pituitrin and 6-chloro-2-(1-piperazinyl)pyrazine

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-HT1C/2 agonist, 0-5 mg/kg i.p.) and 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) (less selective, but predominantly a 5-HT1C 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-amino-propane 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 Bmax for the 5-HT1C/2 agonist sites ([125I]DOI) in the hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenocorticotropic Hormone; Amphetamines; Animals; Desipramine; Drug Synergism; Fluoxetine; Hormones; Ketanserin; Male; Pyrazines; Rats; Rats, Sprague-Dawley; Serotonin Receptor Agonists; Vasopressins

This study was undertaken to examine whether several of the hormones that can be released by activation of serotonin receptors will be affected by long-term cocaine administration. Male rats received cocaine injections (15 mg/kg, IP) twice daily for 7 days. Forty-two hr after the last cocaine injection, the rats were challenged with increasing doses (0, 1, 5, 10 mg/kg, IP) of the 5-HT1/5-HT2 agonist MK-212 (6-chloro-2-[1-piper-azinyl]-pyrazine). The following observations were made: (1) cocaine reduced the rate of body weight gain; (2) cocaine inhibited the stimulatory effect of MK-212 on plasma vasopressin, oxytocin, and prolactin concentrations and on plasma renin activity and concentration; (3) cocaine did not inhibit the stimulatory effect of MK-212 on plasma ACTH or corticosterone concentrations. The data indicate that a wide-spectrum 5-HT (serotonin) agonist such as MK-212 can reveal differential neuroendocrine responses. This effect could be related to cocaine-induced changes in the different 5-HT receptor subtypes that regulate the secretion of these hormones.

Topics: Adrenocorticotropic Hormone; Animals; Arousal; Brain; Cocaine; Corticosterone; Dose-Response Relationship, Drug; Drug Interactions; Hormones; Injections, Intraperitoneal; Male; Neurosecretory Systems; Oxytocin; Prolactin; Pyrazines; Rats; Rats, Sprague-Dawley; Renin; Synaptic Transmission; Vasopressins

In this study we have evaluated a possible role for brain serotoninergic neurons in the regulation of vasopressin secretion using pharmacological methods. In order to accomplish this, we have developed a specific and sensitive vasopressin radioimmunoassay along with a highly reproducible plasma extraction protocol. These tools were used to evaluate the plasma vasopressin response to several pharmacological challenges in conscious rats. Treatment with the serotonin (5-HT) releaser p-chloroamphetamine caused a significant increase in plasma vasopressin concentration. This effect was blocked by posterior hypothalamic deafferentation which separates serotonin cell bodies in the midbrain from their nerve terminals in the hypothalamus. Administration of graded doses of several 5-HT agonists had no effect. However, treatment with MK212, a serotonin agonist with 5-HT1 + 5-HT2 activity, induced a significant increase in plasma vasopressin concentration. The effect of MK212 on plasma vasopressin was completely abolished by the selective 5-HT2 receptor blocker LY53857. These studies confirm and extend studies by others that provide pharmacological evidence for serotoninergic regulation of vasopressin secretion via a selective 5-HT2 receptor mechanism. The specific neuroanatomical site(s) where serotonin exerts this effect are unknown, and the physiological consequences of these studies remain to be established.

Topics: Amphetamines; Animals; Dose-Response Relationship, Drug; Ergolines; Hypothalamic Area, Lateral; Male; p-Chloroamphetamine; Pyrazines; Radioimmunoassay; Rats; Receptors, Serotonin; Serotonin; Vasopressins