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Modulation of the vasopressin system for the treatment of CNS diseases

Pfizer Worldwide Research and Development, 500.2.190 Ramsgate Road ipc 432, Sandwich, Kent, CT13 9NJ, UK.
Current opinion in drug discovery & development (Impact Factor: 5.12). 09/2010; 13(5):538-47.
Source: PubMed

ABSTRACT Vasopressin (also known as arginine vasopressin [AVP]) is a small cyclic peptide that acts at the V1a, V1b and V2 GPCRs to regulate a wide range of physiological functions, including vasoconstriction, smooth muscle contractility, response to stress, and excretion of water and sodium via the kidney. The potential therapeutic applications of AVP receptor ligands have prompted significant interest in this target within the pharmaceutical research community, and several small-molecule drugs targeting the AVP receptor have reached the market, mainly for cardiovascular indications. The development of AVP receptor modulators for the treatment of CNS indications has proven more challenging, and is the focus of this review. The regulatory role of AVP on the hypothalamic-pituitary-adrenal (HPA) axis suggests potential uses for AVP receptor modulators in various CNS indications, including depression, anxiety and post-traumatic stress disorder. Several clinical trials of V1a and V1b receptor antagonists in CNS indications have been conducted, but none of these drugs have reached the market. In recent years, the discovery of the key role of AVP in modulating complex social behaviors has provided a unique opportunity to understand the physiological mechanisms of social interactions. Ultimately, the ongoing research in this field may enable the development of treatments to alleviate the social deficits associated with conditions such as autism and schizophrenia. Given the large unmet medical need in these areas, a renewed interest in the field of CNS-penetrant AVP receptors modulators is expected.

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    • "Using a variety of experimental approaches, it has been clearly shown that AVP is anxiogenic (Neumann and Landgraf 2012). These approaches include central or peripheral administration of V1 receptor antagonists, siRNA, knockout mice, and adenoviral overexpression of V1 receptors (Landgraf 2006; Mak et al. 2012; Pitkow et al. 2001; Ring 2005; Ryckmans 2010; Simon et al. 2008). Hyperactivity of the AVP system shifts behavior towards hyper-anxiety and passive coping. "
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    ABSTRACT: Stress Stress mediates the activation of a variety of systems ranging from inflammatory to behavioral responses. In this review we focus on two neuropeptide systems, corticotropin-releasing factor corticotropin-releasing factor (CRF) and arginine vasopressin arginine vasopressin (AVP), and their roles in regulating stress stress responses. Both peptides have been demonstrated to be involved in anxiogenic and depressive effects, actions mediated in part through their regulation of the hypothalamic-pituitary-adrenal axis and the release of adrenocorticotropic hormone. Because of the depressive effects of CRF and AVP, drugs modifying the stress stress -associated detrimental actions of CRF and AVP are under development, particularly drugs antagonizing CRF and AVP receptors for therapy in depression.
    03/2014; DOI:10.1007/7854_2014_306
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    • "It has been recognized that, besides many other role, including water reabsorption, AVP is critical for stress-coping [9] and contributes to stress-related psychiatric disorders [10] [11] [12] [13] and to inflammatory and autoimmune illnesses like "
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    ABSTRACT: Although it is obvious that preconceptional effects as well as stressors during pregnancy profoundly influence the progeny, the lactation period seems to be at least as important. Here we summarize how maternal stressors during the lactation period affect the offspring. As vasopressin is one of the crucial components both for stress adaptation and social behavior, special emphasis was given to this neuropeptide. We can conclude that stressing the mother does not have the same acute effect on the hypothalamo-pituitary-adrenocortical axis (as the main target of stress adaptation) of the pups as stressing the pups, but later endocrine and behavioral consequences can be similar. Vasopressin plays a role in acute and later consequences of perinatal stressor applied either to the mother or to the offspring, thereby contributing to transmitting the mothers' stress to the progeny. This mother-infant interaction does not necessarily mean a direct transmission of molecules, but rather is the result of programming the brain development through changes in maternal behavior. Thus, there is a time lag between maternal stress and stress-related changes in the offspring. The interactions are bidirectional as not only stress in the dam but also stress in the progeny has an effect on nursing.
    The Scientific World Journal 01/2014; 2014:265394. DOI:10.1155/2014/265394 · 1.73 Impact Factor
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    • "Despite its clinical importance this disease is underdiagnosed and undertreated. Gold et al. were the first to propose a role for AVP in mood disorders (Gold et al., 1978); and several studies since then supported this idea (Dinan and Scott, 2005; Frank and Landgraf, 2008; Ryckmans, 2010). Patients with major depression have significantly elevated plasma AVP compared to healthy controls (van Londen et al., 1997). "
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    ABSTRACT: Early mother–infant relationships exert important long-term effects in offspring and are disturbed by factors such as postpartum depression. We aimed to clarify if lack of vasopressin influences maternal behavior paralleled by the development of a depressive-like phenotype. We compared vasopressin-deficient Brattleboro mothers with heterozygous and homozygous normal ones. The following parameters were measured: maternal behavior (undisturbed and separation-induced); anxiety by the elevated plus maze; sucrose and saccharin preference and forced swim behavior. Underlying brain areas were examined by c-fos immunocytochemistry among rest and after swim-stress. In another group of rats, vasopressin 2 receptor agonist was used peripherally to exclude secondary changes due to diabetes insipidus. Results showed that vasopressin-deficient rats spend less time licking–grooming their pups through a centrally driven mechanism. There was no difference between genotypes during the pup retrieval test. Vasopressin-deficient mothers tended to explore more the open arms of the plus maze, showed more preference for sucrose and saccharin and struggled more in the forced swim test, suggesting that they act as less depressive. Under basal conditions, vasopressin-deficient mothers had more c-fos expression in the medial preoptic area, shell of nucleus accumbens, paraventricular nucleus of the hypothalamus and amygdala, but not in other structures. In these areas the swim-stress-induced activation was smaller. In conclusion, vasopressin-deficiency resulted in maternal neglect due to a central effect and was protective against depressive-like behavior probably as a consequence of reduced activation of some stress-related brain structures. The conflicting behavioral data underscores the need for more sex specific studies.
    Hormones and Behavior 09/2012; 62(4):539–551. DOI:10.1016/j.yhbeh.2012.09.003 · 4.51 Impact Factor
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