Kehne J H, Padich R A, McCloskey T C, Taylor V L, Schmidt C J
Hoechst Marion Roussel Inc., Cincinnati, OH 45215, USA.
Psychopharmacology (Berl). 1996 Mar;124(1-2):95-106. doi: 10.1007/BF02245609.
Increasing evidence suggests an important role for serotonin (5-HT) neurons in the etiology and treatment of schizophrenia. The prepulse inhibition paradigm is used as a model for sensorimotor gating processes that are disrupted in schizophrenia. The present study assessed the general role of 5-HT in modulating auditory and visual prepulse inhibition in Wistar rats. A general overactivation of central serotonerigic pathways was produced pharmacologically by four different agents which all shared the common property of releasing 5-HT, i.e., p-chloroamphetamine, 3,4-methylenedioxymethamphetamine, N-ethyl-3,4-methylenedioxymethamphetamine, or fenfluramine. Within each test session, both sound and light prepulses were used to obtain a cross-modal assessment of auditory and visual sensory gating processes. All four 5-HT releasing agents produced dose-related disruptions of auditory and visual prepulse inhibition, with p-chloroamphetamine being the most potent. The releasers depressed baseline to varying degrees. The alpha 2-adrenergic agonist clonidine decreased baseline startle without substantially disrupting prepulse inhibition, demonstrating that the two effects were dissociable. Using fenfluramine as the most selective 5-HT releaser, two approaches were used to demonstrate 5-HT mediation of its disruptive effect on prepulse inhibition. In the first approach, the selective 5-HT uptake blocker MDL 28,618A was used to prevent fenfluramine-induced 5-HT release. In the second approach, prior exposure to a neurotoxic dose of p-chloroamphetamine (10 mg/kg) was used to produce a substantial, sustained depletion of cortical 5-HT, presumably reflecting the loss of 5-HT terminals. Both approaches reduced the disruptive effect of fenfluramine on auditory and visual prepulse inhibition, thereby demonstrating 5-HT mediation of these effects. Neither manipulation significantly affected the depressant effect of fenfluramine on startle baseline, demonstrating that the baseline-reducing and prepulse inhibition-reducing effects of fenfluramine could be dissociated. MDL 28,618A alone did not affect prepulse inhibition or basal startle levels, demonstrating an important functional difference between pharmacologically induced 5-HT uptake blockade and 5-HT release. In summary, these data indicate that serotonergic overactivation can disrupt auditory and visual sensorimotor gating as measured using sound and light prepulse inhibition in rats. These data support a potential role of excessive 5-HT activity as a contributing factor to disrupted sensory gating processes seen in schizophrenia and possibly other neuropsychiatric disorders.
越来越多的证据表明，血清素（5-羟色胺，5-HT）神经元在精神分裂症的病因和治疗中起着重要作用。预脉冲抑制范式被用作精神分裂症中被破坏的感觉运动门控过程的模型。本研究评估了5-HT在调节Wistar大鼠听觉和视觉预脉冲抑制中的一般作用。通过四种不同的药物在药理学上产生中枢血清素能通路的普遍过度激活，这四种药物都具有释放5-HT的共同特性，即对氯苯丙胺、3,4-亚甲基二氧基甲基苯丙胺、N-乙基-3,4-亚甲基二氧基甲基苯丙胺或芬氟拉明。在每个测试环节中，声音和光预脉冲都被用于对听觉和视觉感觉门控过程进行跨模态评估。所有四种5-HT释放剂都产生了与剂量相关的听觉和视觉预脉冲抑制破坏，其中对氯苯丙胺最为有效。这些释放剂在不同程度上降低了基线水平。α2-肾上腺素能激动剂可乐定降低了基线惊跳反应，而没有实质性地破坏预脉冲抑制，表明这两种效应是可分离的。使用芬氟拉明作为最具选择性的5-HT释放剂，采用两种方法来证明5-HT介导其对预脉冲抑制的破坏作用。在第一种方法中，使用选择性5-HT摄取阻断剂MDL 28,618A来阻止芬氟拉明诱导的5-HT释放。在第二种方法中，预先给予神经毒性剂量的对氯苯丙胺（10毫克/千克）以产生皮质5-HT的大量、持续消耗，这可能反映了5-HT终末的丧失。两种方法都降低了芬氟拉明对听觉和视觉预脉冲抑制的破坏作用，从而证明了5-HT介导这些效应。两种操作都没有显著影响芬氟拉明对惊跳基线的抑制作用，表明芬氟拉明降低基线和降低预脉冲抑制的作用是可分离的。单独使用MDL 28,618A不会影响预脉冲抑制或基础惊跳水平，表明药理学诱导的5-HT摄取阻断和5-HT释放之间存在重要的功能差异。总之，这些数据表明，血清素能过度激活可破坏大鼠听觉和视觉感觉运动门控，这是通过声音和光预脉冲抑制来测量的。这些数据支持了过量5-HT活性作为精神分裂症以及可能其他神经精神疾病中感觉门控过程破坏的一个促成因素的潜在作用。
