Activation of NMDA receptors leads to nitric oxide (NO) synthesis by NO synthase (NOS) from L-arginine. Neuronal NOS colocalizes with somatostatinergic (SRIF) neurons and there is growing evidence of an interaction between NO and the cerebral SRIFergic system in several neurological diseases. Our aim was to study the effect of L-arginine on the regulation of the SRIFergic system in the frontoparietal cortex of male Sprague-Dawley rats. Intraperitoneal administration of L-arginine (150 mg/Kg), twice-daily during eight days, induced a decrease in SRIF receptor density, which was accompanied by a reduction in the capacity of SRIF to stimulate inositol-1,4,5-triphosphate (IP3) accumulation and SRIF-like immunoreactivity (SRIF-LI) levels. To determine if these changes were related to L-arginine-derived NO synthesis, a NOS inhibitor, Nω-nitro-L-arginine methyl ester was coadministered with L-arginine. Its coadministration prevented the reduction in the SRIF receptor density, accumulation of IP3 and SRIF-LI content. These findings indicate that L-arginine induces a deleterious effect on the cortical somatostatinergic system and that the inhibition of NOS could be helpful in some neurological disorders where this neurotransmitter system is affected.