Effects of subchronic antidepressant drug treatment on central serotonergic mechanisms in the male rat.

These studies have examined the effects of a 2 week oral treatment with zimelidine, desipramine and imipramine in clinically relevant doses on 5-HT-1 and 5-HT-2 receptors, on 5-HT synthesis, on 5-HT dependent behaviours and on prolactin secretion in the male rat. 1. Zimelidine, desipramine and imipramine produced the same type of changes in 5-HT-1 and 5-HT-2 binding sites of the cerebral cortex. 2. A marked and selective reduction of 5-HT synthesis could be observed following long-term zimelidine treatment. 3. Long-term zimelidine and desipramine treatment reduced head twitch behaviour in mice induced by 5-HTP and 5-MeODMT. 4. Long-term treatment with zimelidine produced a reduction of basal prolactin secretion. These results suggest that long-term treatment with zimelidine desipramine and imipramine may reduce 5-HT neurotransmission at least in some 5-HT synapses in the brain which may represent part of the basis for their therapeutic activity. The indication of large numbers of low affinity binding sites (10-40 nM) for 3H-5-HT sites may lead to less steep dose effect curves and to a staprolactin secretion while long-term treatment with zimelidine results in significant reductions of prolactin secretion (11). These results support the view of the existence of a reduction of 5-HT neurotransmission at least within the hypothalamus following long-term treatment with zimelidine. Also other behavioural findings suggest that adaptive changes occur in 5-HT synapses involved in regulating the "serotonin syndrome" after long-term antidepressant treatment. Thus, the 5-HT syndrome is no longer enhanced by 5-HT uptake blocking agents. The ability of fluoxetine to enhance haloperidol-induced increases of dopamine metabolites in the striatum also disappears following chronic fluoxetine treatment (6,34).