A DESENSITIZATION OF HYPOTHALAMIC 5-HT1A RECEPTORS BY REPEATED INJECTIONS OF PAROXETINE - REDUCTION IN THE LEVELS OF G(I) AND G(O) PROTEINSAND NEUROENDOCRINE RESPONSES, BUT NOT IN THE DENSITY OF 5-HT1A RECEPTORS

The aim of the present study was to determine whether the previously o bserved desensitization of hypothalamic 5-hydroxytryptamine(1A) (5-HT1 A) receptors, during daily injections of fluoxetine, is mediated by su stained blockade of 5-HT reuptake. In the present study, we examined t he time course effects of another 5-HT uptake inhibitor, paroxetine, P aroxetine reduced the oxytocin, adrenal corticotropic hormone and cort icosterone responses to a challenge with the 5-HT1A agonist 8-hydroxy- 2-(dipropylamino)tetralin. These reductions in hormone responses were significant after 3 daily injections and reached a maximum after 7 dai ly paroxetine injections. These hormone responses remained maximally s uppressed after 14 daily injections of paroxetine. A single day of par oxetine treatment did not alter the hormone responses to 8-hydroxy-2-( dipropylamino)tetralin. Repeated injections of paroxetine did not redu ce the density of 5-HT1A receptors in any brain region but did produce a gradual reduction in the levels of G(i) and G(o) proteins in a regi on-specific manner. The time course of the paroxetine-induced reductio n in the level of G(i1) and G(i3) proteins in the hypothalamus was sim ilar to the effect previously observed with fluoxetine and was also si milar to the time course of paroxetine-induced reductions in oxytocin and adrenal corticotropic hormone responses to 8-hydroxy-2-(dipropylam ino)tetralin. In conclusion, these results suggest that blockade of 5- HT uptake sites produces a delayed and gradual desensitization of 5-HT 1A receptors in the hypothalamus. This desensitization is not due to c hanges in the density of hypothalamic 5-HT1A receptors. Reduction in t he hypothalamic level of G(i3) proteins may play a role in the desensi tization of 5-HT1A receptor systems. However, reductions in G(i1) or G (o) proteins cannot be excluded as potential mediators of the desensit ization of 5-HT1A receptor systems.