Does Bullying Victimization Accelerate Adolescents' Non-suicidal Self-injury? The Mediating Role of Negation Emotions and The Moderating Role of Submissive Behavior.

Based on general strain theory, the current study examined whether bullying victimization was significantly related to adolescents' non-suicidal self-injury and whether negation emotions mediated this association and submissive behavior moderated this mediation process. A total of 1,984 adolescents completed a series of anonymous questionnaires regarding bullying victimization, negative emotions, non-suicidal self-injury, and submissive behavior. Results showed that bullying victimization was significantly and positively associated with non-suicidal self-injury and this relation was partially mediated by negative emotions. Submissive behavior moderated the relation between bullying victimization and non-suicidal self-injury as well as negation emotions and non-suicidal self-injury. Specifically, the victims of bullying with high submissive behavior were more likely to develop non-suicidal self-injury. Adolescents who had higher negative emotions were at greater risk of engaging in non-suicidal self-injury when they also had high submissive behavior. The positive association between negative emotions and non-suicidal self-injury was stronger in females than males.

Submissive behavior as a transdiagnostic construct: Associations with internalizing symptoms and distress intolerance.

OBJECTIVE: Submissive behavior is associated with significant impairment and negative life outcomes. The goal of the present study was to determine the transdiagnostic nature of submissive behavior by observing its association with internalizing symptoms (i.e., social anxiety, depression, and worry) and distress intolerance. Additionally, we sought to determine the moderating role of gender in these relationships. METHOD: We used a community sample (N = 208) to evaluate the hypothesized relationships between submissive behavior and internalizing symptoms. RESULTS: All three internalizing symptoms were uniquely associated with greater submissive behavior when covarying for each other. Distress intolerance was also uniquely positively related to submissive behavior respective of general distress. Moderation analyses revealed that the associations between social anxiety, worry, and distress intolerance with submissive behavior were stronger in men rather than women. CONCLUSION: The present study provides novel evidence for the relevance of submissive behavior to internalizing symptoms and distress intolerance. We discuss clinical implications and directions for future research.

The Biology of BDSM: A Systematic Review.

INTRODUCTION: BDSM is an abbreviation used to reference the concepts of bondage and discipline, dominance and submission, sadism and masochism, enacted by power exchanges between consensual partners. In recent years, attention has shifted from the idea of BDSM as a pathological and tabooed niche practice towards viewing BDSM as a healthy form of intimacy. AIM: This systematic review brings together all existing literature on the biology of BDSM and places it in a broader biological context. METHODS: A systematic search was conducted on PubMed, Web of Science and PsycARTICLES, of which 10 articles are included and discussed in this systematic review. RESULTS: There is evidence for cortisol changes in submissives as a result of a BDSM interaction, suggesting involvement of the physiological stress system. Endocannabinoid changes implicate the pleasure and reward system. In dominants, this biologically measured pleasure seemed to be dependent on power play rather than pain play. Testosterone and oxytocin are also implicated in BDSM, though their role is less evident. Research into brain region activity patterns related to BDSM interest suggests a role for the parietal operculum and ventral striatum in the context of the pleasure and reward system, the primary and secondary somatosensory cortex in the context of pain perception, empathy-related circuits such as the anterior insula, anterior midcingulate cortex and sensorimotor cortex and the left frontal cortex in the context of social and sexual interactions. Pain thresholds are shown to be higher in submissive individuals and a BDSM interaction may cause pain thresholds to rise in submissives as well. CONCLUSION: BDSM interactions are complex and influenced by several psychological, social and biological processes. Though research is limited, there is emerging evidence for an interaction between several biological systems involved in these types of interests and activities. This means there is an important role for future research to replicate and supplement current results. Wuyts E, Morrens M. The Biology of BDSM: A Systematic Review. J Sex Med 2022;19:144-157.

Beyond Pain: A Study on the Variance of Pain Thresholds Within BDSM Interactions in Dominants and Submissives.

