QUANTITATIVE-EVALUATION OF THE AUTOINHIBITORY FEEDBACK OF RELEASE OF 5-HT IN THE CAUDATE-NUCLEUS OF THE RABBIT WHERE AN ENDOGENOUS TONE ON ALPHA-2-ADRENOCEPTORS DOES NOT EXIST

Slices of caudate nucleus of the rabbit were preincubated with [H-3]serotonin ([H-3]5-HT) in the presence of nomifensine, then superfused and twice stimulated electrically. The stimulation-evoked overflow of tritium, representing action potential-induced, exocytotic release of 5-HT, was inhibited concentration-dependently by 5-HT receptor ligands, the potencies of which were compatible with the assumption of a 5-HT1D-like autoreceptor. The inhibitor of the uptake of 5-HT, 6-nitroquipazine, markedly changed the shape of the concentration-response curve of the 5-HT autoreceptor agonist, 5-carboxamido-tryptamine (5-COHT). The maximum effects of the concentration-response curves of 5-COHT and of exogenous 5-HT became more pronounced in the additional presence of the 5-HT autoreceptor antagonists, metitepin or metergoline. Nonlinear regression analysis of these curves was used to estimate the pK(d)-value of endogenous 5-HT and the 5-HT biophase concentration at the autoreceptor, in the absence and in the presence of 6-nitroquipazine and in the additional presence of metitepin or metergoline. This revealed a highly operative autoinhibitory feedback, via a 5-HT1D type autoreceptor of release of 5-HT in tissue from the caudate nucleus. Also the inhibition by the alpha-2-adrenoceptor agonists, clonidine and UK-14,304, of release of 5-HT was concentration-dependent. There was neither an enhancement of release by rauwolscine, being a 5-HT autoreceptor agonist and alpha-2-adrenoceptor antagonist, in the presence of metitepin, or by the alpha-adrenoceptor antagonist, phentolamine (10(-6) M). At variance with the noradrenergic innervation of alpha-2-adrenoceptors on 5-HT terminals in the hippocampus, it was confirmed functionally that alpha-2-adrenoceptors on 5-HT nerve endings in the caudate nucleus were not activated by endogenous noradrenaline, as to be expected in this tissue which hardly contains any noradrenaline.