Department of Psychology, The Ohio State University, Columbus, OH, USA.
Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
Psychopharmacology (Berl). 2020 Jun;237(6):1723-1735. doi: 10.1007/s00213-020-05495-y. Epub 2020 Mar 11.
Working memory deficits are present in schizophrenia (SZ) but remain insufficiently resolved by medications. Similar cognitive dysfunctions can be produced acutely in animals by elevating brain levels of kynurenic acid (KYNA). KYNA's effects may reflect interference with the function of both the α7 nicotinic acetylcholine receptor (α7nAChR) and the glycineB site of the NMDA receptor.
The aim of the present study was to examine, using pharmacological tools, the respective roles of these two receptor sites on performance in a delayed non-match-to-position working memory (WM) task (DNMTP).
DNMTP consisted of 120 trials/session (5, 10, and 15 s delays). Rats received two doses (25 or 100 mg/kg, i.p.) of L-kynurenine (KYN; bioprecursor of KYNA) or L-4-chlorokynurenine (4-Cl-KYN; bioprecursor of the selective glycineB site antagonist 7-Cl-kynurenic acid). Attenuation of KYN- or 4-Cl-KYN-induced deficits was assessed by co-administration of galantamine (GAL, 3 mg/kg) or PAM-2 (1 mg/kg), two positive modulators of α7nAChR function. Reversal of 4-Cl-KYN-induced deficits was examined using D-cycloserine (DCS; 30 mg/kg), a partial agonist at the glycineB site.
Both KYN and 4-Cl-KYN administration produced dose-related deficits in DNMTP accuracy that were more severe at the longer delays. In KYN-treated rats, these deficits were reversed to control levels by GAL or PAM-2 but not by DCS. In contrast, DCS eliminated performance deficits in 4-Cl-KYN-treated animals.
These experiments reveal that both α7nAChR and NMDAR activity are necessary for normal WM accuracy. They provide substantive new support for the therapeutic potential of positive modulators at these two receptor sites in SZ and other major brain diseases.
精神分裂症（SZ）存在工作记忆缺陷，但药物治疗仍未充分解决。通过提高脑中犬尿氨酸（KYNA）的水平，可在动物中急性产生类似的认知功能障碍。KYNA 的作用可能反映了对α7 烟碱型乙酰胆碱受体（α7nAChR）和 NMDA 受体甘氨酸 B 位点的功能的干扰。
本研究旨在使用药理学工具，检查这两个受体位点在延迟非匹配位置工作记忆（WM）任务（DNMTP）中的各自作用。
DNMTP 由 120 次试验/会议（5、10 和 15 秒延迟）组成。大鼠接受两种剂量（25 或 100mg/kg，ip）的 L-犬尿氨酸（KYN；KYNA 的生物前体）或 L-4-氯犬尿氨酸（4-Cl-KYN；选择性甘氨酸 B 位点拮抗剂 7-Cl-犬尿氨酸的生物前体）。通过共同给予加兰他敏（GAL，3mg/kg）或 PAM-2（1mg/kg）来评估 KYN 或 4-Cl-KYN 诱导的缺陷的衰减，这两种药物都是 α7nAChR 功能的正调节剂。使用 D-环丝氨酸（DCS；30mg/kg）检查 4-Cl-KYN 诱导的缺陷的逆转，DCS 是甘氨酸 B 位点的部分激动剂。
KYN 和 4-Cl-KYN 给药均导致 DNMTP 准确性的剂量依赖性缺陷，在较长的延迟时间更为严重。在 KYN 处理的大鼠中，GAL 或 PAM-2 可将这些缺陷逆转至对照水平，但 DCS 不行。相反，DCS 消除了 4-Cl-KYN 处理动物的表现缺陷。
这些实验表明，α7nAChR 和 NMDA 受体活性对正常 WM 准确性都是必需的。它们为这两个受体位点的正调节剂在 SZ 和其他主要脑部疾病中的治疗潜力提供了实质性的新支持。