BACKGROUND: BDSM is an acronym describing bondage and discipline, dominance and submission, and sadism and masochism. Afflicting or receiving pain is usually an important part of the BDSM interaction. AIM: This research will focus on better understanding the aspect of pain within a BDSM interaction. METHODS: Submissive and dominant counterparts of 35 couples were recruited to participate in a BDSM interaction, of which 34 dominants and 33 submissives were included in the analyses. A non-BDSM interested control group (n = 27) was included to control for social interaction, of which 24 were included in the analyses. OUTCOMES: This research investigates the differences in (i) baseline pain thresholds, (ii) the impact of a BDSM interaction on those thresholds, and (iii) threshold moderating factors like pain cognition between submissive and dominant BDSM participants and control individuals. RESULTS: BDSM practitioners have a higher pain threshold overall and a BSDM interaction will result in a temporary elevation of pain thresholds for submissives. Additionally, pain thresholds in dominants will be dependent upon their fear of pain and tendency to catastrophize pain and submissives will experience less fear of pain than the control group. CLINICAL IMPLICATIONS: By further enhancing our understanding of the mechanisms behind a BDSM interaction in this way, we aspire to relieve the stigma these practitioners still endure. STRENGTHS & LIMITATIONS: This is one of the first studies of its kind with a large sample size compared to similar research, which makes it a significant contribution to the field. It must be mentioned that there is a possible selection bias because recruitment was only done through the Flemish BDSM community and specifically those who visit clubs. Additionally, pain threshold remains a subjective measurement, which must be taken into account. CONCLUSION: This study helps shed further light on the biological processes behind a BDSM interaction through pain threshold measurements. Wuyts E, De Neef N, Coppens V, et al. Beyond Pain: A Study on the Variance of Pain Thresholds Within BDSM Interactions in Dominants and Submissives. J Sex Med 2021;18:556-564.

Higher levels of submissive behaviors at the onset of the pairing process of rhesus macaques (Macaca mulatta) are associated with lower risk of wounding following introduction.

Social housing of rhesus macaques (Macaca mulatta) is considered to be the cornerstone of behavioral management programs in biomedical facilities. However, it also involves the risk of socially inflicted trauma. The ability to avoid such trauma would contribute to the animals' well-being and alleviate staff's concerns, thus paving the path for more introductions. Here, we sought to address the conflict between the need to socially house rhesus macaques and the need to bring social wounding to a minimum by identifying behaviors expressed early in social introductions, that may serve as predictors of later wounding events. We employed logistic regression analysis to predict the occurrence of wounding for 39 iso-sexual, adult pairs in the 30 days following the introduction into full contact using the levels of behaviors that were observed at the onset of the introduction. The results show that the levels of submissive behaviors were the only significant predictor to later stage wounding. Higher levels of submissive behaviors expressed during the early phases of the introduction were associated with a decreased likelihood of wounding. Interestingly, levels of affiliative behaviors have not added any power to the predictability of the statistical model. Therefore, it may be suggested that the exchange of submissive signals at the earliest stages of the introduction is critical in the determination of relative rank and preclude the need to establish dominance via aggression when allowed full contact. While the observation of clear-cut dominance relationships is commonly considered a harbinger of success, our findings suggest that it is the acknowledgment of subordination, rather than the expression of dominance that underlies this observed pattern. The value of our findings for guiding social housing decision-making may be strongest in situations in which the composition of potential partners is constrained, and therefore requiring that wise decisions be relied upon early behaviors.

Behaviour of Arctic charr Salvelinus alpinus during an induced mating season in captivity: how male relative size influences male behavioural investment and female preference over time.

The behaviour of sexually mature Arctic charr Salvelinus alpinus specimens (fifth farm generation) was observed in captivity for four consecutive days. Only agonistic interactions between males of different size were facilitated on the first 2 days, while both agonistic and courtship interactions were possible from the third day up to the end of the experiment. The reliability of behavioural analysis was assessed in order to reduce the possibility of observer errors within the generated datasets. The behavioural investment of big males, small males and females was analysed using general linear models (two-way repeated measures ANOVAs with time and male size as factors). A peak in the agonistic interactions between males occurred during the first day of interactions, where the agonistic investment of big males was significantly higher than that of small males. This resulted in an increased investment in submissive behaviour by the small males, who consistently performed submissive behaviours from the second day of interactions up to the end of the trial. Big males were found to invest significantly more than small males in courtship behaviours for the duration of the trial. Even though females performed inter-sexual behaviours towards both big and small males for the entire observation period, female interaction rate towards big males was higher than towards small males. This study suggests that both male investment in mating behaviour and female preference might be related to male characteristics such as body length and that S. alpinus behavioural patterns and mate choice cues might be strongly context-related and characterized by high levels of behavioural plasticity (i.e. presence-absence of certain behavioural units or potential reversal of a mate choice cue) within the same species. Finally, in light of this, some conservation measures are discussed. In particular, effective management plans should take into account the high level of behavioural plasticity likely to be occurring in this species.

