Acetaminophen modifies hippocampal synaptic plasticity via a presynaptic 5-HT₂ receptor

Acetaminophen (APAP) has recently been found to target COX-3, a newly identified COX isozyme. We discovered previously that selective COX-2 inhibitors reduce membrane excitability and long-term potentiation (LTP) in the hippocampus. The purpose of this study was to investigate whether APAP had effects on hippocampal LTP. We found that APAP reduced LTP induction and increased the paired-pulse facilitation (PPF). APAP-induced changes in LTP and PPF were blocked by a 5-hydroxytryptamine (serotonin, 5-HT_2/1) receptor antagonist. The results suggest that APAP-induced modification of synaptic plasticity at hippocampal lateral perforant path-dentate granule cell synapses may be mediated by a presynaptic 5-HT₂ receptor.