Chronic Antidepressant Treatments Decrease Pro‐Opiomelanocortin mRNA Expression in the Pituitary Gland: Effects of Acute Stress and 5‐HT_1A Receptor Activation

Abstract

Consistent findings in depressed patients are hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis with high plasma concentrations of adrenocorticotropic hormone and cortisol. Long-term antidepressant treatments seem to normalize this hyperactivity, suggesting a link between the HPA axis and the action of antidepressant treatments. The present study was carried out to study the effects of antidepressant treatments on pro-opiomelanocortin (POMC) mRNA expression, with a focus on interaction with acute stress and 5-HT(1A) receptor activation. Male rats were treated for 21 days with saline, citalopram, fluoxetine, moclobemide or desipramine, and the expression of POMC mRNA in the anterior pituitary was analysed by semi-quantitative in situ hybridization. All antidepressants, but not saline, cocaine and haloperidol, reduced POMC mRNA expression. The decrease in POMC mRNA was not observed until 9 days of citalopram treatment. Decreased POMC mRNA levels were also observed after 14 days of repeated electroconvulsive stimulation. The decreased POMC mRNA levels did not affect the stress-induced POMC mRNA increase, measured following swim stress and restraint stress. Finally, using Fos as a marker for neural activity, we showed attenuation of 8-OH-DPAT-stimulated activity in the paraventricular nucleus following 21 days of citalopram treatment. In conclusion, antidepressant treatments decrease basal POMC mRNA expression without affecting the acute stress response, and the reduced POMC mRNA may be related to reduced 5-HT(1A)-stimulated hypothalamic output.

Time course of hypothalamic-pituitary-adrenocortical axis activity during treatment with reboxetine and mirtazapine in depressed patients

“…During reboxetine treatment, a gradual and significant reduction in HPA axis activity was observed. Apparently, reuptake inhibiting antidepressants, such as reboxetine, SSRIs, or tricyclics, acutely stimulate cortisol and ACTH secretion both in healthy subjects (Laakmann 1988;Schüle et al 2004a) and in depressed patients (Asnis et al 1985(Asnis et al , 1992 and may gradually normalize HPA axis hyperactivity in depressed patients via upregulation of mineralocorticoid receptor (MR) and GR mRNA levels (Brady et al 1991;Seckl and Fink 1992;Reul et al 1993;Barden et al 1995), downregulation of proopiomelanocortin mRNA expression in the pituitary gland (Jensen et al 2001), and decrease of CRH gene expression and CRH mRNA synthesis in the paraventricular nucleus (Mori et al 1998;Stout et al 2002), thereby enhancing MR and GR function and restoring the disturbed feedback control. One may assume that these effects of antidepressants on gene expression represent physiological adaptive mechanisms, which are triggered by the primarily acute stimulatory effects of reuptake inhibitors on the ACTH and cortisol release and take several weeks to become effective.…”

Regulation of Proopiomelanocortin Gene Transcription during Single and Repeated Immobilization Stress

“…Several investigators have reported increased expression of POMC mRNA in the AP during various types of acute stress [22,23,24]. Mamalaki et al[ 25] also demonstrated that acute immobilization for 2 h markedly increased POMC mRNA in the AP by 60%.…”

Pro-Opiomelanocortin Gene Variation Related to Alcohol or Drug Dependence: Evidence and Replications Across Family- and Population-based Studies

“…Studies in rodents have shown that physiological or psychological stressors elevate POMC mRNA levels in the pituitary (8), and chronic antidepressant treatment decrease pituitary levels of POMC mRNA (9). Stress is a common trigger for drug or alcohol use, and individuals experiencing stress (or depression and/or anxiety) are more prone to abuse drugs or alcohol.…”