Are Child Abusers Sexually Attracted to Submissiveness? Assessment of Sex-Related Cognition With the Implicit Association Test.

Child sexual abuse is associated with social anxiety, low self-esteem, and intimacy deficits. This, in combination with the core belief of a dangerous world, might suggest that child abusers are sexually attracted to submissiveness. The Implicit Association Test (IAT) was used to examine this hypothesis. Results indicated that child abusers have a stronger sexual preference for submissiveness than rapists, although there were no differences between child abusers and non-sexual offenders. Multinomial logistic regression analysis revealed that submissive-sexy associations have incremental value over child-sex associations in differentiating child abusers from other offenders. The predictive value of both implicit associations was explored by correlating IAT scores with measures for recidivism risk, aggression, and interpersonal anxiety. Child abusers with stronger child-sex associations reported higher levels of interpersonal anxiety and hostility. More research on implicit cognition in sex offenders is required for a better understanding of what these and similar implicit measures are exactly measuring and what role implicit cognition may play in sexual offending.

Social anxiety, submissiveness, and shame in men and women: a moderated mediation analysis.

OBJECTIVES: Research suggests a positive relationship between social anxiety and shame; however, few studies have examined this relationship or potential mechanisms. Common behaviours of persons with social anxiety disorder (SAD), such as submissive behaviours, may be more consistent with societal expectations of women than men and therefore more likely to be associated with shame in socially anxious men than women. We examined the hypothesis that submissive behaviours would mediate the relationship between social anxiety and shame in men, but not in women, with SAD. DESIGN: Moderated mediation was examined in a cross-sectional dataset. Gender was modeled to moderate the paths from social anxiety to submissive behaviours and from submissive behaviours to shame. We also examined an alternative model of the relationships among these variables and the potential contributory role of depression. METHODS: Men (n = 48) and women (n = 40) with SAD completed the Social Interaction Anxiety Scale, Submissive Behaviour Scale, Internalized Shame Scale, and Beck Depression Inventory. RESULTS: Analyses supported the hypothesized model. The relationship between submissive behaviours and shame was greater in men than women with SAD; the relationship between social anxiety and submissive behaviours was not. Controlling for depression, moderation remained evident although diminished. Results for the comparison model did not support gender moderation. CONCLUSIONS: Submissive behaviours mediated the relationship between social anxiety and shame in men, but not women, with SAD. These findings provide preliminary evidence for a model of shame in SAD and may help to further elucidate specific features of SAD that differ between men and women. PRACTITIONER POINTS: Although researchers have argued that the display of submissive behaviours might allow the socially anxious individual to limit or prevent attacks on the self, our results suggest that there are greater costs, with regard to feelings of shame, associated with such behaviours for men. In men with SAD, the greater shame associated with submissive behaviours can be understood when considering that socially anxious individuals appear to be particularly concerned with concealing aspects of the self believed to violate perceived societal norms and that traditional masculine gender roles revolve around the theme of dominance. Because the study was conducted in individuals with SAD, it is possible that the restricted range of social anxiety severity may have precluded the observation of gender differences in the relationship between social anxiety and submissive behaviour. Measures were administered in a cross-sectional design, which limits potential inferences of causality.

Differences between depression and paranoia: the role of emotional memories, shame and subordination.

