Acute (1 h) intraperitoneal (i.p.) treatment with interferon (IFN)-alpha-2a (300 IU/g) significantly inhibited wet-dog shakes (WDS) induced by (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane (DOI; 0.5, 1.0 mg/kg), which is mediated by serotonin (5-hydroxytryptamine; 5-HT)2 receptor in rats. IFN-alpha did not affect spontaneous locomotion. The inhibition of DOI (0.5 mg/kg)-induced WDS by IFN-alpha was dose (90-300 IU/g)- and time (1-6 h)-dependent, and was prevented by 30 min pretreatment with naltrexone (NLTX; 1.0 mg/kg, i.p.), an opioid receptor antagonist. Acute (1 h) intracerebroventricular (i.c.v.) treatment with IFN-alpha (1,500 IU/rat) also inhibited DOI (0.5 mg/kg)-induced WDS, and the effect was blocked by NLTX (50 micrograms/rat, i.c.v.). These results suggest that IFN-alpha may modulate 5-HT2 receptor-mediated behavior through opioid receptors in the central nervous system.