Noradrenaline potently antagonizes the effects of N-methyl-D-aspartate (NMDA) (80 microM) on cyclic GMP production in immature rat cerebellar slices in vitro (IC50 = 0.6 microM). The effect is stereospecific (D-noradrenaline, IC50 = 100 microM), and also observed with adrenaline (IC50 = 0.5 microM) and isoprenaline (IC50 = 1.2 microM). The alpha 1-adrenoceptor agonists methoxamine or phenylephrine or the mixed alpha 1/alpha 2 agonists oxymetazoline or xylometazoline (100 microM) do not block the effects of NMDA, but the alpha 2-adrenoceptor agonist clonidine is weakly active (IC50 = 200 microM). Salbutamol and terbutaline were also inactive except at high concentrations (300 microM), as were a number of other catechol and phenylethylamine derivatives. The antagonistic effects of noradrenaline on the NMDA response were insensitive to phentolamine, atenolol, or propranolol (up to 100 microM), but were blocked by the alpha 2 antagonist idazoxan (1-10 microM). The Na+,K+-ATPase inhibitor ouabain (0.1-10 microM) markedly potentiates the effects of NMDA in this model, and also antagonizes and reverses the ability of noradrenaline (10 microM) to block the effects of NMDA. The results suggest that noradrenaline and Na+,K+-ATPase activity have potent modulatory effects on the NMDA response.