Shilling P D, Feifel D
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
Psychopharmacology (Berl). 2002 Nov;164(3):285-93. doi: 10.1007/s00213-002-1214-z. Epub 2002 Sep 4.
Converging evidence has demonstrated that cholecystokinin (CCK) inhibits mesolimbic brain dopamine (DA) function via activation of CCK-A (CCK-1) receptors. These effects of CCK have stimulated interest in the potential use of CCK agonists as antipsychotic drugs. Most research on the antipsychotic-like drug effects of CCK has used CCK or CCK analogues that nonselectively activate both CCK-A and CCK-B (CCK-2) receptors, which may produce opposite effects. SR146131, a CCK-A selective nonpeptide agonist, has recently been developed (Sanofi-Synthelabo).
To determine whether SR146131 exhibits antipsychotic-like qualities in the prepulse inhibition (PPI) paradigm.
We performed experiments to determine whether SR146131 (vehicle, 0.01, 0.1, 1.0 mg/kg) would attenuate PPI deficits induced by amphetamine (2.0 mg/kg), an indirect dopamine agonist, and dizocilpine (0.1 mg/kg), a noncompetitive N-methyl-D-aspartate (NMDA) antagonist. Since SR146131 demonstrated significant effects on PPI disrupted by the noncompetitive NMDA antagonist, an effect associated with drugs that inhibit serotonin (5HT)2A transmission, we also tested the effects of SR146131 on PPI disruption produced by 2,5-dimethoxy-4-iodoamphetamine (DOI, 0.5 mg/kg), a direct 5HT2A agonist.
SR146131 did not significantly affect startle magnitude, baseline PPI, or amphetamine-induced PPI deficits. However, it dose-dependently antagonized dizocilpine and DOI-induced PPI deficits.
The lack of an effect of SR146131 on amphetamine-induced disruption of PPI suggests that a selective nonpeptide CCK-A agonist may not produce antipsychotic-like effects on dopamine transmission. However, the unexpected effects of SR146131 on dizocilpine and DOI-induced PPI deficits are consistent with the effects of drugs that inhibit transmission in the 5HT2A receptor system, including atypical antipsychotic drugs. Possible mechanisms underlying these findings are discussed.
越来越多的证据表明，胆囊收缩素（CCK）通过激活CCK-A（CCK-1）受体来抑制中脑边缘脑区的多巴胺（DA）功能。CCK的这些作用激发了人们对将CCK激动剂用作抗精神病药物的潜在用途的兴趣。大多数关于CCK抗精神病样药物作用的研究使用的CCK或CCK类似物会非选择性地激活CCK-A和CCK-B（CCK-2）受体，这可能会产生相反的效果。SR146131是一种CCK-A选择性非肽激动剂，最近已被研发出来（赛诺菲-圣德拉堡公司）。
确定SR146131在预脉冲抑制（PPI）范式中是否表现出抗精神病样特性。
我们进行了实验，以确定SR146131（溶剂、0.01、0.1、1.0毫克/千克）是否会减轻由间接多巴胺激动剂苯丙胺（2.0毫克/千克）和非竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂地佐环平（0.1毫克/千克）诱导的PPI缺陷。由于SR146131对非竞争性NMDA拮抗剂破坏的PPI有显著影响，这一作用与抑制5-羟色胺（5HT）2A传递的药物相关，我们还测试了SR146131对由直接5HT2A激动剂2,5-二甲氧基-4-碘苯丙胺（DOI，0.5毫克/千克）产生的PPI破坏的影响。
SR146131对惊吓幅度、基线PPI或苯丙胺诱导的PPI缺陷没有显著影响。然而，它能剂量依赖性地拮抗地佐环平和DOI诱导的PPI缺陷。
SR146131对苯丙胺诱导的PPI破坏没有作用，这表明选择性非肽CCK-A激动剂可能不会对多巴胺传递产生抗精神病样作用。然而，SR146131对地佐环平和DOI诱导的PPI缺陷的意外作用与抑制5HT2A受体系统传递的药物（包括非典型抗精神病药物）的作用一致。讨论了这些发现背后可能的机制。
