LONG-TERM TREATMENT WITH THE ANTIDEPRESSANTS FLUOXETINE AND DESIPRAMINE POTENTIATES ENDOCRINE RESPONSES TO THE SEROTONIN AGONISTS 6-CHLORO-2-[1-PIPERAZINYL]-PYRAZINE (MK-212) AND (+ --1-(2,5-DIMETHOXY-4-IODOPHENYL)-2-AMINOPROPANE HCI (DOI)1/

Various endocrine responses to 5-hydroxytryptamine (serotonin, 5-HT) a gonists were used to assess serotonergic receptor function after chron ic treatment with the antidepressants fluoxetine (10 mg/kg), a 5-HT up take blocker and the norepinephrine uptake blocker desipramine (DMI, 5 mg/kg). Both were injected (i.p.) once a day for 21 days. DOI (5-HT1C /2 agonist, 0-5 mg/kg i.p.) and 6-chloro-2-[1-piperazinyl]-pyrazine (M K-212) (less selective, but predominantly a 5-HT1C agonist, 0-20 mg/kg i.p.) were administered 18 hr after the final antidepressant injectio n and 30 min before decapitation. Chronic treatment with both fluoxeti ne and DMI produced a potentiation in most hormone responses to the 5- HT agonists +/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCI (DO I) and MK-212, although there were several differences in individual h ormone responses to the two 5-HT agonists. Fluoxetine and DMI potentia ted 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 hi gh dose of MK-212 on plasma prolactin concentration was reduced by bot h antidepressants. Only MK-212 increased vasopressin levels and this e ffect was potentiated by fluoxetine, but not by DMI. Fluoxetine also s ignificantly increased the resting level of plasma vasopressin. DMI po tentiated the effect of MK-212 on plasma renin concentration. Pretreat ment with fluoxetine significantly increased (38%) the B(max) for the 5-HT1C/2 agonist sites ([I-125]DOI) in the hypothalamus. Pretreatment with DMI also increased the B(max) for the 5-HT1C/2 agonist sites ([I- 125]DOI) in the hypothalamus by 24.5%, although this increase did not reach statistical significance. In contrast, neither fluoxetine nor DM I influenced the B(max) or K(d) of [H-3]ketanserin-labeled 5-HT2 recep tors in the frontal cortex. The results suggest that fluoxetine and DM I potentiate 5-HT1C/2-Mediated hormonal responses although the influen ces of the two antidepressants were slightly different. The results in dicate that both a 5-HT uptake blocker, fluoxetine, and a norepinephri ne uptake blocker, DMI, produce comparable changes in 5-HT receptor-me diated neuroendocrine responses. Finally, oxytocin should be considere d a reliable hormone to examine the function of 5-HT1C/2 receptors aft er exposure to antidepressants.