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BACKGROUND AND AIMS: Amphetamine, besides its well known psychological and behavioral effects, was found to influence the immune functions. However, the mechanism of amphetamine-induced changes in the immune system remains unknown. In search of a possible mechanism of immunomodulating effect of amphetamine, in the present study we tested the involvement of sympathetic nervous system in that effect. RESULTS: After pretreatment with 6-hydroxydopamine (3×75 mg/kg, ip), we evaluated the effect of acute amphetamine (1 mg/ kg, ip) administration on natural killer cell cytotoxicity (NKCC; Cr-51 release assay) and the number of NK (LGL) cells in the peripheral blood and spleen in male Wistar rats. Amphetamineinduced stimulation of blood and splenic NKCC was completely blocked by chemical sympathectomy. Blood NKCC in amphetamine-injected rats was 260% higher in comparison to a control group. Rats pretreated with 6-hydroxydopamine before amphetamine administration showed over 70% lower NKCC then rats which received amphetamine without chemical sympathectomy. Similarly to the peripheral blood, over 190% increase in NKCC in rats injected with amphetamine was observed in the spleen. Splenic NKCC in rats pretreated with 6-hydroxydopamine was about 60% lower after amphetamine in comparison with rats without chemical sympathectomy. The similar effects were observed in the case of LGL number. CONCLUSIONS: The data clearly show that AMPH-induced stimulation of NK cells numbers and function both in the peripheral blood and spleen are mediated by peripheral sympathetic nervous system.