Psychopharmacology (2005) 178: 78–82 DOI 10.1007/s00213-004-1984-6 ORIGINAL INVESTIGATION Aline S. C. Fabricio . Giuseppe Tringali . Giacomo Pozzoli . Pierluigi Navarra Mirtazapine acutely inhibits basal and K + -stimulated release of corticotropin-releasing hormone from the rat hypothalamus via a non-genomic mechanism Received: 2 February 2004 / Accepted: 6 April 2004 / Published online: 6 August 2004 # Springer-Verlag 2004 Abstract Rationale: Originally described as a pivotal mediator of acute neuroendocrine responses to stress, corticotropin-releasing hormone (CRH) is currently envi- sioned as a peptide neurotransmitter involved in the pathogenesis of anxiety and depressive disorders; it has been postulated that antidepressant drugs are clinically effective insofar as they are able to reduce central CRH production and release. Objectives and methods: In this study we used a well validated in vitro model, i.e. acute rat hypothalamic explants, to investigate the effects of the antidepressant mirtazapine on the production and release of CRH from the hypothalamus in short-term experiments. CRH release was assessed through the measurement of CRH immunoreactivity in the incubation medium. Results: We found that mirtazapine reduces in a concen- tration-dependent manner both basal and K + -stimulated CRH release in 30-min and 60-min experiments. Mirta- zapine had no effect on CRH mRNA expression in 1-h and 3-h experiments; the intra-hypothalamic levels of peptide were not reduced, and even tended to increase, with respect to controls. Conclusion: Mirtazapine reduces CRH release from CRH-containing neurons in the rat hypothalamus through a mechanism independent from the modulation of CRH gene expression and peptide produc- tion. Keywords Mirtazapine . CRH . Hypothalamus . Rat Introduction In recent years, a large body of evidence has emerged linking stressful situations with an increased vulnerability to affective disorders. Stressful events often precede the onset of depression (Persaud 2000) and it is now well established that up to 90% of patients with major depression show altered regulation of the hypothalamo- pituitary-adrenal (HPA) axis, involving higher levels of plasma cortisol and adrenocorticotropin (ACTH), resis- tance to dexamethasone (DEX) suppression test and paradoxical increase in ACTH and cortisol secretions after stimulation with corticotropin-releasing hormone (CRH) in DEX pretreated patients (Rybakowski and Twardowska 1999). The hyperactivity of the HPA axis observed in depressed patients is thought to be caused by reduced feed-back down-regulation, secondary to a functionally impaired corticosteroid receptor signaling (Modell et al. 1997), followed by CRH hypersecretion from hypotha- lamic neurons. This hypothesis is supported by the demonstration of an increased number of CRH-expressing neurons in the paraventricular nuclei (PVN) (Raadsheer et al. 1994), and elevated concentrations of CRH in the cerebrospinal fluid (De Bellis et al. 1993) of depressed patients. Consistent with this hypothesis is also the evidence of marked reduction in the number of CRH binding sites within the frontal cortex, reflecting an adaptive down-regulation to the increased release of CRH in this brain region (Nemeroff et al. 1988). There is evidence that several antidepressant drugs exert effects on the CRH system, and it has been postulated that these agents are clinically effective insofar as they are able to reduce central CRH production and release (Holsboer and Barden 1996). Normalization of the HPA axis was shown to be a prerequisite for both favorable response to treatment and stable remission, since patients who do not respond to antidepressive treatment show persistent HPA dysregulation (for review, see Holsboer 1999), and patients who are full responders but still present HPA dysregulation have a much higher risk of relapse within 6 months compared with patients who are fully remitted with respect to both psychopathology and neuroendocrine disorders (Zobel et al. 1999). Thus, originally considered as a sort of “side effect” of central monoamine derange- ment in depression, the enhanced set-up of the brain CRH A. S. C. Fabricio . G. Tringali . G. Pozzoli . P. Navarra (*) Institute of Pharmacology, Catholic University Medical School, Largo Francesco Vito 1, 00168 Rome, Italy e-mail: pnavarra@rm.unicatt.it Tel.: +39-6-30154367 Fax: +39-6-233235103