Classical and non-classical psychedelic drugs induce common network changes in human cortex.

The neurobiology of the psychedelic experience is not fully understood. Identifying common brain network changes induced by both classical (i.e., acting at the 5-HT2 receptor) and non-classical psychedelics would provide mechanistic insight into state-specific characteristics. We analyzed whole-brain functional connectivity based on resting-state fMRI data in humans, acquired before and during the administration of nitrous oxide, ketamine, and lysergic acid diethylamide. We report that, despite distinct molecular mechanisms and modes of delivery, all three psychedelics reduced within-network functional connectivity and enhanced between-network functional connectivity. More specifically, all three drugs increased connectivity between right temporoparietal junction and bilateral intraparietal sulcus as well as between precuneus and left intraparietal sulcus. These regions fall within the posterior cortical "hot zone," posited to mediate the qualitative aspects of experience. Thus, both classical and non-classical psychedelics modulate networks within an area of known relevance for consciousness, identifying a biologically plausible candidate for their subjective effects.

WASh multicentre randomised controlled trial: water-assisted sigmoidoscopy in English NHS bowel scope screening.

OBJECTIVES: The English Bowel Cancer Screening Programme invites 55 year olds for a sigmoidoscopy (Bowel Scope Screening (BSS)), aiming to resect premalignant polyps, thus reducing cancer incidence. A national patient survey indicated higher procedural pain than anticipated, potentially impacting on screening compliance and effectiveness. We aimed to assess whether water-assisted sigmoidoscopy (WAS), as opposed to standard CO2 technique, improved procedural pain and detection of adenomatous polyps. DESIGN: The WASh (Water-Assisted Sigmoidoscopy) trial was a multicentre, single-blind, randomised control trial for people undergoing BSS. Participants were randomised to either receive WAS or CO2 from five sites across England. The primary outcome measure was patient-reported moderate/severe pain, as assessed by patients on a standard Likert scale post procedure prior to discharge. The key secondary outcome was adenoma detection rate (ADR). The costs of each technique were also measured. RESULTS: 1123 participants (50% women, mean age 55) were randomised (561 WAS, 562 CO2). We found no difference in patient-reported moderate/severe pain between WAS and CO2 (14% in WAS, 15% in CO2; p=0.47). ADR was 15% in the CO2 arm and 11% in the WAS arm (p=0.03); however, it remained above the minimum national performance standard in both arms. There was no statistical difference in mean number of adenomas nor overall polyp detection rate. There was negligible cost difference between the two techniques. CONCLUSION: In the context of enema-prepared unsedated screening sigmoidoscopies performed by screening-accredited endoscopists, no difference in patient-reported pain was seen when using either a CO2 or WAS intubation technique. TRIAL REGISTRATION NUMBER: ISRCTN81466870.

Altered network architecture of functional brain communities in chronic nociplastic pain.

Neuroimaging has enhanced our understanding of the neural correlates of pain. Yet, how neural circuits interact and contribute to persistent pain remain largely unknown. Here, we investigate the mesoscale organization of the brain through intrinsic functional communities generated from resting state functional MRI data from two independent datasets, a discovery cohort of 43 Fibromyalgia (FM) patients and 20 healthy controls (HC) as well as a replication sample of 34 FM patients and 21 HC. Using normalized mutual information, we found that the global network architecture in chronic pain patients is less stable (more variable). Subsequent analyses of node community assignment revealed the composition of the communities differed between FM and HC. Furthermore, differences in network organization were associated with the changes in the composition of communities between patients with varying levels of clinical pain. Together, this work demonstrates that intrinsic network communities differ substantially between patients with FM and controls. These differences may represent a novel aspect of the pathophysiology of chronic nociplastic pain.

Functional and structural magnetic resonance imaging correlates of fatigue in patients with rheumatoid arthritis.

