Abstract The neuropeptide oxytocin (OXT) has been revealed as a profound anxiolytic and antistress factor of the brain, besides its many prosocial and reproductive effects. Therefore, there is ...substantial scientific and medical interest in its potential therapeutic use for the treatment of psychopathologies associated with anxiety, fear, and social dysfunctions, such as generalized anxiety disorder, posttraumatic stress disorder, and social anxiety disorder, as well as autism and schizophrenia, among others. Focusing on preclinical studies, we review the existing evidence for the regulatory capacity of OXT to fine-tune general and social anxiety-related behaviors, as well as cued and social fear conditioning from a translational perspective. The available evidence from animal and human studies substantiates the hypothesis of an imbalance of the endogenous brain OXT system in the etiology of anxiety disorders, particularly those with a social component such as social anxiety disorder. In addition, such an imbalance of the OXT system is also likely to be the consequence of chronic OXT treatment resulting in a dose-dependent reduction in OXT receptor availability and increased anxiety.
The forced swim test (FST) is one of the most commonly used animal models for assessing antidepressant-like behavior. This protocol details using the FST in rats, which takes place over 48 h and is ...followed by the video analysis of the behavior. The swim test involves the scoring of active (swimming and climbing) or passive (immobility) behavior when rodents are forced to swim in a cylinder from which there is no escape. There are two versions that are used, namely the traditional and modified FSTs, which differ in their experimental setup. For both versions, a pretest of 15 min (although a number of laboratories have used a 10-min pretest with success) is included, as this accentuates the different behaviors in the 5-min swim test following drug treatment. Reduction in passive behavior is interpreted as an antidepressant-like effect of the manipulation, provided it does not increase general locomotor activity, which could provide a false positive result in the FST.
Central oxytocin (OXT) has anxiolytic and pro-social properties both in humans and rodents, and has been proposed as a therapeutic option for anxiety and social dysfunctions. Here, we utilized a ...mouse model of social fear conditioning (SFC) to study the effects of OXT on social fear, and to determine whether SFC causes alterations in central OXT receptor (OXTR) binding and local OXT release. Central infusion of OXT, but not arginine vasopressin, prior to social fear extinction training completely abolished social fear expression in an OXTR-mediated fashion without affecting general anxiety or locomotion. SFC caused increased OXTR binding in the dorso-lateral septum (DLS), central amygdala, dentate gyrus, and cornu ammunis 1, which normalized after social fear extinction, suggesting that these areas form part of a brain network involved in the development and neural support of social fear. Microdialysis revealed that the increase in OXT release observed in unconditioned mice within the DLS during social fear extinction training was attenuated in conditioned mice. Consequently, increasing the availability of local OXT by infusion of OXT into the DLS reversed social fear. Thus, alterations in the brain OXT system, including altered OXTR binding and OXT release within the DLS, play an important role in SFC and social fear extinction. Thus, we suggest that the OXT system is adversely affected in disorders associated with social fear, such as social anxiety disorder and reinstalling an appropriate balance of the OXT system may alleviate some of the symptoms.
Abstract Chronic psychosocial stress is a recognized risk factor for various affective and somatic disorders. In an established murine model of chronic psychosocial stress, exposure to chronic ...subordinate colony housing (CSC) results in an alteration of physiological, behavioral, neuroendocrine and immunological parameters, including a long-lasting increase in anxiety, adrenal hypertrophy and thymus atrophy. Based on the stress-protective and anxiolytic properties of oxytocin (OXT) after acute administration in rodents and humans, the major aims of our study were to assess whether chronic administration of OXT dose-dependently affects the behavior and physiology of male mice, as for therapeutic use in humans, mostly chronic treatment approaches will be used. Further, we studied, whether chronic administration during CSC prevents stress-induced consequences. Our results indicate that chronic intracerebroventricular (ICV) infusion of OXT (15 days) at high (10 ng/h), but not at low (1 ng/h) dose, induces an anxiogenic phenotype with a concomitant reduction of OXT receptor (OXTR) binding within the septum, the basolateral and medial amygdala, as well as the median raphe nucleus. Further, we demonstrate that chronic ICV infusion of OXT (1 ng/h) during a 19-day CSC exposure prevents the hyper-anxiety, thymus atrophy, adrenal hypertrophy, and decreased in vitro adrenal ACTH sensitivity. Thus, given both negative, but also beneficial effects seen after chronic OXT treatment, which appear to be dose-dependent, a deeper understanding of long-lasting treatment effects is required before OXT can be considered for long-term therapeutic use for the treatment of psychopathologies such as autism, schizophrenia or anxiety-disorders.
