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OBJECTIVE: To observe the effect of acupuncture intervention on depressive-like behavior and nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS) and nitric oxide (NO) levels in the prefrontal cortex in chronic stress induced depression rats, so as to explore its mechanism underlying antidepressant effect. METHODS: SD rats were randomly divided into control, model, acupuncture and medication (Fluoxetine) groups (8 rats/group). The depression model was established by chro-nic unpredictable stress stimulation (fasting, water deprivation, cold water swimming, tail clamping, constraining, etc., and solitary raising) for 28 days. Acupuncture treatment was applied to "Baihui" (GV 20) and unilateral "Neiguan"(PC 6) once every other day for 14 days. Fluoxetine (10 mg/kg) was given to rats of the medication group by gavage (p.o.) before every stress stimulation, once every day for 28 days. The animals' behavior was tested by using sucrose intake and open field tests (number of crossings and rearings in 5 min). The expression of NF-κB in the prefrontal cortex was detected by Western blot, and the contents of prefrontal iNOS and NO were detected by ELISA and nitric reductases, respectively. RESULTS: After modeling, the sucrose intake and the numbers of crossing and rearing times were significantly decreased (P<0.01), and the expression of NF-κB protein and the contents of iNOS and NO in the prefrontal cortex were significantly increased in the model group compared with the control group (P<0.01). Following the treatment, the sucrose intake and the numbers of crossing and rearing times were significantly increased in both acupuncture and medication groups compared with the model group (P<0.05, P<0.01), and the expression level of NF-κB, and iNOS and NO contents in the prefrontal cortex were significantly lower in both acupuncture and medication groups than in the model group (P<0.01). There were no significant differences between the acupuncture and medication groups in the crossing number and rearing times, NF-κB expression, and iNOS and NO levels (P>0.05). CONCLUSION: Acupuncture treatment can improve the depressive-like behavior of depression rats, which is closely related to its effects in down-regulating the levels of NF-κB protein, iNOS and NO in the prefrontal cortex to reduce brain inflammatory damage.