Baseline-dependent enhancement of working memory by memantine in male rats: Involvement of NMDA receptor subunits and CaMKII signaling

Shuo-Fu Chen; Wan-Ju Cheng; Chih-Chang Chao; Chun-Hsien Kuo; Ruey-Ming Liao

doi:10.1016/j.pbb.2024.173904

Baseline-dependent enhancement of working memory by memantine in male rats: Involvement of NMDA receptor subunits and CaMKII signaling

Pharmacol Biochem Behav. 2024 Nov 8:245:173904. doi: 10.1016/j.pbb.2024.173904. Online ahead of print.

Authors

Shuo-Fu Chen¹, Wan-Ju Cheng², Chih-Chang Chao³, Chun-Hsien Kuo⁴, Ruey-Ming Liao⁵

Affiliations

¹ Department of Psychology, Asia University, Taichung, Taiwan; Institute of Neuroscience, National Cheng-Chi University, Taipei, Taiwan.
² Department of Psychiatry, China Medical University Hospital, China Medical University, Taichung, Taiwan; Department of Public Health, China Medical University, Taichung, Taiwan; National Center for Geriatrics and Welfare Research, National Health Research Institutes, Miaoli, Taiwan.
³ Institute of Neuroscience, National Cheng-Chi University, Taipei, Taiwan.
⁴ Department of Psychology, Asia University, Taichung, Taiwan; Center for Prevention and Treatment of Internet Addiction, Asia University, Taichung, Taiwan.
⁵ Department of Psychology, Asia University, Taichung, Taiwan; Institute of Neuroscience, National Cheng-Chi University, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. Electronic address: rmliao@asia.edu.tw.

PMID: 39522650
DOI: 10.1016/j.pbb.2024.173904

Abstract

N-methyl-d-aspartate (NMDA) receptors, activated by glutamate, play a crucial role in learning and memory. Memantine (MEM), a non-competitive NMDA receptor antagonist, is currently prescribed for the treatment of Alzheimer's disease or dementia, which meanwhile simultaneously promotes a need to clarify its potential pro-cognitive effects that exist in normal healthy individuals. However, the neurobehavioral mechanisms underlying the cognitive improvement by MEM in normal individuals remain to be elucidated. This study aimed to assess the effects of MEM on working memory, measured by a discrete paired-trial delay alternation task in a T-maze in normal male rats. The impacts of MEM were hypothesized to vary depending on different baseline levels of working memory performance. Neurochemical examination of the levels of calcium/calmodulin-dependent kinase 2 (CaMKII) and NMDA receptor subunits within five targeted brain regions was conducted after behavioral tests. The results showed that acute administration of MEM enhanced working memory performance, with 2.5, 5.0, and 10 mg/kg doses increasing task accuracy compared to the vehicle, particularly in low performers. Neurochemically, the protein expression of CaMKII in the amygdala and that of the glutamate (Glu) N2A subunit in the dorsal striatum were greater in the low-performance group than in the high-performance group. Additionally, the protein expression of the GluN2A subunit in the dorsal striatum was negatively associated with task performance at baseline. The expression of GluN1 and GluN2B in the nucleus accumbens was negatively associated with task performance in the retest three weeks after drug treatment. These findings underscore the baseline-dependent improvement of working memory resulting from MEM administration, with observed drug effects associated with alterations in the levels of NMDA receptor subunits in striatal subareas and CaMKII in the amygdala.

Keywords: Amygdala; Cognitive enhancement; Dorsal striatum; NMDA receptor antagonist; Nucleus accumbens.