Regulation of Corticotropin-Releasing Factor Neuronal Systems and Hypothalamic-Pituitary-Adrenal Axis Activity by Stress and Chronic Antidepressant Treatment

Abstract

In a series of experiments, we tested the hypothesis that chronic antidepressant drug administration reduces the synaptic availability of corticotropin-releasing factor (CRF) through one or more effects on CRF gene expression or peptide synthesis. We also determined whether effects of acute or chronic stress on CRF gene expression or peptide concentration are influenced by antidepressant drug treatment. Four-week treatment with venlafaxine, a dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitor, and tranylcypromine, a monoamine oxidase inhibitor, resulted in an attenuation of acute stress-induced increases in CRF heteronuclear RNA (hnRNA) synthesis in the paraventricular nucleus (PVN). Trends toward the same effect were observed after treatment with the 5-HT reuptake inhibitor fluoxetine, or the NE reuptake inhibitor reboxetine.CRF mRNA accumulation in the PVN during exposure to chronic variable stress was attenuated by concurrent antidepressant administration. Basal CRF hnRNA and mRNA expression were not affected by antidepressant treatment in the PVN or in other brain regions examined. Chronic stress reduced CRF concentrations in the median eminence, but there were no consistent effects of antidepressant drug treatment on CRF, serum corticotropin, or corticosterone concentrations. CRF receptor expression and basal and stress-stimulated HPA axis activity were unchanged after antidepressant administration. These results suggest that chronic antidepressant administration diminishes the sensitivity of CRF neurons to stress rather than alters their basal activity. Additional studies are required to elucidate the functional consequences and mechanisms of this interaction.Corticotropin-releasing factor (CRF) is a 41 amino acid peptide that is synthesized and secreted in many regions of the brain, particularly in limbic-associated areas such as the hypothalamus, amygdala, and bed nucleus of the stria terminalis. There is extensive evidence that CRF functions as both a neurohormone and neurotransmitter in coordinating endocrine, autonomic, and behavioral aspects of the stress response (Owens and Nemeroff, 1991). Major depression is a condition that has been associated with a predisposing influence of major stressors, particularly early in life, and with neurochemical and neuroendocrine findings of CRF hypersecretion (Arborelius et al., 1999). On the basis of these observations, we hypothesized that antidepressant agents, whose ultimate therapeutic mechanism(s) of action are poorly understood, may act in part by reducing CRF synthesis or secretion, either tonically or in response to stress.There is clinical evidence that antidepressants exert effects on CRF systems. Hypothalamic-pituitary-adrenal (HPA) axis abnormalities, hypothesized to result at least in part from CRF hypersecretion and elevated cerebrospinal fluid (CSF) CRF concentrations in depressed patients, have been reported to normalize after antidepressant treatment or electroconvulsive therapy. However, in human studies it is currently impossi...

Reduction of Hypothalamic Vasopressinergic Hyperdrive Contributes to Clinically Relevant Behavioral and Neuroendocrine Effects of Chronic Paroxetine Treatment in a Psychopathological Rat Model

“…As CRH and AVP gene expressions are under glucocorticoid control, it has been hypothesized that corticosteroid signalling is impaired in major depression and may be improved via antidepressant drug treatment (Holsboer and Barden, 1996;Ma and Aguilera, 1999). In contrast to antidepressant-induced decreases in CRH, although suggested by in vitro studies, similar changes have not been shown for AVP or its receptors in vivo (Brady et al, 1991;Altemus et al, 1992;Butterweck et al, 2001;Stout et al, 2002). Thus, an appropriate animal model that reflects both significant psychopathological and neuroendocrine features of human depression with face, predictive and construct validity should be used to obtain predictions about the clinical condition in human depression (Geyer and Markou, 1995).…”

“…Correspondingly, basal and stress-induced plasma ACTH and corticosterone levels were comparable in the paroxetine-treated and control HAB and LAB rats during week 9 of paroxetine treatment. Similarly, in other studies, long-term treatment with the SRIs fluoxetine and paroxetine did not prevent adequate activation of the HPA system in response to severe stressors such as FS, immobilization or footshocks (Zhang et al, 2000;Connor et al, 2000;Stout et al, 2002). In contrast, we could show that after DEX pretreatment, basal ACTH levels at the onset of the activity The density of silver grains per cell within the magnocellular part of the PVN was significantly higher in the vehicle-treated HAB (HAB-V) rats than in the LAB rats and decreased after paroxetine treatment in HAB rats (HAB-P) (n ¼ 6 per group).…”

CSF Corticotropin-Releasing Factor in Personality Disorder: Relationship with Self-Reported Parental Care

“…Acute stress causes upregulation of CRF in amygdala (Stout et al, 2002). Stimulation of amygdalar CRF receptors, and consequent increase in amygdalar metabolic activity, results in increased anxiety-like and decreased pro-social behaviors (Strome et al, 2002;DeVries et al, 2002).…”

Involvement of the Endocannabinoid System in the Ability of Long-Term Tricyclic Antidepressant Treatment to Suppress Stress-Induced Activation of the Hypothalamic–Pituitary–Adrenal Axis

“…Furthermore, the ability of glucocorticoid hormones to exert negative feedback on HPA axis activity appears to be deficient in depression, resulting in a feed-forward hyperactivation of this system (Parker et al, 2003;Holsboer, 2000). This enhanced output of the HPA axis appears functionally relevant to depression, as long-term antidepressant treatment attenuates this phenomenon in humans (De Bellis et al, 1993;Pariante et al, 2004;Greden et al, 1983;Michelson et al, 1997), and suppresses stress-induced activation of the HPA axis in other species (Reul et al, 1993;Connor et al, 2000;Holsboer and Barden, 1996;de Medeiros et al, 2005;Butterweck et al, 2001;Stout et al, 2002). The ability of antidepressants to suppress HPA axis hyperactivity has been shown to be coupled to their clinical efficacy (Appelhof et al, 2006;Young et al, 2004).…”