Anxiolytic Effects Of Oxytocin Research Articles

Limbic oxytocin receptor expression alters molecular signaling and social avoidance behavior in female prairie voles (Microtus ochrogaster)

IntroductionThe social defeat paradigm is the most representative animal model to study social anxiety disorder (SAD) and its underlying neuronal mechanisms. We have previously reported that defeat progressively reduces oxytocin receptors (OXTR) in limbic regions of the brain over an eight-week period in female prairie voles (Microtus ochrogaster). Oxytocin receptors activate the mitogen-activated protein kinase (MAPK) pathway, which has been previously associated with the anxiolytic effects of oxytocin. Here, we assessed the functional significance of OXTR in stress-induced social avoidance and the response of the MAPK signaling pathway in the nucleus accumbens (NAc), anterior cingulate cortex (ACC), and basolateral amygdala (BLA) of female prairie voles.MethodsIn experiment 1, Sexually naïve adult female prairie voles were defeated for three consecutive days and tested a week after for social preference/avoidance (SPA) test. Control subjects were similarly handled without defeat conditioning. In experiment 2, sexually and stress naïve adult female prairie voles were bilaterally injected into the NAc, ACC, or the BLA with a CRISPR/Cas9 virus targeting the Oxtr coding sequence to induce OXTR knockdown. Two weeks post-surgery, subjects were tested for SPA behavior. Viral control groups were similarly handled but injected with a control virus. A subgroup of animals from each condition in both experiments were similarly treated and euthanized without being tested for SPA behavior. Brains were harvested for OXTR autoradiography, western blot analysis of MAPK proteins and quantification of local oxytocin content in the NAc, BLA, ACC, and PVN through ELISA.ResultsSocial defeat reduced OXTR binding in the NAc and affected MAPK pathway activity and oxytocin availability. These results were region-specific and sensitive to exposure to the SPA test. Additionally, OXTR knockdown in the NAc, ACC, and BLA induced social avoidance and decreased basal MAPK activity in the NAc. Finally, we found that OXTR knockdown in these regions was associated with less availability of oxytocin in the PVN.ConclusionDysregulation of the oxytocin system and MAPK signaling pathway in the NAc, ACC, and BLA are important in social behavior disruptions in female voles. This dysregulation could, therefore, play an important role in the etiology of SAD in women.

Quiet wakefulness: the influence of intraperitoneal and intranasal oxytocin on sleep-wake behavior and neurophysiology in rats.

Exogenous administration of the neuropeptide oxytocin exerts diverse effects on various neurobehavioral processes, including sleep and wakefulness. Since oxytocin can enhance attention to social and fear-related environmental cues, it should promote arousal and wakefulness. However, as oxytocin can attenuate stress, reduce activity, and elicit anxiolysis, oxytocin might also prime the brain for rest, and promote sleep. At present, little research has comprehensively characterized the neuropsychopharmacology of oxytocin-induced effects on sleep-wake behavior and no reconciliation of these two competing hypotheses has been proposed. This study explored the effects of oxytocin on sleep-wake outcomes using radiotelemetry-based polysomnography in adult male and female Wistar rats. Oxytocin was administered via intraperitoneal (i.p.; 0.1, 0.3 and 1 mg·kg-1) and intranasal (i.n.; 0.06, 1, 3 mg·kg-1) routes. Caffeine (i.p. and i.n.; 10 mg·kg-1) was administered as a wake-promoting positive control. To ascertain mechanism of action, pretreatment experiments with the oxytocin receptor (OXTR) antagonist L-368,899 (i.p.; 5 mg·kg-1) followed by oxytocin (i.p.; 1 mg·kg-1) were also conducted. In both male and female rats, i.p. oxytocin promoted quiet wakefulness at the cost of suppressing active wakefulness, non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Several i.p. oxytocin-induced sleep-wake effects were mediated by OXTR binding. In contrast, i.n. oxytocin did not alter most sleep-wake outcomes at any dose tested. Both i.p. and i.n. caffeine demonstrated wake-promoting effects. These findings help reconcile competing hypotheses of oxytocin-induced effects on sleep-wake behavior: i.p. oxytocin promotes quiet wakefulness-a state of restful environmental awareness compatible with both oxytocin's anxiolytic effects and its enhancement of processing complex stimuli.

