A population of interneurones in the rat striatum contain neuronal nitric oxide synthase (nNOS). The nitric oxide (NO)-cGMP pathway may modulate neurotransmission in this brain area but little is known about the physiological stimulator(s) of nNOS in striatal neurones. Exposure of intact striatal slices to N-methyl-D-aspartate (NMDA) (100 microM, 8 min) caused an almost two-fold increase in cGMP levels (EC50 approximately 25 microM), which was inhibited by the nNOS inhibitor N-omega-L-nitroarginine (IC50 approximately 70 nM) and by removing external Ca2+. Neither (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) nor the kainate receptor agonist (2S,4R)-4-methylglutamate increased basal cGMP levels. Thus, glutamatergic striatal inputs could stimulate a NO-cGMP pathway in the striatum via NMDA receptors but not via AMPA or kainate receptors.