Bruins Slot Liesbeth A, Kleven Mark S, Newman-Tancredi Adrian
Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, F 81106 Castres Cedex, France.
Neuropharmacology. 2005 Dec;49(7):996-1006. doi: 10.1016/j.neuropharm.2005.05.013. Epub 2005 Jul 11.
Considerable interest has arisen in identifying antipsychotic agents with improved efficacy against negative symptoms, such as social withdrawal. In rats, a social interaction deficit can be induced by the NMDA antagonist phencyclidine (PCP). Here, we examined the effects of antipsychotics, reported to exert dual 5-HT(1A)/D(2) actions, on PCP-induced social interaction deficits. Drugs were administered daily for 3 days in combination with either vehicle or PCP (2.5mg/kg, SC) and social interaction was measured on the last day of drug treatment. Pairs of unfamiliar rats receiving the same treatment were placed in a large open field for 10 min and the number of social behaviors were scored. The results indicate that: (1) PCP significantly reduced social interaction by over 50% compared with vehicle-treated controls; (2) haloperidol (0.0025-0.16 mg/kg, SC) and clozapine (0.04-10mg/kg, IP) did not reverse PCP-induced social interaction deficits; (3) the substituted benzamide remoxipride reversed PCP-induced deficits at 0.63 and 2.5mg/kg (4) the 5-HT(1A) agonist 8-OH-DPAT was inactive (at 0.01-0.63 mg/kg, SC); (5) among compounds reported to exert dual 5-HT(1A)/D(2) actions, SSR181507 (at 0.16 mg/kg, SC) and aripiprazole (at 0.04 and 0.16 mg/kg, IP), but not ziprasidone (0.04-2.5mg/kg, IP), SLV313 (0.0025-0.16 mg/kg, SC) or bifeprunox (0.01-0.63 mg/kg, IP), significantly reversed PCP-induced social interaction deficits; and (6) the 5-HT(1A) receptor antagonist WAY100635 blocked the effects of SSR181507 and aripiprazole. These findings indicate that the balance of activity at 5-HT(1A) and D(2) receptors profoundly influences the activity of antipsychotics in this model of social withdrawal, and their potential benefit on at least some of the negative symptoms of schizophrenia.
人们对确定对抗阴性症状（如社交退缩）疗效更佳的抗精神病药物产生了浓厚兴趣。在大鼠中，N-甲基-D-天冬氨酸（NMDA）拮抗剂苯环利定（PCP）可诱发社交互动缺陷。在此，我们研究了据报道具有5-HT(1A)/D(2)双重作用的抗精神病药物对PCP诱发的社交互动缺陷的影响。药物连续3天每日给药，同时给予溶媒或PCP（2.5mg/kg，皮下注射），并在药物治疗的最后一天测量社交互动情况。将接受相同治疗的陌生大鼠对放入一个大的空旷场地中10分钟，并对社交行为的数量进行评分。结果表明：（1）与溶媒处理的对照组相比，PCP使社交互动显著减少了50%以上；（2）氟哌啶醇（0.0025 - 0.16mg/kg，皮下注射）和氯氮平（0.04 - 10mg/kg，腹腔注射）并未逆转PCP诱发的社交互动缺陷；（3）取代苯甲酰胺瑞莫必利在0.63和2.5mg/kg时逆转了PCP诱发的缺陷；（4）5-HT(1A)激动剂8-羟基二丙胺基四氢萘（8-OH-DPAT）无活性（0.01 - 0.63mg/kg，皮下注射）；（5）在据报道具有5-HT(1A)/D(2)双重作用的化合物中，SSR181507（0.16mg/kg，皮下注射）和阿立哌唑（0.04和0.16mg/kg，腹腔注射），但齐拉西酮（0.04 - 2.5mg/kg，腹腔注射）、SLV313（0.0025 - 0.16mg/kg，皮下注射）或比氟普朗（0.01 - 0.63mg/kg，腹腔注射）未显著逆转PCP诱发的社交互动缺陷；（6）5-HT(1A)受体拮抗剂WAY-100635阻断了SSR181507和阿立哌唑的作用。这些发现表明，在这个社交退缩模型中，5-HT(1A)和D(2)受体的活性平衡深刻影响抗精神病药物的活性，以及它们对精神分裂症至少某些阴性症状的潜在益处。
