Padich R A, McCloskey T C, Kehne J H
Hoechst Marion Roussel Inc., Cincinnati, OH 45215, USA.
Psychopharmacology (Berl). 1996 Mar;124(1-2):107-16. doi: 10.1007/BF02245610.
Increasing evidence suggests an important role of 5-HT, and 5-HT2A receptors in particular, 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 used the selective serotonin2A (5-HT2A) antagonist and putative antipsychotic agent MDL 100,907 to evaluate the contribution of 5-HT2A receptors to the disruptions of prepulse inhibition produced by several 5-HT agonists. The D2 antagonist haloperidol was used to evaluate a possible interaction with dopamine neurons. Sound or light prepulses were used to measure the generality of these drug effects on cross-modal prepulse inhibition. In the first study, MDL 100,907 antagonized the disruptions of auditory prepulse inhibition produced by the 5-HT releasing agents fenfluramine and 3,4-methylenedioxymethamphetamine (MDMA). These effects on prepulse inhibition were modality-specific in that MDL 100,907 did not reverse the effects of the 5-HT releasers on visual prepulse inhibition. Haloperidol did not alter the disruptive effects of MDMA or fenfluramine on either auditory or visual prepulse inhibition. In the second study, the direct acting 5-HT2A/2C receptor agonist/hallucinogen (+)1-4-iodo-2,5-dimethoxyphenyl-2-aminopropane (DOI) consistently disrupted auditory prepulse inhibition, and this effect was blocked by MDL 100,907 but not by haloperidol. A dose-response analysis demonstrated that MDL 100,907 potently antagonized DOI disrupted auditory prepulse inhibition, with an ED50 of 0.04 mg/kg, IP. DOI did not consistently disrupt visual prepulse inhibition. In summary, these data indicate that, at least under the conditions of the present studies, the disruptions of auditory prepulse inhibition produced by fenfluramine, MDMA, and DOI result from stimulation of 5-HT2A receptors. Furthermore, these disruptions do not involve direct or indirect stimulation of D2 receptors. The identity of the 5-HT receptor(s) underlying the disruptive effects of fenfluramine or MDMA on visual prepulse inhibition has not yet been identified. MDL 100,907 may be generally useful in CNS disorders in which excessive 5-HT2A receptor tone disrupts sensory gating processes.
越来越多的证据表明5-羟色胺（5-HT），尤其是5-HT2A受体，在精神分裂症的病因学及治疗中发挥着重要作用。前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。本研究使用选择性5-羟色胺2A（5-HT2A）拮抗剂及假定的抗精神病药物MDL 100,907来评估5-HT2A受体对几种5-HT激动剂所产生的前脉冲抑制破坏作用的影响。使用D2拮抗剂氟哌啶醇来评估与多巴胺神经元的可能相互作用。使用声音或光前脉冲来测量这些药物对跨模态前脉冲抑制作用的普遍性。在第一项研究中，MDL 100,907拮抗了由5-HT释放剂芬氟拉明和3,4-亚甲基二氧甲基苯丙胺（摇头丸）所产生的听觉前脉冲抑制破坏作用。这些对前脉冲抑制的作用具有模态特异性，因为MDL 100,907并未逆转5-HT释放剂对视觉前脉冲抑制的作用。氟哌啶醇未改变摇头丸或芬氟拉明对听觉或视觉前脉冲抑制的破坏作用。在第二项研究中，直接作用的5-HT2A/2C受体激动剂/致幻剂（+）1-4-碘-2,5-二甲氧基苯基-2-氨基丙烷（DOI）持续破坏听觉前脉冲抑制，且这种作用被MDL 100,907阻断，但未被氟哌啶醇阻断。剂量反应分析表明，MDL 100,907有效拮抗DOI破坏的听觉前脉冲抑制，腹腔注射时的半数有效剂量（ED50）为0.04 mg/kg。DOI并未持续破坏视觉前脉冲抑制。总之，这些数据表明，至少在本研究的条件下，芬氟拉明、摇头丸和DOI所产生的听觉前脉冲抑制破坏作用是由5-HT2A受体的刺激所致。此外，这些破坏作用并不涉及对D2受体的直接或间接刺激。芬氟拉明或摇头丸对视觉前脉冲抑制破坏作用所涉及的5-HT受体身份尚未确定。MDL 100,907在5-HT2A受体张力过高破坏感觉门控过程的中枢神经系统疾病中可能普遍有用。