The time around birth is accompanied by behavioural and physiological adaptations of the maternal brain, which ensure reproductive
functions, maternal care and the survival of the offspring. In ...addition, profound neuroendocrine and neurobiological adaptations
have been described with respect to behavioural and neuroendocrine stress responsiveness in rodents and human mothers. Thus,
the hormonal response of the hypothalamo-pituitary-adrenal (HPA) axis and the response of the sympathetic nervous system to
emotional and physical stressors are severely attenuated. Moreover, anxiety-related behaviour and emotional responsiveness
to stressful stimuli are reduced with the result of general calmness. These complex adaptations of the maternal brain are
likely to be a consequence of an increased activity of brain systems with inhibitory effects on the HPA axis (such as the
oxytocin and prolactin systems) and of a reduced activity of excitatory pathways (noradrenaline (norepinephrine), corticotrophin-releasing
factor and opioids). Experimental manipulation of these systems using complementary approaches indeed demonstrates their importance
in these maternal brain adaptations. Maternal stress adaptations are not only important for the healthy prenatal development
of the offspring by preventing excessive glucocorticoid responses and in the promotion of postnatal maternal behaviour, but
are also vital for the well-being of the mother and her mental health.
•Sex and stress hormones play a dominant role in the neurobiological underpinnings of stress related disorders.•Males and females substantially differ in basal-and stress-induced neurogentic ...processes.•There are gender differences in behavioural responses to drug administration and a variety of cognitive/emotional processes.•There is a lack of studies elucidating sex-specific mechanisms in one experimental outline.
Men and women differ in their vulnerability to a variety of stress-related illnesses, but the underlying neurobiological mechanisms are not well understood. This is likely due to a comparative dearth of neurobiological studies that assess male and female rodents at the same time, while human neuroimaging studies often don’t model sex as a variable of interest. These sex differences are often attributed to the actions of sex hormones, i.e. estrogens, progestogens and androgens. In this review, we summarize the results on sex hormone actions in the hippocampus and seek to bridge the gap between animal models and findings in humans. However, while effects of sex hormones on the hippocampus are largely consistent in animals and humans, methodological differences challenge the comparability of animal and human studies on stress effects. We summarise our current understanding of the neurobiological mechanisms that underlie sex-related differences in behavior and discuss implications for stress-related illnesses.
Social avoidance and social phobia are core symptoms of various psychopathologies but their underlying etiology remains poorly understood. Therefore, this study aims to reveal pro-social effects of ...the neuropeptide oxytocin (OT), under both basal and stress-induced social avoidance conditions in rodents using a social preference paradigm. We initially show that intracerebroventricular (i.c.v.) application of an OT receptor antagonist (OTR-A) in naïve male rats (0.75 μg/5 μl), or mice (20 μg/2 μl), reduced social exploration of a novel con-specific indicative of attenuated social preference. Previous exposure of male rats to a single social defeat resulted in loss of their social preference and social avoidance, which could be restored by i.c.v. infusion of synthetic OT (0.1 μg/5 μl) 20 min before the social preference test. Although the amygdala has been implicated in both social and OT-mediated actions, bilateral OTR-A (0.1 μg/1 μl) or OT (0.01 μg/1 μl) administration into various subnuclei of the amygdala did not affect basal or stress-induced social preference behavior, respectively. Finally, we demonstrate the social specificity of these OT-mediated effects by showing that neither an arginine vasopressin V1a receptor antagonist (0.75 μg/5 μl, i.c.v.) nor the anxiogenic drug pentylenetetrazol (15 mg/kg, i.p.) altered social preference, with OTR-A not affecting non-social anxiety on the elevated plus-maze. Overall, the data indicate that the basal activity of the endogenous brain OT system is sufficient to promote natural occurring social preference in rodents while synthetic OT shows potential to reverse stress-induced social avoidance and might thus be of use for treating social phobia and social dysfunction in humans.
