Reduced neuronal NOS (nNOS) expression and biochemical activity was found in the striatum (P<0.05) and cerebellum P<0.05) of late-stage R6/1 Huntington's disease (HD) mice. The changes in NOS biochemical activity correlated with body weight (P<0.001), abnormal clasping (P<0.05) and motor functioning (P<0.05) scores. HD transgenic mice missing both copies of the nNOS gene showed accelerated disease progression relative to HD transgenic mice wildtype or heterozygous for the nNOS gene. On the other hand, mice with one copy of the nNOS gene had delayed onset of their HD-related symptoms relative to HD transgenic mice wildtype for nNOS. Administration of an iNOS inhibitor had no effect on behavioral progression. The effects of nNOS genotype on behavior may be related to abnormal expression of nNOS during development, which was increased relative to controls in R6/2 mice 3 weeks of age (presymptomatic), but decreased in R6/2 mice relative to controls at 6 (around the time of symptom onset) and 11 (late-stage disease) weeks of age. Finally, protein expression of calmodulin kinase II and IV, both of which are regulators of nNOS transcription and activation, had a pattern of increased expression early in development, and decreased expression late in development, similar to that seen for nNOS. These findings indicate that nNOS activity is altered in a complex manner in HD transgenic mice and suggest that these abnormalities occur in the setting of a more global disturbance of calcium-regulated proteins.