rats and pigeons provides evidence that modification of excitatory amino neurotransmission may be a physiological function of the PCP receptor and that this receptor complex may be involved in PCP’s discriminative stimulus effects.