UNLABELLED: The present study explores how emotional memories, shame and submissive behaviour in adulthood are differently related to depression and paranoia, in a sample of 255 subjects from the general community population. Results show that emotional memories (especially, shame traumatic memory) are significantly correlated with external and internal shame. Emotional memories are significantly associated with submissive behaviour. Both types of shame are correlated with submissive behaviour, particularly internal shame. Emotional memories, external and internal shame are linked to depressive symptoms. Emotional memories, external and internal shame, and submissive behaviour are significantly related to paranoia. Path analysis results suggested that (1) shame traumatic memory and recall of threat and submissiveness in childhood predicted depressive symptoms through external and internal shame; (2) early emotional memories of shame, threat and submissiveness predicted paranoid ideation both directly and indirectly, through external shame; and (3) emotional memories impact on paranoid ideation both through their effect upon external shame and also through their indirect effect upon submission, which in turn fully mediates the effect of internal shame upon paranoid ideation. These findings highlight the differences between depression and paranoia. In depression, it is the internalization of early experiences of shame, threat and submissiveness that heighten the vulnerability to depressive states. In paranoia, not only shame traumas and recollections of threat and submissiveness directly influence paranoid beliefs but also these memories promote external and internal shame thoughts and feelings and submissive defenses, which in turn increase paranoid ideation. KEY PRACTITIONER MESSAGE: Individuals with shame traumas, threat and submissiveness experiences in childhood and high levels of external and internal shame report more depressive symptoms. High levels of paranoid beliefs are associated with high negative emotional memories, external and internal shame thoughts and feelings, and submissive behaviour defenses. Therapy for depression needs to incorporate strategies that help individuals develop skills to deal with shame experiences and its outputs. Treatment for paranoid ideation must address external and internal shame, as well as emotional memories of shame, threat and submissiveness in childhood and development of assertive skills.

Fluctuations of testosterone and cortisol levels in male dromedary camels in response to behavioral and management situations.

Background: Biostimulation is a management practice that improves the reproductive parameters, potentiates the desire, and improves the reproductive efficiency during the short breeding season in camels. Aim: This study aims to investigate the concurrent changes in hormonal profiles in response to management and behavioral situations on camel farms in the Eastern region of Saudi Arabia. Methods: A total of 10 male and 50 female camels were used in this study. The hormonal profile of male camels was evaluated weekly starting from December to August. Results: The results show that both serum testosterone and cortisol levels increased (p < 0.01) from December to March compared to April to August. A strong negative correlation was observed between testosterone levels and temperature (r = -0.81, p < 0.05), and a similarly robust negative correlation was found between cortisol levels and temperature (r = -0.83, p < 0.05). The dominant rutting males showed higher levels of testosterone than the submissive males. Serum testosterone levels increased (p < 0.01) in males out of rutting after hearing the sounds of other couples before and during mating. Conclusion: Hearing sounds emitted during mating increases the testosterone output, and improves the libido of male camels during the nonrutting period. It is important to keep two individually housed males for mating purposes. One male joins the herd alone in winter (winter rutter), and the other joins in spring (spring rutter), this could keep the libido extended rutting and improve the reproductive performance in camel herds.

Mutual eye gaze and vocal pitch in relation to social anxiety and depression: A virtual interaction task.

BACKGROUND: Individuals with high social interaction anxiety (SIA) and depression often behave submissively in social settings. Few studies have simultaneously examined the associations between objectively assessed submissive behaviors and SIA or depression, despite their high comorbidity and unknown mechanisms regarding submissiveness. METHODS: A sample of 45 young adults self-reported trait SIA and depression, state positive/negative affect (PA/NA) before and after a virtual social interaction. Participants engaged in a four-minute conversation with a confederate who was trained to behave neutrally. Mutual eye gaze, via eye-tracking, and vocal pitch were assessed throughout the interaction. RESULTS: Depression and SIA were positively correlated with NA, poorer self-rated performance, and vocal pitch. Highly socially anxious women engaged in less mutual eye gaze than highly socially anxious men. Also, vocal pitch was inversely associated with mutual eye gaze and positively related to NA and (nonsignificantly) to self-ratings of poor performance. Finally, our data partially replicated past research on the use of vocal pitch during social stress to detect social anxiety disorder. LIMITATIONS: The current sample is relatively homogenous in educational attainment, age, and race. All research confederates were women. Future research should examine whether these archival data replicate with the latest telecommunication technologies. CONCLUSION: Our findings highlight nuanced relationships among SIA, depression, emotions, self-perceptions, and biobehavioral indicators of submissive behavior-in response to an ambiguously negative/positive social interaction. Sex/gender may interact with these effects, emphasizing considerations for research method designs.

