Modulation of the vasopressin system for the treatment of CNS diseases.
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.
- SourceAvailable from: Charles B Nemeroff[Show abstract] [Hide abstract]
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.Current topics in behavioral neurosciences. 03/2014;
- [Show abstract] [Hide abstract]
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. · 1.22 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Central arginine vasopressin receptor 1A (AVPR1A) modulates a wide range of behaviors, including stress management and territorial aggression, as well as social bonding and recognition. Inter- and intra-species variations in AVPR1A brain expression patterns and downstream differential behavioural phenotypes have been attributed to differences in the 5' non-coding region upstream of the AVPR1A gene including polymorphic elements within this regulatory area. Gene association studies have suggested a link between AVPR1A polymorphisms and autism and AVPR1A has emerged as a potential pharmacological target for treatment of social cognitive impairments and mood and anxiety disorders. To further investigate the genetic mechanism giving rise to species differences in AVPR1A expression patterns and associated social behaviors, and to create a preclinical mouse model useful for screening drugs targeting AVPR1A, we engineered and extensively characterized BAC transgenic mice harboring the entire human AVPR1A locus with the surrounding regulatory elements. Compared to wildtype animals, the humanized mice (hAVPR1A) displayed a more widely distributed AVPR1A binding pattern, with overlap with primate expression. Furthermore, hAVPR1A mice displayed increased reciprocal social interactions compared to wildtype animals, but no differences in social approach and preference for social novelty were observed. Aspects of learning and memory, specifically novel object recognition and spatial relocation recognition, were unaffected. The biological alterations in hAVPR1A mice resulted in the rescue of prepulse inhibition impairments observed in knockout mice, indicating conserved functionality. Although further behavioural paradigms and additional cohorts need to be examined in hAVPR1A mice, the results demonstrate that species-specific variations in the genomic content of regulatory regions surrounding the AVPR1A locus are likely responsible for differential receptor protein expression patterns across species and contribute to species-specific behavioral variation. The hAVPR1A mouse is a potential preclinical model for further understanding the regulation of receptor gene expression and the impact of variation in receptor expression on behaviors, and should be useful for screening drugs targeting human AVPR1A.Disease Models and Mechanisms 06/2014; 7(8). · 5.54 Impact Factor