Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
Biol Psychiatry. 2010 May 15;67(10):998-1001. doi: 10.1016/j.biopsych.2010.01.001. Epub 2010 Feb 26.
Ketamine has been used to model cognitive and behavioral symptoms of schizophrenia. Current hypotheses state that inadequate glutamatergic transmission in schizophrenia leads to a deficiency in gamma-aminobutyric acid (GABA)ergic inhibitory mechanisms and treatment with a GABA type A receptor subunits alpha2/alpha3 (GABA(Aalpha2/3)) modulator improved working memory performance in a preliminary study in patients. Here, we used ketamine to impair spatial working memory and disrupt behavior to examine the capacity for the GABA(Aalpha2/3) agonist 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 (TPA023) to reverse these symptoms.
Rhesus monkeys received TPA023 (.7, 2.0, and 5 mg/kg; by mouth) or vehicle 45 minutes before ketamine (1.0-1.7 mg/kg; intramuscular) or saline in a semirandomized Latin square design. Behavioral observations were acquired at approximately 5 minutes, and spatial delayed response performance was tested at 15 minutes postinjection.
Ketamine produced a profound impairment in spatial working memory in association with the emergence of hallucinatory-like behaviors. TPA023 at all doses blocked ketamine's cognitive-impairing ability but did not influence the behavioral symptoms.
Acute GABA(Aalpha2/3) agonist administration reverses the working memory deficits induced by ketamine in primates. This finding indicates that the consequences of N-methyl-D-aspartate deficiency on the function of prefrontal circuits involved in working memory can be completely overcome by acute enhancement of GABA signaling.
氯胺酮已被用于模拟精神分裂症的认知和行为症状。目前的假设是，精神分裂症中谷氨酸能传递不足导致γ-氨基丁酸（GABA）能抑制机制不足，而用 GABA 型 A 受体亚基 α2/α3（GABA(Aα2/3))调节剂治疗可改善初步研究中患者的工作记忆表现。在这里，我们使用氯胺酮损害空间工作记忆并破坏行为，以检查 GABA(Aα2/3)激动剂 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]吡啶（TPA023）逆转这些症状的能力。
恒河猴在半随机拉丁方设计中在氯胺酮（1.0-1.7mg/kg；肌肉注射）或生理盐水前 45 分钟口服接受 TPA023（0.7、2.0 和 5mg/kg）或载体。大约在 5 分钟时进行行为观察，在注射后 15 分钟时测试空间延迟反应表现。
氯胺酮导致空间工作记忆严重受损，同时出现幻觉样行为。TPA023 在所有剂量下均阻断了氯胺酮的认知损害能力，但不影响行为症状。
急性 GABA(Aα2/3)激动剂给药可逆转灵长类动物中氯胺酮引起的工作记忆缺陷。这一发现表明，N-甲基-D-天冬氨酸缺乏对参与工作记忆的前额叶回路功能的影响可以通过急性增强 GABA 信号完全克服。