Are Users Good Assessors of Social Dominance in Domestic Horses?

Horse users and caretakers must be aware of the risks of mixing social groups. The current study investigated whether eight equine practitioners can assess the social dominance rank of 20 horses. The horses' feeding time and agonistic/aggressive and submissive behaviours were observed during the feed confrontation test, and the dominance index (DI) was calculated. Kendal's W, Spearman correlations and factor analysis were applied to test the raters' agreement, the relationship between dominance ranks and the behavioural variables, and to determine the clustered behaviours. The agreement between all raters in the classification of dominance order ranged from moderate to perfect. The ranking by every rater was strongly and negatively correlated with the time of eating in feed confrontation tests and with the DI, evidencing shorter feeding times for more submissive horses. The withdrawal of the horse when threatened was the behavioural variable that was most often correlated with raters' ranking. The current study confirmed the abilities of practitioners to categorise the horses under their care according to their social interactions. Additionally, rolling when denied access to feed was proposed as frustration-releasing (redirected) behaviour.

Benefits but not the dual functions of submissive signals differ between two Malagasy primates.

Many animals use formalized signals to communicate dominance relationships. In some primates, such as macaques, the function of such signals varies with dominance style. Despotic species produce unidirectional submission signals that have a dual function: in conflict contexts, they signal a willingness to withdraw, whereas in peaceful contexts, they indicate the agreement to subordination. More despotic species produce these calls to a lesser extent than less despotic species. Here, we investigated whether the use of unidirectional submission signals is also related to dominance style in two lemur species and whether signalling subordination stabilizes social relationships at the group level. Ring-tailed lemurs (Lemur catta) exhibit a more despotic dominance hierarchy than Verreaux's sifakas (Propithecus verreauxi). We observed social interactions in 75 dyads of Verreaux's sifakas and 118 dyads of ring-tailed lemurs. Both species used unidirectional submissive calls that have a dual function, potentially suggesting convergent evolution of the function of these signals in independent primate lineages. However, signalling subordination did not stabilize social relationships at the group level in both species. Additionally, subordination occurred more frequently in dyads of the more despotic ring-tailed lemurs than in Verreaux's sifakas, indicating opposite patterns to macaques in the coevolution of social traits with dominance style. This article is part of the theme issue 'The power of sound: unravelling how acoustic communication shapes group dynamics'.

The role of serotonin in modulating social competence in a cooperatively breeding fish.

Behavioural interactions between conspecifics rely on the appreciation of social cues, which is achieved through biochemical switching of pre-existing neurophysiological pathways. Serotonin is one of the major neurotransmitters in the central nervous system responsible for the modulation of physiological and behavioural traits, in particular social behaviour. The relative importance of serotonin in modulating optimal social responses to the available social information (i.e., social competence) is yet unknown. Here we investigate how serotonin and the serotonin 1 A receptor (5-HT1A) modulate social competence in a competitive context. In the cooperatively breeding cichlid Neolamprologus pulcher, we pharmacologically manipulated the serotonin availability and 5-HT1A activity to test their effects on social behaviours during an asymmetric contest between the owner of a defended territory containing a shelter and an intruder devoid of a territory. In this contest, the adequate response by the intruders, the focal individuals in our study, is to show submissive behaviour in order to avoid eviction from the vicinity of the shelter. While the serotonin enhancer Fluoxetine did not affect the frequency of submission towards territory owners, reducing serotonin by a low dosage of 4-Chloro-DL-phenylalanine (PCPA) increased submissive behaviour. Furthermore, threat displays towards territory owners were reduced at high dosages of Fluoxetine and also at the lowest dosage of PCPA. 5-HT1A activation increased threat displays by intruders, indicating that this receptor may not be involved in regulating social competence. We conclude that serotonin, but not its receptor 5-HT1A plays an important role in the regulation of social competence.

