The antiserotonin properties of a series of neuroleptics, 5-HT-receptor blockers and some adrenoceptor antagonists were investigated in several in vivo test systems (L-5-HTP syndrome and 5-HT-paw edema in the rat) and in an in vitro test (isolated rat uterus preparation). The results were compared to the results obtained with these drugs in an in vivo 3H-spiperone binding assay in the rat. The computations of the relative ED50 (or IC50) values obtained in different test procedures showed that the ability of drugs to bind to 5-HT receptors labelled by 3H-spiperone in the rat frontal cortex correlates fairly well with their potencies to inhibit the L-5-HTP syndrome or 5-HT-induced rat pawedema (Spearman rank correlation coefficient, r = 0.80 and 0.79 respectively, n = 22). In an in vitro test (rat uterus) the estimated 5-HT-receptor blocking potency of the tested drugs did not, however, correlate with any of the in vivo measures used for this purpose. The results suggest, therefore, that for the determination of central antiserotonin effects of drugs in the rat, functional in vivo tests (L-5-HTP syndrome or 5-HT-induced rat paw-edema) could yield about the same information as the specific, in vivo 3H-spiperone binding assay. The 5-HT-receptor type mediating the behavioral responses to L-5-HTP is tentatively defined as a 5-HT2 receptor.
The effect of beta-adrenoceptor agonists on the behavioral effect of L-5-HTP in rats and mice was studied. All beta-agonists potentiated the behavioral syndrome elicited by L-5-HTP. However no indication for a correlation between their potencies to stimulate peripheral beta-receptors and their potencies to enchance L-5-HTP effect was found. The potentiating effect of salbutamol in rats was intensified by the MAO A inhibitor clorgyline, completely inhibited by (+/-)-propranolol and partly inhibited by WB-4101, while practolol was without effect. Lesions of 5-HT pathways by i.c.v. injections of 5,7-DHT impaired the potentiating effect of salbutamol in rats. In contrast, 6-OHDA lesions or alpha-methyl-p-tyrosine pretreatment were without effect. A central site of action of salbutamol is suggested by the fact that it intensified L-5-HTP effects also after i.c.v. administration. Therefore the results suggest that salbutamol facilitates 5-HT transmission in rat brain probably via stimulation of central beta receptors.
The behavioural syndrome caused by L-5-HTP in rats was used for the study of effects of selective 5-HT uptake inhibitors and inhibitors of MAO on central 5-HT receptors. A good correlation was found between the relative potencies of drugs in inhibiting the 5-HT uptake in the rat brain and in intensifying L-5-HTP-induced behavioural stimulation. The potentiation of the L-5-HTP syndrome by the MAO inhibitors correlated with the inhibition of the A- but not of the B-form of the brain monoamine oxidase. In rats treated with the maximally inhibiting dose of a 5-HT uptake inhibitor, MAO inhibitors were still able to increase the intensity of the L-5-HTP syndrome, while the combination of maximal doses of two 5-HT uptake inhibitors did not produce a more intense syndrome than that produced by one 5-HT uptake inhibitor alone. The L-5-HTP-induced behavioural syndrome in rats seems to afford an experimental model allowing the quantification and characterization of the interaction of drugs with serotonin metabolism in the brain.
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