Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Neurobiology, 12 Smętna Street, 31-343 Kraków, Poland.
Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Neurobiology, 12 Smętna Street, 31-343 Kraków, Poland.
Pharmacol Biochem Behav. 2024 May;238:173749. doi: 10.1016/j.pbb.2024.173749. Epub 2024 Mar 9.
Muscarinic or 5-HT receptors are crucial in learning and memory processes, and their expression is evident in the brain areas involved in cognition. The administration of the activators of these receptors prevents the development of cognitive dysfunctions in animal models of schizophrenia induced by MK-801 (N-methyl-d-aspartate receptor antagonist) administration. GABAergic dysfunction is considered as one of the most important causes of MK-801-induced spatial learning deficits.
Novel object recognition (NOR) and Morris water maze (MWM) tests were used to study the anti-amnestic effect of the biased 5-HT receptor agonist (F15599) alone or in combinations with VU0357017 (M receptor allosteric agonist), VU0152100 (M receptor positive allosteric modulator), and VU0238429 (M receptor positive allosteric modulator) on MK-801-induced dysfunctions. The compounds were administered for 5 consecutive days. Animals tested with the MWM underwent 5-day training. Western blotting was used to study the expressions of 5-HT receptors and the level of GAD in the frontal cortices (FCs) and hippocampi of the animals.
F15599 prevented the amnestic effect induced by MK-801 in the MWM at a dose of 0.1 mg/kg. The co-administration of the compound with muscarinic receptors activators had no synergistic effect. The additive effect of the combinations was evident in the prevention of declarative memory dysfunctions investigated in NOR. The administration of MK-801 impaired 5-HT expression in the hippocampi and decreased GAD levels in both the FCs and hippocampi. The administration of muscarinic ligands prevented these MK-801-induced deficits only in the hippocampi of MWM-trained animals. No effects of the compounds were observed in untrained mice.
Our results indicate that F15599 prevents schizophrenia-related spatial learning deficits in the MWM; however, the activity of the compound is not intensified with muscarinic receptors activators. In contrast, the combined administration of the ligands is effective in the NOR model of declarative memory. The muscarinic receptors activators reversed MK-801-induced 5-HT and GAD dysfunctions in the hippocampi of MWM-trained mice, but not in untrained mice.
毒蕈碱或 5-HT 受体在学习和记忆过程中至关重要，其表达在涉及认知的大脑区域中显而易见。这些受体的激动剂的给药可防止 MK-801（N-甲基-D-天冬氨酸受体拮抗剂）给药诱导的精神分裂症动物模型中认知功能障碍的发展。GABA 能功能障碍被认为是 MK-801 诱导的空间学习缺陷的最重要原因之一。
使用新物体识别（NOR）和 Morris 水迷宫（MWM）测试研究了偏 5-HT 受体激动剂（F15599）单独或与 VU0357017（M 受体变构激动剂）、VU0152100（M 受体正变构调节剂）和 VU0238429（M 受体正变构调节剂）联合给药对 MK-801 诱导的功能障碍的抗健忘作用。连续 5 天给药。接受 MWM 测试的动物接受了 5 天的训练。使用 Western blot 技术研究了动物额叶皮质（FCs）和海马中 5-HT 受体的表达和 GAD 的水平。
F15599 以 0.1mg/kg 的剂量预防了 MWM 中由 MK-801 引起的健忘作用。该化合物与毒蕈碱受体激动剂联合给药没有协同作用。在 NOR 研究中，组合的相加作用在预防陈述性记忆功能障碍方面表现明显。MK-801 给药损伤了海马中的 5-HT 表达，并降低了 FCs 和海马中 GAD 的水平。毒蕈碱配体的给药仅在 MWM 训练动物的海马中预防了这些 MK-801 诱导的缺陷。在未经训练的小鼠中未观察到化合物的作用。
我们的结果表明，F15599 可预防 MWM 中与精神分裂症相关的空间学习缺陷；然而，该化合物的活性并未因毒蕈碱受体激动剂而增强。相比之下，配体的联合给药在陈述性记忆的 NOR 模型中有效。毒蕈碱受体激动剂逆转了 MWM 训练小鼠海马中由 MK-801 引起的 5-HT 和 GAD 功能障碍，但在未经训练的小鼠中没有作用。