Potential roles of arginine-vasotocin in the regulation of aggressive behavior in the mudskipper (Periophthalmus modestus).

The hypothalamic hormones, arginine-vasotocin (VT) and isotocin (IT), play central roles in osmoregulation and in the regulation of social behaviors including aggressive behavior in many vertebrates including fish. Here, we examined whether these hormones are associated with aggressive behavior in the mudskipper (Periophthalmus modestus). The mudskipper is an amphibious fish, which lives in the brackish water of river mouths and displays unique aggressive behavior. Upon introduction to each other in an experimental tank with aquatic and terrestrial areas, a pair of males can be classified as aggressive dominant or submissive subordinate based on the frequency of their aggressive acts, which is significantly higher in dominant male. Additionally, the length of stay in terrestrial area of dominant was longer than that of the subordinate. The latter remained in aquatic area almost throughout the period of behavioral observation. The expression of brain VT mRNA was significantly higher in subordinate than in dominant, whereas neither IT mRNA expression nor plasma cortisol level differed between subordinate and dominant male. On the other hand, an intracerebroventricular injection of VT increased aggressive behaviors in mudskippers. In addition to known roles of VT in mediation of aggressive behavior, these results may shed light on the role of endogenous VT toward water migration in submissive mudskippers. The amphibious fish is a valuable experimental model to observe the relationship between effects of central VT on the osmoregulation and social behavioral regulation in vertebrates.

Psychometric evaluation and validation of Urdu Social Rank Scale for women with infertility in Pakistan.

Background: Infertility negatively affects nearly all aspects of women's life and is a source of demotion in the rank/status of women that they have achieved after marriage. This social rank/status demotion due to infertility may result in depression and several other psychopathologies. No extant instrument is available to measure the phenomenon of social rank in women with infertility in Pakistan. Objective: The aim of the current study was to evaluate the psychometric properties and validate the Social Rank Scale for women experiencing infertility in Pakistan. Methodology: This study was conducted in four phases. The data were collected from women with primary infertility who visited hospitals all over Pakistan from 2016 to 2018. Social Rank Scale for Women with Infertility (SRS-WI) comprising of two scales, the Social Comparison Scale for Women with Infertility (SCS-WI) and the Submissive Behavior Scale for Women with Infertility (SBS-WI), was developed. Results: The factor structure of 37 items of SCS-WI and of 21 items of SBS-WI was determined through exploratory factor analysis (EFA) on a sample of 215 women with primary infertility with an age range of 20-45 years (Mage = 31.03; SD = 6.18). Principal component analysis with varimax rotation method yielded a three-factor solution for SCS-WI, and 32 items were retained for SCS-WI that accounted for 62.38% variance. For SBS-WI, a uni-factor solution was obtained, and 20 items were retained for SBS-WI, which collectively accounted for 42.01% variance. The factor structure for both scales was confirmed via confirmatory factor analysis among a sample of 210 participants with good model fit indices. Conclusion: The study provides acceptable psychometric properties of the SRS-WI in Pakistan. Testing of psychometric properties in different groups of samples would justify the generalized use of the instrument.

"Classifying D/s Profiles Without Prior Assumptions: An Application of Cluster Analysis to Social Data".

Dominant/submissive role-play (D/s) is associated with specialized roles including Mistress, Master, Slave, Switch, Sadist, and Masochist. The current study uses cluster analysis to provide empirical evidence that no binary opposition or single spectrum constitutes a workable typology of individuals based on their affinities for these roles. The optimality of a particular choice of clustering scheme, including the number of clusters, is established using a replication technique which is presented in detail. A large number (n = 236,353) of individualized results (profiles) generated by the BDSM Test, a popular anonymous web survey, were analyzed. We hypothesize a two-dimensional typology of D/s profiles as the inferential result of our cluster analyses.

Introduction to defensive behavior in vertebrates.