OBJECTIVES: Fatigue is a major burden among patients with RA, yet is poorly understood. We sought to conduct the first imaging study to investigate the neurobiological correlates of fatigue in RA and to improve upon the methodological limitations of previous neuroimaging studies that have investigated this symptom in other populations. METHODS: Chronically fatigued RA patients were clinically characterized before undertaking a combined functional and structural mode MRI brain scan. The functional sequences were acquired during a fatigue-evoking task, then network-to-whole-brain analyses were undertaken. The structural analyses employed voxel-based morphometry in order to quantify regional grey matter volume. The scan was repeated 6 months later to test reproducibility. RESULTS: Fifty-four participants attended both scans [n = 41 female; baseline mean (s.d.) age 54.94 (11.41) years]. A number of significant functional and structural neural imaging correlates of fatigue were identified. Notably, patients who reported higher levels of fatigue demonstrated higher levels of functional connectivity between the Dorsal Attention Network and medial prefrontal gyri, a finding that was reproduced in the repeat scans. Structurally, greater putamen grey matter volumes significantly correlated with greater levels of fatigue. CONCLUSION: Fatigue in RA is associated with functional and structural MRI changes in the brain. The newly identified and reproduced neural imaging correlates provide a basis for future targeting and stratification of this key patient priority.

Sex-dependent effects of social isolation on the regulation of arginine-vasopressin (AVP) V1a, oxytocin (OT) and serotonin (5HT) 1a receptor binding and aggression.

It is widely held that social isolation produces higher rates of mortality and morbidity and has deleterious effects on an individual's sociality. Relatedly, it is widely observed that socially isolated adult rodents display significantly higher levels of aggression when placed in a social situation than do their conspecifics living in social groups. In the following study, we investigated the effects of social isolation on several neurochemical signals that play key roles in the regulation of social behavior in adults. More specifically, we examined the effects of social isolation on vasopressin (AVP) V1a, oxytocin (OT) and serotonin (5-HT)1a receptor binding within the neural circuit controlling social behavior. Male and female Syrian hamsters were housed individually or with two other hamsters for four weeks and were then tested with a same-sex nonaggressive intruder in a neutral arena for 5 min. Social isolation significantly increased aggression in both males and females and altered receptor binding in several brain regions in a sex-dependent manner. For example, V1a receptor binding was greater in socially isolated males in the anterior hypothalamus than it was in any other group. Taken together, these data provide substantial new support for the proposition that the social environment can have a significant impact on the structural and neurochemical mechanisms regulating social behavior and that the amount and type of social interactions can produce differential effects on the circuit regulating social behavior in a sex-dependent manner.

Serotonin and arginine-vasopressin mediate sex differences in the regulation of dominance and aggression by the social brain.

There are profound sex differences in the incidence of many psychiatric disorders. Although these disorders are frequently linked to social stress and to deficits in social engagement, little is known about sex differences in the neural mechanisms that underlie these phenomena. Phenotypes characterized by dominance, competitive aggression, and active coping strategies appear to be more resilient to psychiatric disorders such as posttraumatic stress disorder (PTSD) compared with those characterized by subordinate status and the lack of aggressiveness. Here, we report that serotonin (5-HT) and arginine-vasopressin (AVP) act in opposite ways in the hypothalamus to regulate dominance and aggression in females and males. Hypothalamic injection of a 5-HT1a agonist stimulated aggression in female hamsters and inhibited aggression in males, whereas injection of AVP inhibited aggression in females and stimulated aggression in males. Striking sex differences were also identified in the neural mechanisms regulating dominance. Acquisition of dominance was associated with activation of 5-HT neurons within the dorsal raphe in females and activation of hypothalamic AVP neurons in males. These data strongly indicate that there are fundamental sex differences in the neural regulation of dominance and aggression. Further, because systemically administered fluoxetine increased aggression in females and substantially reduced aggression in males, there may be substantial gender differences in the clinical efficacy of commonly prescribed 5-HT-active drugs such as selective 5-HT reuptake inhibitors. These data suggest that the treatment of psychiatric disorders such as PTSD may be more effective with the use of 5-HT-targeted drugs in females and AVP-targeted drugs in males.

Oxytocin (OT) and arginine-vasopressin (AVP) act on OT receptors and not AVP V1a receptors to enhance social recognition in adult Syrian hamsters (Mesocricetus auratus).

