Opposite regulation of serotonin-S2 and dopamine-D2 receptors in rat brain following chronic receptor blockade.

Rats were chronically treated with setoperone, a mixed serotonin and dopamine antagonist. Alterations in serotonin-S2 and dopamine-D2 receptors in the brain and changes in behavioural responses to tryptamine and apomorphine were studied along with duration of treatment and drug withdrawal. As with neuroleptics, behavioural supersensitivity to apomorphine and increase in the number of striatal dopamine-D2 receptor sites were apparent after 2 days setoperone treatment, both effects were maximal with 14 days treatment and were maintained over more than 20 days drug withdrawal. In contrast to the changes in the dopaminergic system, the rats showed a decreased response to tryptamine and serotonin-S2 receptor sites in the frontal cortex were significantly reduced in numbers. Both effects developed in parallel over 14 days treatment and extinguished over 10 days drug withdrawal. KD-values of radioligand binding to dopamine-D2 and serotonin-S2 receptor sites were unchanged by the setoperone treatment. The concomitant development and extinction of the in vivo and in vitro effects suggests a causal relationship between them. Chronic treatment with a selective histamine-H1 antagonist (levocabastine) or the tranquilizer diazepam did not affect dopamine-D2 or serotonin-S2 receptor sites. These observations demonstrate that in contrast to the receptor regulation theory, serotonin-S2 receptors are down regulated following persistent receptor blockade. Implications for the clinical use of serotonin antagonists and possible molecular mechanisms involved in the receptor regulation have been discussed.