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