Schmidt W J, Krähling H, Ruhland M
Biologisches Institut der Universität, Stuttgart, F.R.G.
Life Sci. 1987 Oct 19;41(16):1909-14. doi: 10.1016/0024-3205(87)90742-9.
Bilateral intrastriatal injection of DL-2-amino-5-phosphonovaleric acid (AP-5), that blocks glutamatergic transmission at the N-methyl-d-aspartate preferring receptor, induces sniffing and body turns and reduces grooming in rats. Timelotem, a representative of the newly developed chemical class of anellated benzodiazepines antagonized specifically AP-5-induced sniffing and body turns. Classical (haloperidol) as well as atypical (clozapine) neuroleptics had recently been shown to antagonize AP-5-induced sniffing; clozapine, like timelotem, but not haloperidol, additionally antagonized AP-5-induced body turns. Further, timelotem antagonized amphetamine-induced stereotyped behaviour in rats, but was found less active than haloperidol in this test. Comparing the activity of drugs in both paradigms revealed that haloperidol inhibited AP-5-induced sniffing and amphetamine-induced stereotypies within the same dose range, but timelotem and clozapine were found more potent in the AP-5 test than in the amphetamine test. Thus, detailed drug profiles discriminate timelotem and clozapine from haloperidol, linking timelotem again to atypical antipsychotic compounds.
在大鼠双侧纹状体内注射能阻断 N-甲基-D-天冬氨酸（NMDA）受体处谷氨酸能传递的 DL-2-氨基-5-磷酸戊酸（AP-5），会诱发大鼠嗅探和身体转动，并减少梳理行为。替洛替姆是新开发的一类稠合苯二氮䓬类化合物的代表，它能特异性拮抗 AP-5 诱导的嗅探和身体转动。经典抗精神病药物（氟哌啶醇）以及非典型抗精神病药物（氯氮平）最近已被证明能拮抗 AP-5 诱导的嗅探；氯氮平与替洛替姆一样，但与氟哌啶醇不同，它还能拮抗 AP-5 诱导的身体转动。此外，替洛替姆能拮抗大鼠中由苯丙胺诱导的刻板行为，但在该试验中发现其活性低于氟哌啶醇。比较两种范式下药物的活性发现，氟哌啶醇在相同剂量范围内既能抑制 AP-5 诱导的嗅探，又能抑制苯丙胺诱导的刻板行为，但替洛替姆和氯氮平在 AP-5 试验中比在苯丙胺试验中更有效。因此，详细的药物特征将替洛替姆和氯氮平与氟哌啶醇区分开来，再次将替洛替姆与非典型抗精神病化合物联系起来。