In this introductory chapter we describe the ethological basis of defensive behavior, including tonic immobility (TI). The defensive repertoire activated in response to threatening stimuli, both in natural and experimental conditions, consists of a system of interrelated behaviors influenced by two main dimensions, as distance from the threat and escapable/inescapable context. When the active strategy of escape is not feasible, passive immobility forms are adopted, the latter representing substitutes of actual escape. In an inescapable context, and at very short distance or in contact with the threatening stimulus, TI is adopted, or submissive posture in a social context. Physical restraint represents the strongest stimulus for TI induction. As a result of behavioral flexibility, subsets of animals within a population show a different capacity and modality to cope with aversive stimuli (animal personality). TI can be regarded as a trait of behavioral syndromes in species as mammals and avians.

Ropanicant (SUVN-911), an α4ß2 nicotinic acetylcholine receptor antagonist intended for the treatment of depressive disorders: pharmacological, behavioral, and neurochemical characterization.

RATIONALE: Ropanicant (SUVN-911) (3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo (3.1.0) hexane hydrochloride) is a novel α4ß2 nicotinic acetylcholine receptor (nAChR) antagonist being developed for the treatment of depressive disorders. OBJECTIVES: Pharmacological and neurochemical characterization of Ropanicant to support a potential molecule for the treatment of depressive disorders. METHODS: Ropanicant was assessed for antidepressant-like activity using the rat forced swimming test (FST) and differential reinforcement of low rate -72 s (DRL-72 s). Alleviation of anhedonia was assessed in chronic mild stress model using sucrose preference test. To understand the mechanism of action, serotonin levels, ionized calcium-binding adaptor molecule 1 (Iba1), and brain-derived neurotrophic factor (BDNF) were determined. The onset of antidepressant-like activity was determined using the reduction in submissive behavior assay. The effects on cognition and sexual functions were assessed using the object recognition task and sexual dysfunction assay respectively. Interaction of Ropanicant, TC-5214, and methyllycaconitine (MLA) with citalopram was investigated individually in mice FST. RESULTS: Ropanicant exhibited antidepressant like properties in the FST and DRL-72 s. A significant reduction in anhedonia was observed in the sucrose preference test. Oral administration of Ropanicant produced a significant increase in serotonin and BDNF levels, with a reduction in the Iba1 activity. The onset of antidepressant like effect with Ropanicant was within a week of treatment, and was devoid of cognitive dulling and sexual dysfunction. While Ropanicant potentiated the effect of citalopram in FST, such an effect was not observed with MLA or TC-5214. CONCLUSIONS: Preclinical studies with Ropanicant support the likelihood of its therapeutic utility in the treatment of depressive disorders.

TAK-653, an AMPA receptor potentiator with minimal agonistic activity, produces an antidepressant-like effect with a favorable safety profile in rats.

The N-methyl-d-aspartate receptor antagonist, ketamine, exhibits rapid and sustained antidepressant activity in patients with treatment-resistant depression (TRD), but its use is associated with psychotomimetic side effects. Evidence has suggested that the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors followed by activation of the mechanistic target of rapamycin (mTOR) signaling pathway and production of brain derived neurotrophic factor (BDNF) protein may underlie the antidepressant efficacy of ketamine. In this study, we characterized the antidepressant-like effects of TAK-653, a novel AMPA receptor potentiator with virtually no agonistic activity. In rat primary cortical neurons, TAK-653 significantly increased phosphorylated and activated forms of mTOR and p70S6 kinase and their upstream regulators Akt and extracellular signal-regulated kinase (ERK). TAK-653 also significantly increased BDNF protein levels in rat primary cortical neurons. Ketamine at 30 mg/kg, i.p. produced antidepressant-like effects in the reduction of submissive behavior model (RSBM) in rats. Ketamine's antidepressant-like effect was blocked by pretreatment with the AMPA receptor antagonist NBQX at 10 mg/kg, i.p., indicating the essential role of AMPA receptor activation in the antidepressant-like effect of ketamine. Consistent with this finding, a sub-chronic administration of TAK-653 for 6 days produced significant antidepressant-like effect in the rat RSBM. Unlike ketamine, however, TAK-653 did not induce a hyperlocomotor response in rats, which is a behavioral index associated with psychotomimetic side effects in humans. TAK-653 may be a promising drug for the treatment of major depressive disorders including TRD with the potential for an improved safety profile compared with ketamine.