Sex hormones affect structural and functional plasticity in the rodent hippocampus. However, hormone levels not only differ between males and females, but also fluctuate across the female estrous ...cycle. While sex- and cycle-dependent differences in dendritic spine density and morphology have been found in the rodent CA1 region, but not in the CA3 or the dentate gyrus, comparable structural data on CA2, i.e. the hippocampal region involved in social recognition memory, is so far lacking. In this study, we, therefore, used wildtype male and female mice in diestrus or proestrus to analyze spines on dendritic segments from identified CA2 neurons. In basal stratum oriens, we found no differences in spine density, but a significant shift towards larger spine head areas in male mice compared to females. Conversely, in apical stratum radiatum diestrus females had a significantly higher spine density, and females in either cycle stage had a significant shift towards larger spine head areas as compared to males, with diestrus females showing the larger shift. Our results provide further evidence for the sexual dimorphism of hippocampal area CA2, and underscore the importance of considering not only the sex, but also the stage of the estrous cycle when interpreting morphological data.
The metabotropic gamma-aminobutyric acid B (GABAB) receptor was the first described obligate G protein–coupled receptor heterodimer and continues to set the stage for discoveries in G protein–coupled ...receptor signaling complexity. In this review, dedicated to the life and work of Athina Markou, we explore the role of GABAB receptors in depression, reward, and the convergence of these domains in anhedonia, a shared symptom of major depressive disorder and withdrawal from drugs of abuse. GABAB receptor expression and function are enhanced by antidepressants and reduced in animal models of depression. Generally, GABAB receptor antagonists are antidepressant-like and agonists are pro-depressive. Exceptions to this rule likely reflect the differential influence of GABAB1 isoforms in depression-related behavior and neurobiology, including the anhedonic effects of social stress. A wealth of data implicate GABAB receptors in the rewarding effects of drugs of abuse. We focus on nicotine as an example. GABAB receptor activation attenuates, and deactivation enhances, nicotine reward and associated neurobiological changes. In nicotine withdrawal, however, GABAB receptor agonists, antagonists, and positive allosteric modulators enhance anhedonia, perhaps owing to differential effects of GABAB1 isoforms on the dopaminergic system. Nicotine cue–induced reinstatement is more reliably attenuated by GABAB receptor activation. Separation of desirable and undesirable side effects of agonists is achievable with positive allosteric modulators, which are poised to enter clinical studies for drug abuse. GABAB1 isoforms are key to understanding the neurobiology of anhedonia, whereas allosteric modulators may offer a mechanism for targeting specific brain regions and processes associated with reward and depression.
Rationale
Oxytocin (OXT) has been proposed as a potential therapeutic agent for post-traumatic stress disorder (PTSD).
Objectives
We aimed to verify whether pharmacological manipulation of the brain ...OXT system affects cued fear conditioning and fear extinction.
Methods
Male rats and mice were intracerebroventricularly administered synthetic OXT (rats, 0.1 or 1.0 μg/5 μl; mice, 0.1 or 0.5 μg/2 μl) and/or an OXT receptor antagonist (OXTR-A; rats, 0.75 μg/5 μl) either prior to fear conditioning or extinction training.
Results
Preconditioning administration of OXT did not affect fear conditioning in rats, but decreased fear expression and facilitated fear extinction. In contrast, preconditioning blockade of OXT neurotransmission by OXTR-A did not affect fear conditioning or fear expression, but impaired fear extinction. When administered before extinction training, OXT impaired fear extinction in both rats and mice, indicating that the effects of OXT on fear extinction are conserved across species. This impairment was OXTR-mediated, as the inhibitory effect of OXT on fear extinction was abolished by prior treatment with OXTR-A. The impaired fear extinction was not a result of reduced locomotion in rats, whereas an apparent decrease in fear expression and facilitation of fear extinction with the higher OXT dose in mice was the result of behavioral hyperactivity.
Conclusions
These results suggest that increasing OXT neurotransmission during traumatic events is likely to prevent the formation of aversive memories. In contrast, OXT treatment before fear extinction training, which would be the comparable timepoint for psychotherapy in PTSD patients, rather delays fear extinction and, therefore, caution is needed before recommending OXT for the treatment of PTSD.
PDF
