Effect of Neuroleptics and Other Drugs on Monoamine Uptake by Membranes of Adrenal Chromaffin Granules

Abstract

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. 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. 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. The inhibition of NA uptake by chlorpromazine and Ro 4–1284 appeared to be of the noncompetitive type. Chlorpromazine did not influence the decrease in ATP induced by granule membranes in the incubation medium. 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). 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.

General Pharmacology and Neuropharmacology of Benzodiazepine Derivatives

“…Diazepam 1 mg· kg -I failed to significantly alter the uptake of intracerebroventricularly injected 3H-NA (NAKAMURA and THOENEN, 1972). Benzodiazepines were very weak inhibitors of the uptake of 14C_NA by isolated membranes of bovine adrenal medulla (PLETSCHER, 1977); the IC 50 were 7x 10-5 mol·l-I and 5x 10-4 mol·l-I for diazepam and chlordiazepoxide, respectively. TAYLOR andLAVERTY (1969, 1973) found the uptake or 3H-NA into synaptosomes of rat hypothalamus hardly affected by even high concentrations of benzodiazepines.…”

Vesicular monoamine transporter 2: Role as a novel target for drug development

“…10 Reserpine inhibits the transport of amines into chromaffi n granules and synaptic storage vesicles 11 , 12 by binding with high affi nity to VMAT, presumably at the amine recognition site. It has been suggested that TBZ, on the other hand, binds to a site on VMAT that is different from the substrate binding site at which reserpine interacts.…”

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease

“…Reserpine and Tetrabenazine. Reserpine and TBZ are "classical" VMAT2 inhibitors (Pletscher, 1977) that prevent the transport of amines into synaptic vesicles. Although these agents are the most widely studied, their clinical utility is relatively limited.…”