Oro-mucosal administration of oxytocin using medicated lollipops alters social attention, similar to intranasal and lingual routes: Implications for therapeutic use.

A key functional effect of intranasal administration of the neuropeptide oxytocin is on top-down control of social attention. However, an oro-mucosal administration route may be better tolerated for chronic therapeutic use and evidence suggests that some functional effects of oxytocin can be mediated via peripheral routes. The current study investigated if oxytocin administered orally using medicated lollipops can both increase blood oxytocin concentrations and influence social attention and state anxiety. In a randomized, double-blind, clinical trial adult male participants received oral oxytocin (24IU) or placebo 30-min before completing a well-established anti-saccade paradigm which can assess treatment effects on both top-down and bottom-up attention. Oxytocin administration modulated top-down social attentional processing by increasing anti-saccade error rates on both social and non-social stimuli although it only increased response latencies for social cues. Anti-saccade errors were also positively associated with the proportionate increase in plasma oxytocin concentrations. A comparison analysis showed that oral oxytocin administration increased blood concentrations to a similar degree as given by lingual spray, although less than when given intranasally. Importantly, attentional and anxiolytic effects of oxytocin in the anti-saccade task were similar across intranasal, lingual, and oral administration routes. These findings demonstrate that oral administration of oxytocin, similar to via intranasal and lingual routes, can modulate top-down social attention and state anxiety and support its potential for therapeutic use. They also provide further evidence that functional effects of exogenously administered oxytocin can be mediated indirectly either by crossing the blood brain barrier or producing receptor mediated vagal stimulation, as opposed to via direct entry into the brain.

Anxiety and Depression: What Do We Know of Neuropeptides?

In modern society, there has been a rising trend of depression and anxiety. This trend heavily impacts the population’s mental health and thus contributes significantly to morbidity and, in the worst case, to suicides. Modern medicine, with many antidepressants and anxiolytics at hand, is still unable to achieve remission in many patients. The pathophysiology of depression and anxiety is still only marginally understood, which encouraged researchers to focus on neuropeptides, as they are a vast group of signaling molecules in the nervous system. Neuropeptides are involved in the regulation of many physiological functions. Some act as neuromodulators and are often co-released with neurotransmitters that allow for reciprocal communication between the brain and the body. Most studied in the past were the antidepressant and anxiolytic effects of oxytocin, vasopressin or neuropeptide Y and S, or Substance P. However, in recent years, more and more novel neuropeptides have been added to the list, with implications for the research and development of new targets, diagnostic elements, and even therapies to treat anxiety and depressive disorders. In this review, we take a close look at all currently studied neuropeptides, their related pathways, their roles in stress adaptation, and the etiology of anxiety and depression in humans and animal models. We will focus on the latest research and information regarding these associated neuropeptides and thus picture their potential uses in the future.

Anxiolytic Effects of Chronic Intranasal Oxytocin on Neural Responses to Threat Are Dose-Frequency Dependent

Introduction: Anxiety disorders are prevalent mental conditions characterized by exaggerated anxious arousal and threat reactivity. Animal and human studies suggest an anxiolytic potential of the neuropeptide oxytocin (OT), yet, while a clinical application will require chronic administration protocols, previous human studies have exclusively focused on single-dose (acute) intranasal OT effects. Objective: To facilitate the translation of the potential anxiolytic mechanism of OT into clinical application, we determined whether the anxiolytic effects of OT are maintained with repeated (chronic) administration or are influenced by dose frequency and trait anxiety. Methods: In a pre-registered double-blind randomized placebo-controlled pharmaco-fMRI trial the acute (single dose) as well as chronic effects of two different dose frequencies of OT (OT administered daily for 5 days or every other day) on emotional reactivity were assessed in n = 147 individuals with high versus low trait anxiety (ClinicalTrials.gov ID: NCT03085654). Results: OT produced valence, dose frequency, and trait anxiety-specific effects, such that the low-frequency (intermittent) chronic dosage specifically attenuated a neural reactivity increase in amygdala-insula-prefrontal circuits observed in the high anxious placebo-treated subjects in response to threatening but not positive stimuli. Conclusions: The present trial provides the first evidence that low-dose frequency chronic intranasal OT has the potential to alleviate exaggerated neural threat reactivity in subjects with elevated anxiety levels, suggesting a treatment potential for anxiety disorders.

