Chronic clomipramine alters presynaptic 5-HT1B and postsynaptic 5-HT1A receptor sensitivity in rat hypothalamus and hippocampus, respectively

Clomipramine is a tricyclic antidepressant drug with a high affinity for the serotonin (5-HT) uptake site or transporter. Electrophysiological experiments have provided evidence that repeated administration of clomipramine induces an increase in the sensitivity of postsynaptic 5-HT1A receptors in the hippocampus. We have studied the effects of clomipramine, administered to rats at a dose of 10 mg/kg/day for 28 days by osmotic minipumps, on presynaptic 5-HT1A and 5-HT1B autoreceptors in the hypothalamus, and on postsynaptic 5-HT1A receptors in the hippocampus, by using in vivo microdialysis to measure 5-HT and cyclic adenosine monophosphate (cAMP) levels. Postsynaptic 5-HT1A receptor sensitivity in the hypothalamus was determined by means of a neuroendocrine challenge procedure. Although the sensitivity of presynaptic 5-HT1A autoreceptors, as measured by the effect of a subcutaneous (s.c.) injection of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.2 mg/kg or 50 mu g/kg) to reduce 5-HT levels, did not change, there was a reduction in sensitivity of presynaptic 5-HT1B receptors, as measured by the effect of an injection of the 5-HT1B/1D antagonist GR 127935 (5 mg/kg, s.c.) to increase 5-HT levels. This effect probably accounted for the increase in basal 5 HT levels observed in the hypothalamus after chronic clomipramine administration. Postsynaptic 5-HT,, receptor sensitivity in the hippocampus, measured by the effect of 8-OH-DPAT to increase cAMP levels in the dialysate, was increased after chronic clomipramine. Animals that had received daily intraperitoneal injections of 10 mg/kg clomipramine for 28 days did not show a change in postsynaptic 5-HT1A receptor sensitivity in the hypothalamus as measured by the ability of 8-OH-DPAT (50 mu g/kg, s.c.) to stimulate secretion of corticosterone. Taken together with the results of previous experiments involving the cerebral cortex, these in vivo results show that chronic clomipramine exerts effects on both pre- and postsynaptic serotonin receptors. but that these effects are highly region-specific. (C) 2000 Elsevier Science Ltd. All rights reserved.