Sensitivity of the response of 5-HT autoreceptors to drugs modifying synaptic availability of 5-HT.

The effect of midalcipran, an equipotent inhibitor of the uptake of 5-hydroxytryptamine (5-HT) and noradrenaline (NA), on the inhibition of release of 5-HT induced by lysergic acid diethylamide (LSD), was investigated by studying the overflow of transmitter from slices of hypothalamus from the rat prelabelled with [3H]5-HT. The (Z)-enantiomer of midalcipran, at 0.1 microM, displaced to the right the concentration-effect curve of inhibition of release of [3H]5-HT elicited by electrical stimulation induced by LSD. In contrast, the (E)-enantiomer, which does not inhibit the uptake of monoamines, was devoid of any antagonizing effect. The inhibitory effect of 0.1 microM LSD was not modified in the presence of maprotiline, bupropion or mianserin at 1 microM. The results of this study show that the interaction between the 5-HT autoreceptor and the inhibitors of the uptake of 5-HT is related exclusively to their potency at inhibiting the uptake of 5-HT. The effect of the monoamine oxidase inhibitor, pargyline (1-10 microM), was also studied on the field-stimulated release of [3H]5-HT. The inhibitory effect of this drug was antagonized by methiothepin at 0.1 and 1 microM, by phentolamine 1 microM and 10 microM and by the inhibitor of the uptake of 5-HT, citalopram at 0.1 and 1 microM. The action of pargyline appeared to be mediated through the activation of the serotonergic autoreceptor and of the presynaptic alpha-adrenoceptor located on serotonergic nerve terminals. The results obtained with pargyline are consistent with the hypothesis of an interaction between the 5-HT autoreceptor and the uptake site for 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)