Noradrenaline Antagonizes and Ouabain Potentiates the Effects of iV-Methyl-D-Aspartate on Rat Cerebellar Cyclic GMP Production

: Noradrenaline potently antagonizes the effects of N-methyl-D-aspartate (NMDA) (80 μM) on cyclic GMP production in immature rat cerebellar slices in vitro (IC50 = 0.6 μM). The effect is stereospecific (D-noradrenaline, IC50 = 100 μM), and also observed with adrenaline (IC50= 0.5 μM) and isoprenaline (IC50= 1.2 μM). The α1-adrenoceptor agonists methoxamine or phenylephrine or the mixed α/α2 agonists oxymetazoline or xylometazoline (100 μM) do not block the effects of NMDA, but the α2-adrenoceptor agonist clonidine is weakly active (IC50 = 200 μM). Salbutamol and terbutaline were also inactive except at high concentrations (300 μM), 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 μM), but were blocked by the α2 antagonist idazoxan (1–10 μM). The Na+,K+-ATPase inhibitor ouabain (0.1–10 μM) markedly potentiates the effects of NMDA in this model, and also antagonizes and reverses the ability of noradrealine (10 μM) to block the effects of NMDA. The results suggest that noradrenaline and Na+,K+-ATPase activity have potent modulatory effects on the NMDA response.