Anxiolytic effects of oxytocin in chronic immobilization stress condition are modulated by sex hormones

Anxiolytic effects of oxytocin in chronic immobilization stress condition are modulated by sex hormones

Oxytocinergic Modulation of Threat-Specific Amygdala Sensitization in Humans Is Critically Mediated by Serotonergic Mechanisms

BackgroundOverarching conceptualizations propose that the complex social-emotional effects of oxytocin (OXT) in humans are partly mediated by interactions with other neurotransmitter systems. Recent animal models suggest that the anxiolytic effects of OXT are critically mediated by the serotonin (5-HT) system, yet direct evidence in humans is lacking. MethodsTo determine the role of 5-HT in OXT-induced attenuation of amygdala threat reactivity and sensitization/desensitization, we conducted a parallel-group, randomized, placebo-controlled, double-blind experiment during which 121 healthy subjects underwent a transient decrease in 5-HT signaling via acute tryptophan depletion or the corresponding placebo-control protocol before the administration of intranasal OXT or placebo intranasal spray, respectively. Mean and repetition-dependent changes in threat-specific amygdala reactivity toward threatening stimuli (angry faces) as assessed by functional magnetic resonance imaging served as the primary outcome. ResultsNo main or interaction effects of treatment on amygdala threat reactivity were observed, yet OXT switched bilateral amygdala threat sensitization to desensitization, and this effect was significantly attenuated during decreased central 5-HT signaling via pretreatment with acute tryptophan depletion. ConclusionsThe present findings provide the first evidence for a role of OXT in threat-specific amygdala desensitization in humans and suggest that these effects are critically mediated by the 5-HT system. OXT may have a therapeutic potential to facilitate amygdala desensitization, and adjunct upregulation of 5-HT neurotransmission may facilitate OXT’s anxiolytic potential.

The role of D2 dopamine receptors in oxytocin induced place preference and anxiolytic effect

Neuropeptide oxytocin (OT) is involved in the regulation of social and non-social behaviour. The central nucleus of amygdala (CeA), part of the limbic system, plays an important role in learning, memory, anxiety and reinforcing mechanisms. CeA has been shown to be rich in OT receptors in rodents. Our previous findings indicated that OT in the rat CeA has a dose dependent rewarding and anxiolytic effect. The aim of our present study was to examine in the CeA the possible interaction of OT and D2 dopamine (DA) receptor antagonist Sulpiride on reinforcement in place preference test and on anxiety in elevated plus maze test.Wistar rats were microinjected bilaterally with 10 ng OT. In different group of animals 4 μg D2 DA receptor antagonist was applied. Other animals received D2 DA receptor antagonist 15 min before 10 ng OT treatment or vehicle solution into the CeA. Rats receiving 10 ng OT spent significantly longer time in the treatment quadrant during the test session in conditioned place preference test. Prior treatment with D2 DA receptor antagonist blocked the rewarding effects of OT. Antagonist in itself did not influence the time rats spent in the treatment quadrant. In elevated plus maze test, rats receiving 10 ng OT spent significantly longer time on the open arms. Prior treatment with D2 DA receptor antagonist blocked the effects of OT.Our results show that DA system plays a role in positive reinforcing and anxiolytic effects of OT because D2 DA receptor antagonist can block these actions.

Cooperation with closely bonded individuals reduces cortisol levels in long-tailed macaques.

Many animal species cooperate with conspecifics in various social contexts. While ultimate causes of cooperation are being studied extensively, its proximate causes, particularly endocrine mechanisms, have received comparatively little attention. Here, we present a study investigating the link between the hormone cortisol, cooperation and social bonds in long-tailed macaques (Macaca fascicularis). We tested 14 macaques in a dyadic cooperation task (loose-string paradigm), each with two partners of different social bond strength and measured their salivary cortisol before and after the task. We found no strong link between the macaques' cortisol level before the task and subsequent cooperative success. By contrast, we did find that the act of cooperating in itself led to a subsequent decrease in cortisol levels, but only when cooperating with closely bonded individuals. Two control conditions showed that this effect was not due to the mere presence of such an individual or the pulling task itself. Consequently, our study shows an intricate way in which the hypothalamic–pituitary–adrenal axis is involved in cooperation. Future studies should reveal whether and how our findings are driven by the anxiolytic effect of oxytocin, which has been associated with social bonding.

