Because extracts of kudzu have been used as a hangover remedy in China for many centuries, we tested the ability of NPI-031G (puerarin), an isoflavone isolated from kudzu, to counteract anxiogenic effects associated with withdrawal from chronic alcohol exposure. NPI-O31G (50 and 150 mg/kg ip) significantly increased the social interaction and locomotor activity reduced by withdrawal from 17 days of alcohol (7%) diet. The effects of NPI-031G resembled those of the benzodiazepine antagonist, flumazenil (5 mg/kg), and the 5-HT(2C) antagonist, SB 242084 (1 mg/kg). In a separate study, control rats were pretreated with NPI-031G (30 min) and then given the anxiogenic compounds DMCM, a benzodiazepine inverse agonist, or Ro 600175, a 5-HT(2C) agonist. NPI-031G significantly counteracted the reduction in social interaction induced by either compound. To identify a potential mechanism of action of NPI-031G, synaptoneurosomes were isolated from the cerebral cortex of untreated rats and chloride uptake assays were carried out. NPI-031G did not have any effect on the stimulation of chloride uptake by muscimol, a GABA(A) agonist. However, it reduced the potentiation of muscimol-stimulated chloride uptake by flunitrazepam, a benzodiazepine agonist, at a concentration of 100 microM. A reduction in [3H]flunitrazepam binding was also seen at this concentration. These findings are consistent with NPI-031G being a weak benzodiazepine site antagonist.