This study provides the first evidence that CCK-8 (0.01 pM to 0.1 mM) stimulates Na,K-ATPase in the cortical membranes of wild-type and CCK(2) receptor-deficient mice. In each genotype, the maximal stimulation was about 40%. Homozygous mice revealed substantially lower EC50 (4 pM) than heterozygous (37 pM) or wild-type animals (682 pM). In homozygous CCK2 receptor-deficient mice, the expression of CCK1 receptor gene was 5-fold higher than in wild-type animals. CCK1 receptor antagonist devazepide counteracted effect of CCK-8 in all three genotypes, whereas CCK2 receptor antagonist L-365, 260 showed significant antagonism in wild-type and heterozygous mice. The cooperativity of Na,K-ATPase for Na+, but not for K+, was lost in homozygous mice. Altogether, very low concentrations of CCK-8 via CCK1 and CCK2 receptors stimulate Na,K-ATPase in the cerebral cortex. CCK2 receptor-deficiency leads to the altered functionality of Na,K-ATPase that might be compensated by CCK1 receptor mediated influence of CCK (and its agonists) on the enzyme.