Nitric oxide synthase mediates the ability of darbepoetin alfa to improve the cognitive performance of STOP null mice

STOP (stable tubule only polypeptide) null mice display neurochemical and behavioral abnormalities that resemble several well-recognized features of schizophrenia. Recent evidence suggests that the hematopoietic growth factor erythropoietin improves the cognitive performance of schizophrenics. The mechanism, however, by which erythropoietin is able to improve the cognition of schizophrenics is unclear. To address this question, we first determined whether acute administration of the erythropoietin analog known as darbepoetin alfa (D. alfa) improved performance deficits of STOP null mice in the novel objective recognition task (NORT). NORT performance of STOP null mice, but not wild-type littermates, was enhanced 3 h after a single injection of D. alfa (25 g/kg, i.p.). Improved NORT performance was accompanied by elevated NADPH diaphorase staining in the ventral hippocampus as well as medial and cortical aspects of the amygdala, indicative of increased nitric oxide synthase (NOS) activity in these structures. NOS generates the intracellular messenger nitric oxide (NO) implicated in learning and memory. In keeping with this hypothesis, D. alfa significantly increased NO metabolite levels (nitrate and nitrite, NOx) in the hippocampus of both wild-type and STOP null mice. The NOS inhibitor, N (G)-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg, i.p.), completely reversed the increase in hippocampal NOx levels produced by D. alfa. Moreover, L-NAME also inhibited the ability of D. alfa to improve the NORT performance of STOP null mice. Taken together, these observations suggest D. alfa enhances the NORT performance of STOP null mice by increasing production of NO.