Trends in Neurosciences
OpinionBalance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors
Introduction
Over the past years, substantial progress has been achieved with respect to our neurobiological understanding of the link between anxiety and stress-coping, on the one hand, and social behaviors on the other. A dynamic interplay of genetic, epigenetic, and environmental factors orchestrates both individual behavioral variations and the etiology of anxiety- and depression-related disorders. Despite this progress, available treatment options are far from being mechanism-based, which explains the need for innovative therapeutic interventions. One focus of modern psychiatric research for future therapies has been on neuropeptide systems, with oxytocin (OXT) and arginine vasopressin (AVP) featuring prominently in such endeavors 1, 2, 3, 4, 5. The synthesis and release of OXT and AVP within the brain are driven by anxiogenic, stressful, and notably social (both positive and negative) stimuli 1, 6. In turn, once released, both neuropeptides are key regulators of anxiety-related behavior, passive versus active stress-coping as an indicator of depression-like behavior, and multiple aspects of social behavior 1, 2, 3, 4, 7.
We here discuss experimental evidence, primarily from rodents, but with complementary data from human studies ([5] for review of human data), for opposing effects of OXT and AVP on the fine-tuned regulation of emotional behavior. Specifically, OXT exerts anxiolytic and antidepressive effects, whereas AVP predominantly increases anxiety- and depression-related behaviors. We will therefore put forward the hypothesis that a dynamic balance between the activities of brain OXT and AVP systems impacts upon hypothalamic and limbic circuitries involved in a broad spectrum of emotional behaviors extending to psychopathology.
Section snippets
Central release patterns of OXT and AVP: coordinated and independent secretion into blood
Following their neuronal synthesis in the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei (OXT, AVP), or in regions of the limbic system (AVP), both neuropeptides are centrally released to regulate neuronal processes in a spatially and temporally fine-tuned manner. As neurotransmitters, following release from axon terminals they contribute to the synaptic mode of rapid information processing via hard-wired neuronal connections 1, 8. A complementary mode of OXT and AVP release is
OXT and AVP: anxiety and social phobia
Brain OXT and AVP are important regulators of anxiety, although usually in opposing directions. Once released in brain regions involved in stress and anxiety regulation, for example in response to anxiogenic stimuli 1, 15, 16, OXT exerts anxiolytic effects and modulates neuronal functions related to physiological stress responses, mainly at the levels of the PVN and amygdala 8, 17, 18, 19, 20, 21. Particularly intriguing is the reduction in emotional responsiveness during periods of high
OXT, AVP, and depression-like behavior
Due to the high degree of comorbidity between anxiety and depression disorders, common mediators are likely to underlie both conditions. Indeed, in addition to its anxiolytic effect, synthetic OXT was shown to shift stress-coping in rodents towards a more active coping style, after either central or peripheral administration, indicating antidepressive-like effects (4, 61, 62 for review). Further, there is preclinical and clinical evidence that OXT may also contribute to the improvement of other
Mechanisms of effects of OXT and AVP related to anxiety and depression
Multiple brain neurotransmitter and neuromodulator systems are presumed to interact at various brain levels to shape individual variations in emotionality. The mechanisms underlying anxiolytic and antidepressive effects of OXT are likely to include interactions with monoaminergic, in particular the serotonergic, and corticotropin-releasing factor (CRF) systems, both of which have been implicated in anxiety disorders and depression 2, 72, 74. A subpopulation of OXTR-expressing serotonergic
OXT, AVP, and social behaviors
According to the social brain hypothesis, the need to adapt behaviorally to increasing social complexity has substantially contributed to the development of brain mass, cognitive abilities, emotions, and language [83]. Brain OXT and AVP, as well as their evolutionary ancestors, are major players in the complex orchestra shaping sociality, and this impacts upon both anxiety and stress-coping 3, 7, 31. Following their central release, both OXT and AVP promote important aspects of social behavior,
Influence of the social environment on brain OXT and AVP activity
Positive and rewarding social stimuli (such as mother–offspring or socio-sexual interactions, and social support), and negative social experiences (such as defeat, subordination, or interruption of maternal care early in life), differentially affect both neuropeptide systems. This is reflected by alterations in the expression, release, and receptor binding of OXT/AVP within limbic regions and, partly, in plasma OXT or AVP concentrations 15, 41, 42, 100, 101, 102. We propose that in this way the
Gender-dependent effects of OXT and AVP
An important aspect of neuropeptide functions that balance emotional behavior is the sexual dimorphism of OXT/AVP systems, and this may underlie the higher incidence of anxiety disorders and depression in women, and antisocial behavior and autism in males [112]. Estrogens upregulate OXT synthesis within the PVN and regulate OXTR expression in the amygdala via estrogen α- and β-receptor actions, respectively. Sexually dimorphic amygdala reactivity to intranasal OXT [48], and gender-dependent
Genes of the OXT and AVP systems in association studies
The data described so far, suggesting reliable OXT and AVP effects on socio-emotional behaviors, stand in contrast to how little is currently known about candidate genes underlying such behaviors and psychiatric disorders [116]. One approach that can shed light on the genes involved is to associate polymorphic variations, particularly single nucleotide polymorphisms (SNPs), with variations in emotional and social behaviors. However, genetic associations generally raise issues related to
Neuropeptide balance in the regulation of emotional behaviors
The opposing effects of brain OXT and AVP systems on anxiety and depression-related neuronal functions and behaviors, as discussed above, support our hypothesis that a dynamic balance of the activities of the brain OXT and AVP systems impacts upon emotional behaviors along a continuum from mental health to psychopathology (Figure 3). Accordingly, psychiatric disorders can be considered as extremes of quantitative dimensions at the negative end of a given continuum [120], explaining why, for
Concluding remarks
Individual variations in anxiety- and depression-related behaviors are determined by the dynamic interplay of theoretically unlimited combinations of underlying genetic, epigenetic, environmental, and social (risk) factors. Based on preclinical and clinical evidence, we propose that each of these factors, alone or in concert, also contributes to individual differences in central OXT/AVP release patterns or receptor binding, thereby modulating their balance and thus, in turn, emotionality.
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