Synaptic Transmission I, Neuroscience Research DK, H Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
Psychopharmacology (Berl). 2012 Jun;221(3):451-68. doi: 10.1007/s00213-011-2593-9. Epub 2011 Nov 29.
A growing body of evidence suggests that negative modulation of γ-aminobutyric acid (GABA) GABA(A) α5 receptors may be a promising strategy for the treatment of certain facets of cognitive impairment; however, selective modulators of GABA(A) α5 receptors have not yet been tested in "schizophrenia-relevant" cognitive assay/model systems in animals.
The objectives of this study were to investigate the potential of RO4938581, a negative modulator of GABA(A) α5 receptors, and to attenuate cognitive impairments induced following sub-chronic (sub-PCP) and early postnatal PCP (neo-PCP) administration in the novel object recognition (NOR) and intra-extradimensional shift (ID/ED) paradigms in rats. Complementary in vitro, ex vivo and in vivo studies were performed to confirm negative modulatory activity of RO4938581 and to investigate animal model validity, concept validity and potential side effect issues, respectively.
In vitro studies confirmed the reported negative modulatory activity of RO4938581, whilst immunohistochemical analyses revealed significantly reduced parvalbumin-positive cells in the prefrontal cortex of sub-PCP- and neo-PCP-treated rats. RO4938581 (1 mg/kg) ameliorated both sub-PCP- and neo-PCP-induced cognitive deficits in NOR and ID/ED performance, respectively. In contrast, QH-II-066 (1 and 3 mg/kg), a GABA(A) α5 receptor positive modulator, impaired cognitive performance in the NOR task when administered to vehicle-treated animals. Additional studies revealed that both RO4938581 (1 mg/kg) and QH-II-066 (1 and 3 mg/kg) attenuated amphetamine-induced hyperactivity in rats.
Taken together, these novel findings suggest that negative modulation of GABA(A) α5 receptors may represent an attractive treatment option for the cognitive impairments, and potentially positive symptoms, associated with schizophrenia.
越来越多的证据表明，γ-氨基丁酸（GABA）A 型受体α5 亚基的负向调控可能是治疗某些认知障碍的有前途的策略；然而，GABA A 型受体α5 亚基的选择性调节剂尚未在动物的“与精神分裂症相关”认知测定/模型系统中进行测试。
本研究的目的是研究 RO4938581（GABA A 型受体α5 亚基的负向调节剂）的潜力，以减轻亚慢性（亚 PCP）和早期新生期 PCP（新生 PCP）给药后在大鼠新型物体识别（NOR）和内-外维度转换（ID/ED）范式中引起的认知障碍。进行了补充的体外、离体和体内研究，以分别确认 RO4938581 的负向调节活性、研究动物模型的有效性、概念有效性和潜在的副作用问题。
体外研究证实了 RO4938581 的报道的负向调节活性，而免疫组织化学分析显示亚 PCP 和新生 PCP 处理大鼠的前额叶皮层中明显减少了 parvalbumin 阳性细胞。RO4938581（1 mg/kg）改善了 NOR 和 ID/ED 表现中的亚 PCP 和新生 PCP 诱导的认知缺陷。相比之下，QH-II-066（1 和 3 mg/kg），一种 GABA A 型受体正向调节剂，当给予载体处理的动物时，会损害 NOR 任务中的认知表现。进一步的研究表明，RO4938581（1 mg/kg）和 QH-II-066（1 和 3 mg/kg）均可减弱安非他命引起的大鼠多动。
总之，这些新发现表明，GABA A 型受体α5 亚基的负向调节可能是治疗与精神分裂症相关的认知障碍和潜在阳性症状的有吸引力的治疗选择。
