Domperidone Treatment Enhances Corticotropin-Releasing Hormone Stimulated Adrenocorticotropic Hormone Release from the Dog Pituitary

Abstract

While dopamine (DA) is known to inhibit pituitary intermediate lobe proopiomelanocortin (POMC) peptide secretion and synthesis in most species, its influence on anterior-lobe (AL) POMC peptide synthesis and secretion is less clear. We, therefore, sought to determine the effects of daily treatment with the DA receptor antagonist, domperidone (DOM), on secretion of the POMC peptides adrenocorticotropic hormone (ACTH) and α-melanocyte-stimulating hormone (α-MSH) from the dog pituitary, and on concentrations of another pituitary hormone regulated by DA, prolactin (PRL). Dogs treated for 7 days with DOM had significantly higher peak ACTH concentrations in response to corticotropin-releasing hormone (CRH) injection (329 ± 37 pg/ml, mean ± SD) than did controls (164 ± 42 pg/ml). PRL was also significantly (p < 0.05) increased in samples collected on a daily basis after DOM injections (9.5 ± 4.6 vs. 4.3 ± 3.3 ng/ml in controls). However, plasma α-MSH concentrations were unaffected by DOM. In a subsequent study, dogs were again treated daily with DOM or vehicle (controls), and additionally were given dexamethasone (DEX) to block AL ACTH release. DEX-treated controls showed low daily and CRH-stimulated ACTH and cortisol concentrations (generally below assay sensitivity). In contrast, DEX + DOM-treated dogs had daily mean ACTH concentrations ranging from 10 ± 8.1 to 32 ± 26 pg/ml and mean peak post-CRH ACTH concentrations of 174 ± 16 pg/ml. Although daily cortisol concentrations were below assay sensitivity, the mean peak post-CRH cortisol concentration was 6.7 ± 1.8 µg/dl, indicating that the immunoreactive ACTH was biologically active. Daily and post-CRH PRL, but not α-MSH concentrations, were higher in the DOM-treated dogs than in control. However, plasma concentrations of PRL and α-MSH did not increase in response to CRH injection in either group. These results show that treatment with a DA receptor antagonist enhances CRH-responsive ACTH release from the dog pitutiary. Additionally, if the pituitary lobe of origin of this ACTH is the AL, the enhancement associated with DA antagonism appears capable of overriding the potent inhibitory effect of glucocorticoid-negative feedback.