The present study was designed to clarify whether the arachidonic acid cascade contributes to the decreased threshold for pentylenetetrazole-induced seizure under benzodiazepine withdrawal in mice. The seizure threshold for pentylenetetrazole was significantly decreased by the discontinuation of chronic treatment with diazepam. The decrease in the seizure threshold for pentylenetetrazole during diazepam withdrawal was significantly suppressed by intracerebroventricular (i.c.v.) pretreatment with the phospholipase A₂ inhibitor quinacrine (30, 100 nmol) and the lipoxygenase inhibitor nordihydroguaiaretic acid (10, 30 nmol). In contrast, the decreased seizure threshold in the diazepam-withdrawal group was intensified by pretreatment with the cyclooxygenase inhibitor diclofenac (56 nmol). These compounds did not alter the threshold for seizure in a control group. These findings suggest that enhancement of the arachidonic acid cascade may contribute to the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal.