oxytocin and ipsapirone

The present study investigated whether administration of a 5-HT1A receptor agonist would increase growth hormone (GH) and oxytocin levels in normal human subjects, and whether the responses would be modified according to the age and gender of the subjects.. Ipsapirone (0.3 mg/kg body weight), or placebo was administered to 30 normal subjects (14 males, 19-74 years and 16 females, 22-69 years) using a randomized, double blind design.. Stimulation of GH secretion by ipsapirone was significantly greater in male compared to female subjects, with no apparent effect of age. Oxytocin secretion was not stimulated by ipsapirone compared to placebo in any of the groups.. The effects of gender and age on the degree of stimulation of GH secretion by 5-HT1A agonists in human subjects differ from their effects on secretion of the hormones ACTH and cortisol. A higher dose of ipsapirone is required to stimulate oxytocin secretion in normal human subjects.

Topics: Adult; Age Factors; Aged; Analysis of Variance; Double-Blind Method; Female; Growth Hormone; Humans; Male; Middle Aged; Oxytocin; Pyrimidines; Serotonin Receptor Agonists; Sex Factors

The neuroendocrine effects of 5-hydroxytryptamine-1A (5-HT1A) receptor stimulation remain uncertain in humans, in respect to both anterior and posterior pituitary hormone release. This is important because these endocrine responses are often used as indications of 5-HT1A receptor sensitivity. The link between receptor stimulation and subsequent hormone release is more direct with posterior pituitary hormones because there is no intermediate hypothalamic peptide in the pathway. Theoretically, therefore, posterior pituitary hormones should be more valid indicators of central 5-HT1A receptor sensitivity. We used the 5-HT1A receptor partial agonist ipsapirone (20 mg) as an oral serotonergic challenge drug in a random-order, double-blind placebo-controlled study of 12 healthy men. Blood sampling occurred at 30 min intervals up to 180 min after the administration of drug or placebo. Ipsapirone caused clear and significant elevations in adrenocorticotrophin (ACTH), cortisol (CORT), prolactin (PRL), and growth hormone (GH) release. Peak hormone and ipsapirone blood levels both occurred at 60 min after ipsapirone administration. Release of the posterior pituitary hormone oxytocin was also stimulated, but less robustly and with more baseline variation. Temperature fell significantly more after ipsapirone than placebo. These results contrast with previous studies, which found no effect of ipsapirone on PRL and GH release in humans, but are in accordance with data using other 5-HT1A agonist drugs. The presence of an oxytocin response to ipsapirone suggests that oxytocin is a potential marker for serotonergic function in neuroendocrine challenge studies, but this awaits further study.

Topics: Administration, Oral; Adrenocorticotropic Hormone; Adult; Double-Blind Method; Human Growth Hormone; Humans; Hydrocortisone; Hypothermia; Male; Neurosecretory Systems; Oxytocin; Pituitary Gland; Prolactin; Pyrimidines; Receptors, Serotonin; Serotonin Receptor Agonists

The present study had two objectives: (1) to provide information on neuroendocrine challenge tests that can lead to diagnostic tests in humans; and (2) to confirm our previous observation that chronic fluoxetine selectively inhibits serotonin (5-HT1A) receptor function. We determined the effect of chronic fluoxetine and desipramine (DMI) on the hormone response to ipsapirone, a 5-HT1A agonist and a potential anxiolytic drug. Ipsapirone increased oxytocin, adrenocorticotropic hormone (ACTH), corticosterone, and prolactin, but not renin or vasopressin concentrations in plasma. Chronic fluoxetine, but not DMI, significantly inhibited the effect of ipsapirone on plasma oxytocin, ACTH and corticosterone concentrations. Chronic fluoxetine also reduced the Bmax for 3H-8-hydroxy-2-(dipropylamino) tetralin (3H-8-OH-DPAT) labelled 5-HT1A receptors in the midbrain. Neither antidepressant altered the density or affinity of 5-HT uptake sites. In conclusion, the present results confirm our previous results using 8-OH-DPAT as a challenge, and suggest that chronic 5-HT uptake inhibition results in adaptive changes leading to decreased function of the 5-HT1A receptor system. Finally, because ipsapirone may be administered to humans, it might be usable to evaluate 5-HT1A receptor function in depressed patients.

Topics: Adrenocorticotropic Hormone; Animals; Anti-Anxiety Agents; Brain; Desipramine; Dose-Response Relationship, Drug; Fluoxetine; Hormones; Male; Oxytocin; Prolactin; Pyrimidines; Rats; Rats, Wistar; Receptors, Serotonin; Renin; Vasopressins

A number of receptor subtypes mediate hormonal responses to serotonin (5-HT). To test the hypothesis that the hypothalamic paraventricular nucleus (PVN) mediates 5-HT1A and 5-HT2 receptor-mediated oxytocin, PRL, and corticosterone responses, we studied the effects of the 5-HT1A agonist ipsapirone and the 5-HT2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane (DOI) after surgical PVN lesions or sham operations. Chronically cannulated, conscious, freely moving, male Wistar rats were injected iv (1 mg/kg) shortly after (3-4 days) and 5 weeks after (35-37 days) the operations. In sham-operated rats, ipsapirone caused marked elevations in plasma PRL and corticosterone, but not oxytocin concentrations, whereas DOI increased plasma concentrations of all three hormones. Short term PVN lesions prevented ipsapirone-induced corticosterone and DOI-induced oxytocin responses. DOI-induced PRL and corticosterone responses were also markedly inhibited 3-4 days after lesioning, although small rises over the baseline values were still observed. The ipsapirone-induced PRL response was unaffected by the lesioning. Five weeks after PVN lesioning, partial recoveries were observed in ipsapirone- and DOI-induced corticosterone and DOI-induced oxytocin responses, whereas DOI-induced PRL responses remained suppressed. The present findings suggest that the PVN or neural pathways close to it mediate oxytocin, PRL, and corticosterone responses to the 5-HT2 receptor agonist DOI as well as corticosterone, but not PRL, responses to the 5-HT1A receptor agonist ipsapirone. The results after long term PVN lesioning show that the oxytocin and corticosterone responses may be partially restored with time after lesioning.

Topics: Amphetamines; Animals; Corticosterone; Male; Oxytocin; Paraventricular Hypothalamic Nucleus; Prolactin; Pyrimidines; Rats; Rats, Wistar; Receptors, Serotonin; Serotonin Receptor Agonists; Time Factors

Plasma oxytocin responses to the 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), buspirone and ipsapirone, and the 5-HT2/5-HT1C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane (DOI) have been studied in conscious, freely moving male rats. All four compounds caused dose-related increases in plasma oxytocin concentrations after intravenous administration. Oxytocin responses to 8-OH-DPAT were significantly attenuated by pretreatment with the 5-HT1A receptor antagonist NAN-190 while responses to DOI were blocked by pretreatment with the 5-HT2/5-HT1C receptor antagonist ritanserin. Since vasopressin concentration did not change despite the marked elevation in plasma oxytocin, these results suggest that 5-HT1A and 5-HT2/5-HT1C receptors all stimulate oxytocin secretion, and this effect does not reflect a general neurohypophyseal hormone release.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Animals; Buspirone; Male; Oxytocin; Piperazines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Ritanserin; Serotonin Antagonists; Serotonin Receptor Agonists