Social recognition is a fundamental requirement for all forms of social relationships. A majority of studies investigating the neural mechanisms underlying social recognition in rodents have investigated relatively neutral social stimuli such as juveniles or ovariectomized females over short time intervals (e.g., 2h). The present study developed a new testing model to study social recognition among adult males using a potent social stimulus. Flank gland odors are used extensively in social communication in Syrian hamsters and convey important information such as dominance status. We found that the recognition of flank gland odors after a 3min exposure lasted for at least 24h, substantially longer than the recognition of other social cues in rats and mice. Intracerebroventricular injections of OT and AVP prolonged the recognition of flank gland odor for up to 48h. Selective OTR but not V1aR agonists, mimicked these enhancing effects of OT and AVP. Similarly, selective OTR but not V1aR antagonists blocked recognition of the odors after 20min. In contrast, the recognition of non-social stimuli was not blocked by either the OTR or the V1aR antagonists. Our findings suggest both OT and AVP enhance social recognition via acting on OTRs and not V1aRs and that the recognition enhancing effects of OT and AVP are limited to social stimuli.

Sustained activation of GABAA receptors in the suprachiasmatic nucleus mediates light-induced phase delays of the circadian clock: a novel function of ionotropic receptors.

The suprachiasmatic nucleus (SCN) contains a circadian clock that generates endogenous rhythmicity and entrains that rhythmicity with the day-night cycle. The neurochemical events that transduce photic input within the SCN and mediate entrainment by resetting the molecular clock have yet to be defined. Because GABA is contained in nearly all SCN neurons we tested the hypothesis that GABA serves as this signal in studies employing Syrian hamsters (Mesocricetus auratus). Activation of GABAA receptors was found to be necessary and sufficient for light to induce phase delays of the clock. Remarkably, the sustained activation of GABAA receptors for more than three consecutive hours was necessary to phase-delay the clock. The duration of GABAA receptor activation required to induce phase delays would not have been predicted by either the prevalent theory of circadian entrainment or by expectations regarding the duration of ionotropic receptor activation necessary to produce functional responses. Taken together, these data identify a novel neurochemical mechanism essential for phase-delaying the 'master' circadian clock within the SCN as well as identifying an unprecedented action of an amino acid neurotransmitter involving the sustained activation of ionotropic receptors.

Temporal Summation but Not Expectations of Pain Relief Predict Response to Acupuncture Treatment in Fibromyalgia.

Fibromyalgia (FM) is a common chronic pain condition for which acupuncture treatment is increasingly utilized. However, there is no universally accepted measure to predict whether a specific patient will benefit from acupuncture. This is a single-center, single-blind, sham-controlled, randomized, noncrossover, longitudinal trial of 76 subjects with FM, assigned to either electroacupuncture (EA) or a placebo control, mock laser (ML) acupuncture. Outcome measures included clinical pain severity (Brief Pain Inventory [BPI]), degree of nociplastic pain (Fibromyalgia Survey Questionnaire), and pressure pain tolerance (PPtol). Baseline measures of temporal summation of pain and expectations for treatment relief were used as predictors. Individuals in both treatment groups experienced significant reductions in BPI (EA: P < .001, ML: P = .018) and Fibromyalgia Survey Questionnaire (EA: P = .032, ML: P = .002) after treatment; however, neither group showed a significant increase in PPtol. Lower temporal summation at baseline was correlated with greater post-treatment improvement in BPI in the EA group (rho = .389, P = .025) but not in the ML group (rho = -.272, P = .109). Lower-baseline temporal summation was correlated with greater decreases in PPtol following EA (rho = .400, P = .040), whereas the opposite was seen for ML (rho = -.562, P = .001). Treatment expectancy at baseline was not correlated with any outcome after EA or ML treatments. Our results support using a quantitative sensory testing metric, temporal summation of pain, but not expectations, to predict analgesia following acupuncture treatment for pain. PERSPECTIVE: A randomized study of acupuncture in FM found baseline temporal summation, but not expectations of pain relief, to be predictive of treatment response. CLINICAL TRIAL REGISTRATION: Registered under ClinicalTrials.gov identifier NCT02064296.

Large-scale momentary brain co-activation patterns are associated with hyperalgesia and mediate focal neurochemistry and cross-network functional connectivity in fibromyalgia.