Gaze-Following and Reaction to an Aversive Social Interaction Have Corresponding Associations with Variation in the OXTR Gene in Dogs but Not in Human Infants.

It has been suggested that dogs' remarkable capacity to use human communicative signals lies in their comparable social cognitive skills; however, this view has been questioned recently. The present study investigated associations between oxytocin receptor gene (OXTR) polymorphisms and social behavior in human infants and dogs with the aim to unravel potentially differential mechanisms behind their responsiveness to human gaze. Sixteen-month-old human infants (N = 99) and adult Border Collie dogs (N = 71) participated in two tasks designed to test (1) their use of gaze-direction as a cue to locate a hidden object, and (2) their reactions to an aversive social interaction (using the still face task for children and a threatening approach task for dogs). Moreover, we obtained DNA samples to analyze associations between single nucleotide polymorphisms (SNP) in the OXTR (dogs: −213AG, −94TC, −74CG, rs8679682, children: rs53576, rs1042778, rs2254298) and behavior. We found that OXTR genotype was significantly associated with reactions to an aversive social interaction both in dogs and children, confirming the anxiolytic effect of oxytocin in both species. In dogs, the genotypes linked to less fearful behavior were associated also with a higher willingness to follow gaze whereas in children, OXTR gene polymorphisms did not affect gaze following success. This pattern of gene-behavior associations suggests that for dogs the two situations are more alike (potentially fear-inducing or competitive) than for human children. This raises the possibility that, in contrast to former studies proposing human-like cooperativeness in dogs, dogs may perceive human gaze in an object-choice task in a more antagonistic manner than children.

Oxytocin and Anxiety Disorders: Translational and Therapeutic Aspects.

This review aims to evaluate the most recent literature examining the oxytocin (OXT) system's role in human anxiety by surveying various fields of preclinical and clinical research supporting this role, and queries whether the OXT system might be a target for novel anxiolytics. Evidence from the diverse body of literature presented here, from translational research, genetic and neuroimaging studies, to clinical trials of intranasal (IN) OXT reveals a positive association. In addition, some moderators (e.g., sex, specificities to cues) of OXT's anxiolytic effects can have an important influence on its outcomes, awaiting further research. Evidence for the role of OXT in regulating anxiety is undeniable. We expect that the diverse particularities of the OXT system will help broaden our understanding of anxiety and stress-related disorders. We conclude that OXT promises an enticing treatment option for human anxiety disorders especially those associated with socio-emotional dysfunctions.

Oxytocin in the medial prefrontal cortex attenuates anxiety: Anatomical and receptor specificity and mechanism of action

Numerous studies in animals and humans have established that oxytocin (OT) reduces anxiety. In rats, the prelimbic (PL) subregion of the medial prefrontal cortex (mPFC) is among the brain areas implicated in the anxiolytic actions of OT. However, questions remain about the anatomical and receptor specificity of OT and its mechanism of action. Here we assessed whether the regulation of anxiety by mPFC OT is restricted to the PL subregion and evaluated whether oxytocin receptor (OTR) activation is required for OT to have an anxiolytic effect. We also examined whether OT interacts with GABA in the mPFC to reduce anxiety and investigated the extent to which OT in the mPFC affects activation of mPFC GABA neurons as well as neuronal activation in the amygdala, a primary target of the mPFC which is part of the neural network regulating anxiety. We found that OT reduced anxiety-like behavior when delivered to the PL, but not infralimbic or anterior cingulate subregions of the mPFC. The anxiolytic effect of OT in the PL mPFC was blocked by pretreatment with an OTR, but not a vasopressin receptor, antagonist as well as with a GABAA receptor antagonist. Lastly, administration of OT to the PL mPFC was accompanied by increased activation of GABA neurons in the PL mPFC and altered neuronal activation of the amygdala following anxiety testing. These results demonstrate that OT in the PL mPFC attenuates anxiety-related behavior and may do so by engaging GABAergic neurons which ultimately modulate downstream brain regions implicated in anxiety.

