EFFECT OF NEUROLEPTICS AND OTHER DRUGS ON MONOAMINE UPTAKE BY MEMBRANES OF ADRENAL CHROMAFFIN GRANULES

Abstract

1 The effects have been investigated of various reserpine-like, neuroleptic, antidepressant and other compounds on the adenosine-5′-triphosphate (ATP)-dependent uptake of noradrenaline (NA) (reserpine-sensitive) and tryptamine (reserpine-resistant) by membranes of isolated chromaffin granules of bovine adrenal medulla. 2 Reserpine and Ro 4–1284 (2-hydroxy-2-ethyl-3-isobutyl-9,10-dimethoxy-hexahydro-11bH-benzo(a)quinolizine) as well as neuroleptics (e.g. chlorpromazine and haloperidol) inhibited the NA uptake, but the reserpine-like drugs were more potent. In contrast, Ro 4–1284 showed a considerably weaker effect than the neuroleptics in interfering with tryptamine uptake. Chlorpromazine had about the same potency in inhibiting NA and tryptamine uptake, whereas the action of haloperidol was more pronounced on the uptake of NA than of tryptamine. 3 The relative potencies of neuroleptic drugs in inhibiting NA uptake by granule membranes in vitro corresponded only partly to their relative potencies in enhancing dopamine turnover in vivo. 4 The inhibition of NA uptake by chlorpromazine and Ro 4–1284 appeared to be of the noncompetitive type. 5 Chlorpromazine did not influence the decrease in ATP induced by granule membranes in the incubation medium. 6 Other basic, but not acidic compounds also inhibited NA uptake by granule membranes; their potency was of the order of that of chlorpromazine (antidepressants) or weaker (e.g. benzodiazepines). 7 In conclusion, the mechanism of action of neuroleptics probably differs from that of reserpine-like drugs in the inhibition of monoamine uptake by membranes of catecholamine storage organelles. While interference with the granular storage of dopamine at the granule membrane level may contribute to the in vivo action of neuroleptics (e.g. in enhancing dopamine turnover), additional effects of these drugs must be involved in vivo, e.g. blockade of pre- and postsynaptic dopamine receptors.