Acute and chronic zolpidem administration changes hippocampal long-term potentiation (LTP) as a possible mechanism of memory impairment

Iran J Basic Med Sci. 2026;29(11):1670-1676. doi: 10.22038/ijbms.2026.95516.20587.

ABSTRACT

OBJECTIVES: Zolpidem is a non-benzodiazepine GABAA receptor positive modulator commonly used to treat short-term insomnia. Given its widespread use, understanding its potential impact on cognitive function and synaptic mechanisms is of great interest. This study aimed to investigate the effects of acute and chronic zolpidem administration on hippocampal long-term potentiation (LTP) as a possible mechanism underlying memory impairment in rats.

MATERIALS AND METHODS: Three groups of rats were used in this study: control, acute (received a single dose of zolpidem, 15 mg/kg), and chronic (received daily doses of zolpidem, 15 mg/kg, for 30 consecutive days). Spatial learning and memory were assessed using the Morris water maze. Basic synaptic transmission and LTP were assessed by recording field excitatory postsynaptic potentials in the hippocampus.

RESULTS: No significant differences were observed in spatial learning among the groups. However, evaluation of spatial memory showed that acute and chronic treatment significantly impaired memory performance compared to the control group. Spatial memory was more severely impaired in the chronic group than in the acute group. Electrophysiological data showed that although LTP was induced in both acute and chronic treatment groups, both had significantly lower LTP magnitude than the control group.

CONCLUSION: Chronic zolpidem administration caused significantly greater impairment of spatial memory than acute administration, whereas LTP induction was similarly reduced in both groups. These findings suggest that long-term zolpidem use may pose a greater risk to cognitive function than acute exposure.

PMID:42889607 | PMC:PMC13669783 | DOI:10.22038/ijbms.2026.95516.20587