Abstract:Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is related to melancholic or endogenous depression; however, the strength of this relationship depends on the definition of the specific depression subcategory. A two-dimensionally defined subcategory, anxious-retarded depression, is related to melancholic depression. Since arginine vasopressin (AVP) activates the HPA axis, and both major depression and the melancholic subcategory are associated with elevated plasma AVP levels, we investigated whet… Show more
“…In contrast, AVP mRNA expression in the PVN and SON is unchanged in depressed patients with Alzheimer's disease compared with nondepressed patients with Alzheimer's disease (338). Interestingly, two studies found a correlation between plasma AVP levels and cortisol levels in depression, particularly in suicide victims (112,232), but this finding was contradicted by another report (75). Increased expression of the V1a receptor gene was found in the PVN of depressed patients (529).…”
The neurohypophysial hormone arginine vasopressin (AVP) is essential for a wide range of physiological functions, including water reabsorption, cardiovascular homeostasis, hormone secretion, and social behavior. These and other actions of AVP are mediated by at least three distinct receptor subtypes: V1a, V1b, and V2. Although the antidiuretic action of AVP and V2 receptor in renal distal tubules and collecting ducts is relatively well understood, recent years have seen an increasing understanding of the physiological roles of V1a and V1b receptors. The V1a receptor is originally found in the vascular smooth muscle and the V1b receptor in the anterior pituitary. Deletion of V1a or V1b receptor genes in mice revealed that the contributions of these receptors extend far beyond cardiovascular or hormone-secreting functions. Together with extensively developed pharmacological tools, genetically altered rodent models have advanced the understanding of a variety of AVP systems. Our report reviews the findings in this important field by covering a wide range of research, from the molecular physiology of V1a and V1b receptors to studies on whole animals, including gene knockout/knockdown studies.
“…In contrast, AVP mRNA expression in the PVN and SON is unchanged in depressed patients with Alzheimer's disease compared with nondepressed patients with Alzheimer's disease (338). Interestingly, two studies found a correlation between plasma AVP levels and cortisol levels in depression, particularly in suicide victims (112,232), but this finding was contradicted by another report (75). Increased expression of the V1a receptor gene was found in the PVN of depressed patients (529).…”
The neurohypophysial hormone arginine vasopressin (AVP) is essential for a wide range of physiological functions, including water reabsorption, cardiovascular homeostasis, hormone secretion, and social behavior. These and other actions of AVP are mediated by at least three distinct receptor subtypes: V1a, V1b, and V2. Although the antidiuretic action of AVP and V2 receptor in renal distal tubules and collecting ducts is relatively well understood, recent years have seen an increasing understanding of the physiological roles of V1a and V1b receptors. The V1a receptor is originally found in the vascular smooth muscle and the V1b receptor in the anterior pituitary. Deletion of V1a or V1b receptor genes in mice revealed that the contributions of these receptors extend far beyond cardiovascular or hormone-secreting functions. Together with extensively developed pharmacological tools, genetically altered rodent models have advanced the understanding of a variety of AVP systems. Our report reviews the findings in this important field by covering a wide range of research, from the molecular physiology of V1a and V1b receptors to studies on whole animals, including gene knockout/knockdown studies.
“…197 Disturbances (hyperactivity) in vasopressinergic activity have also been reported clinically in patients with depression. 198,199 Together, this has led many to hypothesize the utility of central vasopressinergic receptor antagonism as a potentially novel antidepressant strategy.…”
Summary: Depression is a highly debilitating disorder that has been estimated to affect up to 21% of the world population. Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), there continue to be many unmet clinical needs with respect to both efficacy and side effects. These needs range from efficacy in treatment resistant patients, to improved onset, to reductions in side effects such as emesis or sexual dysfunction. To address these needs, there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas. There is tremendous diversity in the types of targets and approaches being taken. At one end of a spectrum is combination therapies that maintain the benefits associated with SSRIs but attempt to either improve efficacy or reduce side effects by adding additional mechanisms (5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 2C , ␣-2A). At the other end of the spectrum are more novel targets, such as neurotrophins (BDNF, IGF), based on recent findings that antidepressants induce neurogenesis. In between, there are many approaches that range from directly targeting serotonin receptors (5-HT 2C , 5-HT 6 ) to targeting the multiplicity of potential mechanisms associated with excitatory (glutamate, NMDA, mGluR2, mGluR5) or inhibitory amino acid systems (GABA) or peptidergic systems (neurokinin 1, corticotropin-releasing factor 1, melanin-concentrating hormone 1, V1b). The present review addresses the most exciting approaches and reviews the localization, neurochemical and behavioral data that provide the supporting rationale for each of these targets or target combinations.
“…Several clinical studies suggest that AVP could play an important role in the aetiology of these conditions and elevated plasma levels of AVP have been described in subjects suffering from depression (van Londen et al 1997, 2001, de Winter et al 2003 or post-traumatic stress disorders (de Kloet et al 2007). Post-mortem studies have also shown increased numbers of AVP-expressing neurons in the PVN of depressed patients (Purba et al 1996, Merali et al 2006.…”
Vasopressin (AVP), produced in parvocellular neurons of the hypothalamic paraventricular nucleus, regulates, together with CRH, pituitary ACTH secretion. The pituitary actions of AVP are mediated through the G protein receptor V 1b (V 1b jR). In man, hyperactivity of the hypothalamicpituitary-adrenal axis has been associated with depression and other stress-related conditions. There are also clinical data suggesting a role for AVP in the dysfunctional HPA axis described in some depressed patients. In this study, we have investigated the effect of a recently synthesised selective antagonist of the V 1b R both on exogenous AVP-induced ACTH and corticosterone secretion, and on basal and stressinduced pituitary-adrenal activity. Adult male SpragueDawley rats treated with the V 1b R antagonist (Org, 30 mg/kg, s.c.) or vehicle (5% mulgofen in 0 . 9% saline, 2 ml/kg, s.c.). We found that blockade of the V 1b R reduced the increase in both ACTH and corticosterone secretion induced by AVP (100 ng, i.v.). The same treatment had no effect either on basal ACTH and corticosterone levels or on the ultradian or diurnal rhythms of corticosterone secretion. Acute administration of the V 1b R antagonist reduced ACTH secretion following both restraint and lipopolysaccharide, but did not antagonise the ACTH response to noise. The same treatment did not reduce corticosterone secretion in response to any of the three stressors used in this study. Our results confirm that this compound is an antagonist of the V 1b R in the rat, and that its ability to reduce stress-induced ACTH responses is stressor dependent with differential modulation of pituitary and adrenal responses.
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