N-methyl-D-aspartate Receptors Are Involved in Caffeine-Induced Facilitation on Memory Retention of Passive Avoidance Learning in Rats

Abstract

Background: Caffeine is an antagonist of adenosine receptors. It preserves cognition and reduces neurodegeneration. The MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, has also shown amnesic properties in animal models. The effect of caffeine on MK-801-induced amnesia has not been the subject of any recent study. Methods: In this study, the effects of different doses (10 and 30 mg/kg) of caffeine on Wistar male rats (eight in each group), passive-avoidance (PA) response, and the impairment of this response by the NMDA receptor antagonist MK-801 (dizocilpine) were evaluated. The PA response was examined by measuring the step-through latency, 1 and 3 days after the animals received foot-shock training. Results: When given intraperitoneally before the training session, 10 mg/kg caffeine elongated the PA response, but 30 mg/kg did not, and it even reduced the step-through latency significantly. Before and after training, administration of 0.2 mg/kg MK-801 significantly elongated the PA response. This finding showed that MK-801 had a detrimental effect on learning, consolidation, and memory. We found the first evidence that pre-training and pre-testing administration of 10 mg/kg caffeine significantly reversed the learning and memory consolidation process disrupted by MK-801. Conclusion: These results show an interaction between caffeine and the glutamatergic system, suggesting that low-dose caffeine can prevent learning deficit and amnesia produced by a NMDA antagonist in rats (model of schizophrenia in human) when injected in pre-and post-training phase and may be clinically useful for treating cognitive impairments in schizophrenia.

Quantitative Structure–Neurotoxicity Assessment and In Vitro Evaluation of Neuroprotective and MAO-B Inhibitory Activities of Series N′-substituted 3-(1,3,7-trimethyl-xanthin-8-ylthio)propanehydrazides

“…Caffeine has neuroprotector and cytoprotector effects in cases of dopamine-induced damage by regulating the levels of this neurotransmitter [29]. Caffeine has also been associated with an effect that retards signs of neuronal degeneration in diseases like Parkinson's and Alzheimer's, effects that occur through interaction with adenosine receptors and a possible association with N-methyl D-aspartate receptors (NMDA), which increase cognition and delay the onset of the associated signs [35][36][37].…”

Neurobehavioral and neuroprotector effects of caffeine in animal models

“…The mechanism that induces memory enhancement may be mediated by the interaction between the NMDA receptors and treatment with caffeine at low doses, which have been shown to induce memory improvement in male Wistar rats (Diler et al 2013). Recently, Kim et al (2018) refuted the hypothesis of interaction with the GRIN2A receptor -which functions as a subunit of NMDA-because they failed to detect any significant interaction (P = 0.47).…”

“…Moreover, it has neuroprotector and cytoprotector J Anim Behav Biometeorol (2020) 8:298-307 effects in cases of dopamine-induced damage by regulating the levels of this neurotransmitter (Kalda et al 2006). Caffeine has also been associated with an effect that retards signs of neuronal degeneration in diseases like Parkinson's and Alzheimer's; effects that occur through interaction with adenosine receptors and a possible association with N-methyl-D-aspartate receptors (NMDA), which increase cognition and delay the onset of the associated signs (Diler et al 2013;Kim et al 2018).…”