The serotonin (5-hydroxytryptamine, 5-HT) system has consistently been implicated in the actions of (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and other hallucinogens. Recent evidence suggest that the 5-HT2A/2C receptor subtypes may be major targets for such drugs in the CNS. DOI-treated hooded rats (0.1-5.0 mg/kg) and DOI treated ICR mice (0.1-2.0 mg/kg), displayed aversions at lower doses and anti-aversions at higher doses to the open arms of the plus-maze. Mianserin (0.5 mg/kg) and ketanserin (0.1 mg/kg) blocked the anti-aversive behavior, but only mianserin was effective at reversing the aversions produced by the higher doses of DOI in the ICR mice. DOI produced an intense aversion in the DBA/2 and anti-aversion in the C57/BL6 mice to the open arms of the plus-maze. These opposing actions of DOI in the plus-maze may be exploited in studying the neurobehavioral effects of hallucinogens. Since flumazenil was ineffective at blocking the DOI induced changes, it was concluded that the mechanism of DOI induced anxiolysis or anxiogenesis may not involve an action at the benzodiazepine receptors.