Various endocrine responses to 5-hydroxytryptamine (serotonin, 5-HT) agonists were used to assess serotonergic receptor function after chronic treatment with the antidepressants fluoxetine (10 mg/kg), a 5-HT uptake blocker and the norepinephrine uptake blocker desipramine (DMI, 5 mg/kg). Both were injected (i.p.) once a day for 21 days. DOI (5-HT(1C/2) agonist, 0- 5 mg/kg i.p.) and 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) (less selective, but predominantly a 5-HT(1C) agonist, 0-20 mg/kg i.p.) were administered 18 hr after the final antidepressant injection and 30 min before decapitation. Chronic treatment with both fluoxetine and DMI produced a potentiation in most hormone responses to the 5-HT agonists (±)-1-(2,5- dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) and MK-212, although there were several differences in individual hormone responses to the two 5-HT agonists. Fluoxetine and DMI potentiated the MK-212- and DOI-induced increase of plasma oxytocin levels and potentiated the effect of DOI on plasma adrenocorticotropic hormone (corticotropin) and prolactin levels. In contrast, the effect of the high dose of MK-212 on plasma prolactin concentration was reduced by both antidepressants. Only MK-212 increased vasopressin levels and this effect was potentiated by fluoxetine, but not by DMI. Fluoxetine also significantly increased the resting level of plasma vasopressin. DMI potentiated the effect of MK-212 on plasma renin concentration. Pretreatment with fluoxetine significantly increased (38%) the B(max) for the 5-HT(1C/2) agonist sites ([125I]DOI) in the hypothalamus. Pretreatment with DMI also increased the B(max) for the 5-HT(1C/2) agonist sites ([125I]DOI) in the hypothalamus by 24.5%, although this increase did not reach statistical significance. In contrast, neither fluoxetine nor DMI influenced the B(max) or K(d) of [3H]ketanserin-labeled 5-HT2 receptors in the frontal cortex. The results suggest that fluoxetine and DMI potentiate 5- HT(1C/2)-mediated hormonal responses although the influences of the two antidepressants were slightly different. The results indicate that both a 5- HT uptake blocker, fluoxetine, and a norepinephrine uptake blocker, DMI, produce comparable changes in 5-HT receptor-mediated neuroendocrine responses. Finally, oxytocin should be considered a reliable hormone to examine the function of 5-HT(1C/2) receptors after exposure to antidepressants.
|Original language||English (US)|
|Number of pages||9|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1993|
ASJC Scopus subject areas
- Molecular Medicine