The effects of chronic activation of mu- and kappa-opioid receptors on the release of [3H]dopamine from cultured ventral mesencephalic neurons and that of [3H]noradrenaline from cultured locus ceruleus neurons were studied. It was found that a 4-day exposure of cultured mesencephalic neurons to the kappa-agonist U69,593 (5 alpha, 7 alpha, 8 beta)-(-)-N-methyl-N-[7(1-pyrrolidinyl)-1-oxaspiro(4,5)-dec-8-yl] benzeneacetamide; 1 microM] increased markedly 25 mM K(+)-induced dopamine release upon opioid withdrawal by about 70%, with no change in the release-inhibitory effects of U69,593 (EC50, 3-6 nM; maximal inhibition about 50%). Moreover, 1.2 mM Ca++ (in the continuous presence of K+) and 100 microM N-methyl-D-aspartic acid receptor-mediated dopamine release also was potentiated to a similar extent after chronic kappa receptor activation. Similarly, 4-day treatment of cultured locus ceruleus neurons with morphine (1 microM) caused an enhanced release of [3H]noradrenaline induced by K+, Ca++ or N-methyl-D-aspartic acid upon opioid withdrawal by 55 to 150%. In addition, the release-inhibitory effect of the mu-selective agonist [D-Ala2,MePhe4,Gly-ol5]-enkephalin on the K(+)-induced [3H]noradrenaline release remained unaffected (EC50, 10-12 nM; maximal effect, 80-90%). Interestingly, chronic activation of autoreceptors on cultured mesencephalic neurons by the dopamine D-2 receptor-selective agonist LY171,555 [(trans)-(-)-(4aR)-4, 4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4g]quinoline; 1 microM] or those of cultured locus ceruleus neurons by the alpha-2 adrenoceptor-selective agonist clonidine (1 microM) did not affect K(+)-induced neurotransmitter release upon agonist withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)