Pichat Philippe, Bergis Olivier E, Terranova Jean-Paul, Urani Alexandre, Duarte Christine, Santucci Vincent, Gueudet Christiane, Voltz Carole, Steinberg Régis, Stemmelin Jeanne, Oury-Donat Florence, Avenet Patrick, Griebel Guy, Scatton Bernard
Central Nervous System Research Department, Sanofi-Aventis, Bagneux, France.
Neuropsychopharmacology. 2007 Jan;32(1):17-34. doi: 10.1038/sj.npp.1301188. Epub 2006 Aug 23.
SSR180711 (4-bromophenyl 1,4diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride) is a selective alpha7 nicotinic receptor (n-AChR) partial agonist. Based on the purported implication of this receptor in cognitive deficits associated with schizophrenia, the present study assessed efficacy of SSR180711 (i.p. and p.o.) in different types of learning and memory involved in this pathology. SSR180711 enhanced episodic memory in the object recognition task in rats and mice (MED: 0.3 mg/kg), an effect mediated by the alpha7 n-AChR, as it was no longer seen in mice lacking this receptor. Efficacy was retained after repeated treatment (eight administrations over 5 days, 1 mg/kg), indicating lack of tachyphylaxia. SSR180711 also reversed (MED: 0.3 mg/kg) MK-801-induced deficits in retention of episodic memory in rats (object recognition). The drug reversed (MED: 0.3 mg/kg) selective attention impaired by neonatal phencyclidine (PCP) treatment and restored MK-801- or PCP-induced memory deficits in the Morris or linear maze (MED: 1-3 mg/kg). In neurochemical and electrophysiological correlates of antipsychotic drug action, SSR180711 increased extracellular levels of dopamine in the prefrontal cortex (MED: 1 mg/kg) and enhanced (3 mg/kg) spontaneous firing of retrosplenial cortex neurons in rats. Selectivity of SSR180711 was confirmed as these effects were abolished by methyllycaconitine (3 mg/kg, i.p. and 1 mg/kg, i.v., respectively), a selective alpha7 n-AChR antagonist. Additional antidepressant-like properties of SSR180711 were demonstrated in the forced-swimming test in rats (MED: 1 mg/kg), the maternal separation-induced ultrasonic vocalization paradigm in rat pups (MED: 3 mg/kg) and the chronic mild stress procedure in mice (10 mg/kg o.d. for 3 weeks). Taken together, these findings characterize SSR180711 as a promising new agent for the treatment of cognitive symptoms of schizophrenia. The antidepressant-like properties of SSR180711 are of added interest, considering the high prevalence of depressive symptoms in schizophrenic patients.
SSR180711（4-溴苯基 1,4-二氮杂双环(3.2.2)壬烷-4-羧酸酯，盐酸盐）是一种选择性α7 烟碱型受体（n-AChR）部分激动剂。基于该受体据称与精神分裂症相关的认知缺陷有关，本研究评估了 SSR180711（腹腔注射和口服）在该病症所涉及的不同类型学习和记忆方面的疗效。SSR180711 增强了大鼠和小鼠在物体识别任务中的情景记忆（最小有效剂量：0.3 毫克/千克），这一效应由α7 n-AChR 介导，因为在缺乏该受体的小鼠中不再出现这种效应。重复给药（5 天内给药 8 次，1 毫克/千克）后疗效得以维持，表明不存在快速耐受性。SSR180711 还逆转了（最小有效剂量：0.3 毫克/千克）MK-801 诱导的大鼠情景记忆保持缺陷（物体识别）。该药物逆转了（最小有效剂量：0.3 毫克/千克）新生期苯环利定（PCP）治疗所致的选择性注意力损害，并恢复了 MK-801 或 PCP 诱导的 Morris 或直线迷宫中的记忆缺陷（最小有效剂量：1 - 3 毫克/千克）。在抗精神病药物作用的神经化学和电生理相关性方面，SSR180711 增加了前额叶皮质中多巴胺的细胞外水平（最小有效剂量：1 毫克/千克），并增强了（3 毫克/千克）大鼠扣带回皮质神经元的自发放电。SSR180711 的选择性得到了证实，因为这些效应分别被甲基-lycaconitine（腹腔注射 3 毫克/千克和静脉注射 1 毫克/千克）所消除，甲基-lycaconitine 是一种选择性α7 n-AChR 拮抗剂。SSR180711 在大鼠强迫游泳试验（最小有效剂量：1 毫克/千克）、大鼠幼崽母体分离诱导的超声发声范式（最小有效剂量：3 毫克/千克）和小鼠慢性轻度应激程序（连续 3 周每天 10 毫克/千克）中还表现出额外的抗抑郁样特性。综上所述，这些发现表明 SSR180711 是一种有前景的治疗精神分裂症认知症状的新型药物。考虑到精神分裂症患者中抑郁症状的高患病率，SSR180711 的抗抑郁样特性更具意义。
