Abstract

The aim of the present study was to determine whether the previously observed desensitization of hypothalamic 5-hydroxytryptamine_1A (5-HT_1A) receptors, during daily injections of fluoxetine, is mediated by sustained blockade of 5-HT reuptake. In the present study, we examined the time course effects of another 5-HT uptake inhibitor, paroxetine. Paroxetine reduced the oxytocin, adrenal corticotropic hormone and corticosterone responses to a challenge with the 5-HT_1A agonist 8-hydroxy-2-(dipropylamino)tetralin. These reductions in hormone responses were significant after 3 daily injections and reached a maximum after 7 daily paroxetine injections. These hormone responses remained maximally suppressed after 14 daily injections of paroxetine. A single day of paroxetine treatment did not alter the hormone responses to 8-hydroxy-2-(dipropylamino)tetralin. Repeated injections of paroxetine did not reduce the density of 5-HT_1Areceptors in any brain region but did produce a gradual reduction in the levels of G_i and G_o proteins in a region-specific manner. The time course of the paroxetine-induced reduction in the level of G_i1 and G_i3 proteins in the hypothalamus was similar to the effect previously observed with fluoxetine and was also similar to the time course of paroxetine-induced reductions in oxytocin and adrenal corticotropic hormone responses to 8-hydroxy-2-(dipropylamino)tetralin. In conclusion, these results suggest that blockade of 5-HT uptake sites produces a delayed and gradual desensitization of 5-HT_1Areceptors in the hypothalamus. This desensitization is not due to changes in the density of hypothalamic 5-HT_1A receptors. Reduction in the hypothalamic level of G_i3 proteins may play a role in the desensitization of 5-HT_1A receptor systems. However, reductions in G_i1 or G_oproteins cannot be excluded as potential mediators of the desensitization of 5-HT_1A receptor systems.