Functional evidence that chronic drugs induce adaptive changes of central autoreceptors regulating serotonin release.

Following long-term in vivo treatment of rats with methiothepin (a serotonin autoreceptor antagonist) or with clorgyline (a monoamine oxidase A inhibitor) plus CGP 6085A (a selective serotonin uptake inhibitor), the release of [3H]serotonin evoked by high-K+ from the cortical synaptosomes was inhibited by exogenous serotonin respectively more or less than following acute treatment with the drugs. The autoreceptor subsensitivity disappeared 10 days after drug withdrawal. The results indicate that, after long-term blockade or stimulation, serotonin autoreceptors become respectively hyper- or hyposensitive towards serotonin.