Effects of chronically administered venlafaxine on 5-HT receptor activity in rat hippocampus and hypothalamus

The effects of chronic administration of the mixed serotonin [5-hydroxytryptamine (5-HT)]/norepinephrine re-uptake inhibitor venlafaxine (5 mg/kg daily by osmotic minipump for 28 days) on the sensitivity of somatodendritic 5-HT_1A autoreceptors on serotonergic neurons innervating the hypothalamus, and on 5-HT_1B autoreceptors in both hypothalamus and hippocampus, were determined using in vivo microdialysis in freely moving rats. Venlafaxine induced a reduction in sensitivity of 5-HT_1B autoreceptors in hypothalamus, but did not affect the sensitivity of 5-HT_1A autoreceptors, or of 5-HT_1B autoreceptors in hippocampus. The corticosterone and oxytocin responses to the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.05 or 0.2 mg/kg), a measure of postsynaptic 5-HT_1A receptor activity in the hypothalamus, were reduced in animals administered 5 or 10 mg/kg venlafaxine daily by intraperitoneal injection for 21 days. This desensitization of post-synaptic 5-HT_1A receptors in the hypothalamus may be a consequence of increased 5-HT levels induced by desensitization of the presynaptic 5-HT_1B receptors. These results taken together with those of previous studies suggest that the hypothalamus might be an important site of drug action, and that venlafaxine has an overall mechanism similar to that of selective serotonin re-uptake inhibitors.