Mouse Clinical Institute, Illkirch, France.
Neuropsychopharmacology. 2012 Jan;37(2):378-89. doi: 10.1038/npp.2011.175. Epub 2011 Aug 31.
Nociceptin/orphanin FQ (N/OFQ) peptide and its receptor (NOP receptor) have been implicated in a host of brain functions and diseases, but the contribution of this neuropeptide system to behavioral processes of relevance to psychosis has not been investigated. We examined the effect of the NOP receptor antagonists, Compound 24 and J-113397, and the synthetic agonist, Ro64-6198, on time function (2-2000 ms prepulse-pulse intervals) of acoustic (80 dB/10 ms prepulse) and visual (1000 Lux/20 ms prepulse) prepulse inhibition of startle reflex (PPI), a preattentive sensory filtering mechanism that is central to perceptual and mental integration. The effects of the dopamine D1-like receptor agonist, SKF-81297, the D2-like receptor agonist, quinelorane, and the mixed D1/D2 agonist, apomorphine, were studied for comparison. When acoustic stimulus was used as prepulse, BALB/cByJ mice displayed a monotonic time function of PPI, and consistent with previous studies, apomorphine and SKF-81279 induced PPI impairment, whereas quinelorane had no effect. None of the NOP receptor ligands was effective on acoustic PPI. When flash light was used as prepulse, BALB/cByJ mice displayed a bell-shaped time function of PPI and all dopamine agonists were active. Ro64-6198 was also effective in reducing visual PPI. NOP receptor antagonists showed no activity but blocked disruptive effect of Ro64-6198. Finally, coadministration of the typical antipsychotic, haloperidol, attenuated PPI impairment induced by Ro64-6198, revealing involvement of a dopaminergic component. These findings show that pharmacological stimulation of NOP or dopamine D2-like receptors is more potent in disrupting visual than acoustic PPI in mice, whereas D1-like receptor activation disrupts both. They further suggest that dysfunction of N/OFQ transmission may be implicated in the pathogenesis of psychotic manifestations.
孤啡肽（N/OFQ）肽及其受体（NOP 受体）参与了许多大脑功能和疾病，但该神经肽系统对与精神病相关的行为过程的贡献尚未得到研究。我们研究了 NOP 受体拮抗剂化合物 24 和 J-113397 以及合成激动剂 Ro64-6198 对听觉（80dB/10ms 预备脉冲）和视觉（1000Lux/20ms 预备脉冲）惊跳反射预备脉冲抑制（PPI）的时间功能（2-2000ms 预备脉冲-脉冲间隔）的影响，预备脉冲抑制是一种非注意性感觉过滤机制，是知觉和心理整合的核心。多巴胺 D1 样受体激动剂 SKF-81297、D2 样受体激动剂喹那洛林和混合 D1/D2 激动剂阿扑吗啡的作用也进行了研究。当使用听觉刺激作为预备脉冲时，BALB/cByJ 小鼠表现出 PPI 的单调时间功能，与先前的研究一致，阿扑吗啡和 SKF-81279 诱导 PPI 损伤，而喹那洛林没有作用。NOP 受体配体均对听觉 PPI 无效。当闪光光用作预备脉冲时，BALB/cByJ 小鼠表现出 PPI 的钟形时间功能，所有多巴胺激动剂均有效。Ro64-6198 也能有效降低视觉 PPI。NOP 受体拮抗剂没有活性，但阻断了 Ro64-6198 的破坏作用。最后，典型抗精神病药氟哌啶醇的共同给药减弱了 Ro64-6198 诱导的 PPI 损伤，表明涉及多巴胺成分。这些发现表明，在小鼠中，NOP 或多巴胺 D2 样受体的药理学刺激在破坏视觉 PPI 方面比听觉 PPI 更为有效，而 D1 样受体的激活则破坏了两者。它们进一步表明，孤啡肽传递功能障碍可能与精神病表现的发病机制有关。
