In vivo [(3)H]ketanserin binding: effect of modifying synaptic serotonin levels

Most antidepressant therapies aim to increase the synaptic concentration of one or more of the monoamines. Synaptic monoamine levels are, however, extremely difficult to measure. In order to estimate synaptic levels of serotonin, an indirect method has been used. Since [(3)Hjketanserin is an antagonist at the 5HT(2) serotonin receptor, one would expect its in vivo binding to be inhibited by increased levels of synaptic serotonin. This hypothesis was tested in mice by measuring the effect of compounds which are considered to raise the synaptic concentration of serotonin. Directly acting agents such as quipazine, methysergide and mianserin inhibited [(3)H]ketanserin binding in vitro and in vivo. On the other hand, indirect agonists such as the monoamine oxidase inhibitors, pargyline and niamide, the serotonin uptake blockers, paroxetine and midalcipran, the serotonin releasers, p-chloroamphetamine and H75/12 and the serotonin precursor, 5-hydroxytryptophan had no effect on [(3)H]ketanserin binding in vivo. This was in spite of the fact that at doses used a very marked serotonin-induced behaviour was observed. In view of its insensitivity to changes in synaptic concentrations of serotonin, it is possible that the sites labelled in vivo by [(3)H]ketanserin are not innervated by the serotonin nerve terminals through which these indirect serotonin agonists act.