GABAergic drugs are of interest for the treatment of anxiety, depression, bipolar disorder, pain, cognitive impairment associated with schizophrenia (CIAS), and other neuropsychiatric disorders. Some evidence suggests that TPA-023, (7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b] pyridazine), a GABA_A α2,3 subtype-selective GABA_A partial agonist and α_1/5 antagonist, and the neurosteroid, pregnenolone sulfate, a GABA_A antagonist, may improve CIAS in pilot clinical trials. The goal of this study was to investigate the effect of TPA-023 in mice after acute or subchronic (sc) treatment with the N-methyl-D-aspartate receptor (NMDAR) antagonist, phencyclidine (PCP), on novel object recognition (NOR), reversal learning (RL), and locomotor activity (LMA) in rodents. Acute TPA-023 significantly reversed scPCP-induced NOR and RL deficits. Co-administration of sub-effective dose (SED) TPA-023 with SEDs of the atypical antipsychotic drug, lurasidone, significantly potentiated the effect of TPA-023 in reversing the scPCP-induced NOR deficit. Further, scTPA-023 co-administration significantly prevented scPCP-induced NOR deficit for 5 weeks. Also, administration of TPA-023 for 7 days following scPCP reversed the NOR deficit for 1 week. However, TPA-023 did not blunt acute PCP-induced hyperactivity, suggesting lack of efficacy as a treatment for psychosis. Systemic TPA-023 significantly blocked lurasidone-induced increases in cortical acetylcholine, dopamine, and glutamate without affecting increases in norepinephrine and with minimal effect on basal release of these neurotransmitters. TPA-023 significantly inhibited PCP-induced cortical and striatal dopamine, serotonin, norepinephrine, and glutamate efflux. These results suggest that TPA-023 and other GABA_A agonists may be of benefit to treat CIAS.

中文翻译：

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TPA-023通过GABAA受体激动剂机制减轻了亚慢性苯环利定引起的声明性和逆向学习缺陷：精神分裂症认知缺陷的可能治疗靶标。

GABA能药物对于治疗焦虑症，抑郁症，躁郁症，疼痛，与精神分裂症（CIAS）相关的认知障碍和其他神经精神疾病具有重要意义。一些证据表明TPA-023，（7-（1,1-二甲基乙基）-6-（2-乙基-2H-1,2,4-三唑-3-基甲氧基）-3-（2-氟苯基）-1 ，2,4-三唑并[4,3-b]哒嗪），一个GABA_甲α2,3亚型选择性GABA_阿部分激动剂和α _1/5拮抗剂和神经类固醇，孕烯醇酮硫酸盐，一个GABA_甲拮抗剂，可能会改善中试临床试验中的CIAS。这项研究的目的是研究在用N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂苯环利定（PCP）进行急性或亚慢性（sc）治疗后，TPA-023在小鼠中对新物体识别（NOR）的影响），逆转学习（RL）和啮齿动物的运动能力（LMA）。急性TPA-023显着逆转了scPCP诱导的NOR和RL缺陷。亚有效剂量（SED）TPA-023与非典型抗精神病药Lurasidone的SED共同给药显着增强了TPA-023在逆转scPCP诱导的NOR缺乏症方面的作用。此外，scTPA-023共同给药可有效预防scPCP诱导的NOR缺乏症持续5周。同样，在scPCP后给予TPA-023 7天可使NOR缺陷逆转1周。然而，TPA-023不能抑制急性PCP诱导的机能亢进，提示缺乏治疗精神病的功效。全身性TPA-023显着阻止了卢拉西酮诱导的皮质乙酰胆碱，多巴胺和谷氨酸的增加，而不影响去甲肾上腺素的增加，并且对这些神经递质的基础释放影响最小。TPA-023显着抑制PCP诱导的皮质和纹状体多巴胺，5-羟色胺，去甲肾上腺素和谷氨酸外排。这些结果表明，TPA-023和其他GABA TPA-023显着抑制PCP诱导的皮质和纹状体多巴胺，5-羟色胺，去甲肾上腺素和谷氨酸外排。这些结果表明，TPA-023和其他GABA TPA-023显着抑制PCP诱导的皮质和纹状体多巴胺，5-羟色胺，去甲肾上腺素和谷氨酸外排。这些结果表明，TPA-023和其他GABA_一激动剂可能有利于治疗CIAS。