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The D2-family receptor agonist bromocriptine but, not nicotine, reverses NMDA receptor antagonist-induced working memory deficits in the radial arm maze in mice.
Neurobiology of Learning and Memory ( IF 2.7 ) Pub Date : 2020-01-03 , DOI: 10.1016/j.nlm.2020.107159
David A MacQueen 1 , Jared W Young 2
Affiliation  

Hypofunction of the NMDA receptor (NMDAr) may underlie cognitive deficits associated with schizophrenia and other psychiatric conditions including working memory (WM) impairments. Given that these deficits link closely to functional outcome, treatments remediating such deficits require identification. NMDAr hypofunction can be modeled via treatment with the antagonist MK-801. Hence, the present study determined whether cholinergic or dopaminergic agonists attenuate MK-801-induced WM deficits in mice. WM was assessed in male C57BL/6 mice trained on an automated 12-arm radial arm maze (RAM) paradigm, wherein rewards were delivered after the first but, not after subsequent entries into WM arms (8/12) and never delivered for entries into reference memory (RM) arms (4/12). Mice were then treated with MK-801 (vehicle or 0.3 mg/kg) and nicotine (vehicle, 0.03 or 0.30 mg/kg) in a cross-over design. After a 2-week washout, mice were then retested with MK-801 and the dopamine D2-family receptor agonist bromocriptine (vehicle, 3 or 10 mg/kg). In both experiments, MK-801 reduced WM span and increased RM and WM error rates. Nicotine did not attenuate these deficits. In contrast, a bromocriptine/MK-801 interaction was observed on WM error rate, where bromocriptine attenuated MK-801 induced deficits without affecting MK-801-induced RM errors. Additionally, bromocriptine produced the main effect of slowing latency to collect rewards. Hence, while NMDAr hypofunction-induced deficits in WM was unaffected by nicotine, it was remediated by treatment with the dopamine D2-family agonist bromocriptine. Future studies should determine whether selective activation of dopamine D2, D3, or D4 receptors remediate this NMDAr hypofunction-induced WM deficit.

中文翻译:

D2-家族受体激动剂溴隐亭而非尼古丁可逆转NMDA受体拮抗剂诱导的小鼠arm臂迷宫中的工作记忆缺陷。

NMDA受体(NMDAr)的功能低下可能是精神分裂症和其他精神疾病(包括工作记忆(WM)障碍)相关的认知缺陷的基础。鉴于这些缺陷与功能结局密切相关,因此需要鉴定纠正此类缺陷的治疗方法。NMDAr功能减退可以通过使用拮抗剂MK-801进行建模。因此,本研究确定了胆碱能或多巴胺能激动剂是否能减轻小鼠中MK-801诱导的WM缺陷。在经过自动12臂放射状迷宫(RAM)范例训练的雄性C57BL / 6小鼠中评估了WM,其中奖励是在第一次进入WM臂后(8/12)之后而不是在随后进入WM臂后才提供的,并且从不为进入而提供放入参考内存(RM)臂(4/12)。然后用MK-801(媒介物或0.3 mg / kg)和尼古丁(媒介物,0.03或0.30 mg / kg)。经过2周的冲洗后,然后用MK-801和多巴胺D2家族受体激动剂溴隐亭(车辆3或10 mg / kg)重新测试小鼠。在两个实验中,MK-801减少了WM跨度,并增加了RM和WM错误率。尼古丁没有减轻这些缺陷。相反,在WM错误率上观察到了溴隐亭/ MK-801相互作用,其中溴隐亭减弱了MK-801诱导的缺陷,而没有影响MK-801诱导的RM错误。此外,溴隐亭产生了延缓潜伏期以收集奖励的主要作用。因此,尽管尼古丁不影响NMDAr机能减退引起的WM缺陷,但可以通过多巴胺D2家族激动剂溴隐亭治疗来纠正。未来的研究应确定多巴胺D2,D3,
更新日期:2020-01-04
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