Oxytocin reduces food sharing in capuchin monkeys by modulating social distance

Recent evidence indicates that oxytocin plays an important role in promoting prosocial behaviour amongst humans and other species. We tested whether oxytocin affected cooperation and food-sharing in capuchin monkeys, a highly cooperative New World primate. Subjects received either 2IU oxytocin or an inert adjuvent intranasally prior to each session. Oxytocin influenced food sharing in capuchins in ways we did not anticipate. Recipients were less likely to passively acquire food from possessors when either individual had received OT than in the control, and also spent less time in proximity to their partner. Passive food sharing requires proximity, and oxytocin decreased the capuchins’ typical congregating behaviour, apparently resulting in decreased sharing. We propose that the likely mechanism for increased social distance is the known anxiolytic effect of oxytocin. Our results indicate a need to consider how oxytocin affects the context of interactions and interacts with modes of sociality unique to each species.

Anxiolytic effects of oxytocin in cue-induced cocaine seeking behavior in rats.

Oxytocin (OT) is a neuropeptide previously related to reward, learning, memory, and stress, events associated with cocaine addiction. OT has shown anxiolytic properties in different animal models of anxiety. Moreover, previous data have demonstrated an increase in mRNA OT levels within the nucleus accumbens (NAc) following acute and chronic cocaine exposure in rats. Therefore, OT might play a modulatory role in the rewarding properties of cocaine. The present set of experiments aims to examine the role of OT on environmentally elicited cocaine-seeking behavior and whether OT could reduce anxiety associated with this behavior. Separate groups of rats were trained in a cue-elicited cocaine-seeking behavior paradigm. Prior to the reinstatement phase, animals received microinfusions of artificial cerebrospinal fluid (aCSF), OT, OT agonist (TgOT), or OT antagonist (OTA) within the intracerebral ventricular intracerebroventricular (ICV) system. To test OT anxiolytic effects in reinstatement behavior, separate groups of animals were trained in a cue-elicited cocaine-seeking behavior protocol or in a cocaine-conditioning paradigm. At the end of each behavioral training, all animals were ICV pretreated with aCSF or OT, and then exposed to an elevated plus maze. Results showed that OT and TgOT pretreatment significantly reduced reinstatement of cocaine-seeking behavior. Most significantly, OT treatment reduced the anxiety triggered by cue-induced reinstatement conditions and cocaine-paired conditioned locomotion. The present study demonstrates for the first time that OT actions within the brain mediate the anxiety response triggered by cues previously paired with cocaine intake.

Oxytocin specifically enhances valence-dependent parasympathetic responses

The evolutionarily highly conserved neuropeptide oxytocin seems to be involved in the regulation of complex forms of social behavior. It enhances the processing of positive social stimuli, reduces behavioral and neuroendocrine stress responses and modulates amygdala activity in humans. Moreover, it has been proposed that oxytocin dampens sympathetic nervous system activity. This hypothesis was tested in a double-blind, placebo-controlled study with 38 men either receiving 24 IU oxytocin intranasally or a placebo spray. While accomplishing an emotion classification task, electrodermal responses were measured as an index of sympathetic activity. Moreover, heart rate changes were recorded that are additionally mediated by the parasympathetic nervous system. Oxytocin enhanced differential heart rate responses to facial expressions as a function of the emotional valence, but had no effect on electrodermal activity or tonic measures of physiological arousal. These results indicate that oxytocin specifically modulates phasic activity of the parasympathetic nervous system which potentially reflects an increased motivational value of facial expressions following oxytocin treatment. Findings suggest that anxiolytic effects of oxytocin are not reflected in short-term sympathetic responses and may even be a consequence of rather than a prerequisite for improved social information processing.

Anxiety, cortisol, and attachment predict plasma oxytocin

Oxytocin and attachment seem to interact in suppressing subjective anxiety and physiological stress responses. In this study we investigated the relationships between individual differences in trait attachment scores, state and trait anxiety, plasma cortisol, and plasma oxytocin levels in healthy premenopausal women. Attachment proved to be a strong positive predictor of oxytocin levels, which were also positively predicted by cortisol levels and state and trait anxiety. The relationship between oxytocin and state anxiety was modulated by attachment scores. The present results may help interpreting seeming contradictions in the recent literature on oxytocin, attachment, and stress in humans, by suggesting that context effects determine which relationships are found in different studies: anxiolytic effects of oxytocin in a context of partner support versus stress- or cortisol-induced oxytocin responses in a context of distress or increased cortisol.