ABSTRACT: Fibromyalgia has been characterized by augmented cross-network functional communication between the brain's sensorimotor, default mode, and attentional (salience/ventral and dorsal) networks. However, the underlying mechanisms of these aberrant communication patterns are unknown. In this study, we sought to understand large-scale topographic patterns at instantaneous timepoints, known as co-activation patterns (CAPs). We found that a sustained pressure pain challenge temporally modulated the occurrence of CAPs. Using proton magnetic resonance spectroscopy, we found that greater basal excitatory over inhibitory neurotransmitter levels within the anterior insula orchestrated higher cross-network connectivity between the anterior insula and the default mode network through lower occurrence of a CAP encompassing the attentional networks during sustained pain. Moreover, we found that hyperalgesia in fibromyalgia was mediated through increased occurrence of a CAP encompassing the sensorimotor network during sustained pain. In conclusion, this study elucidates the role of momentary large-scale topographic brain patterns in shaping noxious information in patients with fibromyalgia, while laying the groundwork for using precise spatiotemporal dynamics of the brain for the potential development of therapeutics.

Psychedelic concentrations of nitrous oxide reduce functional differentiation in frontoparietal and somatomotor cortical networks.

Despite the longstanding use of nitrous oxide and descriptions of its psychological effects more than a century ago, there is a paucity of neurobiological investigation of associated psychedelic experiences. We measure the brain's functional geometry (through analysis of cortical gradients) and temporal dynamics (through analysis of co-activation patterns) using human resting-state functional magnetic resonance imaging data acquired before and during administration of 35% nitrous oxide. Both analyses demonstrate that nitrous oxide reduces functional differentiation in frontoparietal and somatomotor networks. Importantly, the subjective psychedelic experience induced by nitrous oxide is inversely correlated with the degree of functional differentiation. Thus, like classical psychedelics acting on serotonin receptors, nitrous oxide flattens the functional geometry of the cortex and disrupts temporal dynamics in association with psychoactive effects.

Association of Inflammation With Pronociceptive Brain Connections in Rheumatoid Arthritis Patients With Concomitant Fibromyalgia.

OBJECTIVE: Rheumatoid arthritis (RA) patients with concomitant fibromyalgia (FM) exhibit alterations in brain connectivity synonymous with central sensitization. This study was undertaken to investigate how peripheral inflammation, the principal nociceptive stimulus in RA, interacts with brain connectivity in RA patients with FM. METHODS: RA patients with concomitant FM and those without FM (FM+ and FM-, respectively; n = 27 per group) underwent functional connectivity magnetic resonance imaging. Seed-to-whole-brain functional connectivity analyses were conducted using seeds from the left mid/posterior insula and left inferior parietal lobule (IPL), which are regions that have been previously linked to FM symptoms and inflammation, respectively. The association between functional connectivity and erythrocyte sedimentation rate (ESR) was assessed in each group separately, followed by post hoc analyses to test for interaction effects. Cluster-level, family-wise error (FWE) rates were considered significant if the P value was less than 0.05. RESULTS: The group of RA patients with FM and those without FM did not differ by age, sex, or ESR (P > 0.2). In FM+ RA patients, increased functional connectivity of the insula-left IPL, left IPL-dorsal anterior cingulate, and left IPL-medial prefrontal cortex regions correlated with higher levels of ESR (all FWE-corrected P < 0.05). Post hoc interaction analyses largely confirmed the relationship between ESR and connectivity changes as FM scores increased. CONCLUSION: We report the first neurobiologic evidence that FM in RA may be linked to peripheral inflammation via pronociceptive patterns of brain connectivity. In patients with such "bottom-up" pain centralization, concomitant symptoms may partially respond to antiinflammatory treatments.

Social experience and sex-dependent regulation of aggression in the lateral septum by extrasynaptic δGABAA receptors.

RATIONALE: Understanding the neurobiological mechanisms mediating dominance and competitive aggression is essential to understanding the development and treatment of various psychiatric disorders. Previous research suggests that these mechanisms are both sexually differentiated and influenced substantially by social experience. In numerous species, GABAA receptors in the lateral septum have been shown to play a significant role in aggression in males. However, very little is known about the role of these GABAA receptors in female aggression, the role of social experience on GABAA receptor-mediated aggression, or the roles of different GABAA subtypes in regulating aggression. OBJECTIVES: Thus, in the following set of experiments, we determined the role of social experience in modulating GABAA receptor-induced aggression in both male and female Syrian hamsters, with a particular focus on the GABAA receptor subtype mediating these effects. RESULTS: Activation of GABAA receptors in the dorsal lateral septum increased aggression in both males and females. Social housing, however, significantly decreased the ability of GABAA receptor activation to induce aggression in males but not females. No significant differences were observed in the effects of GABAA receptor activation in dominant versus subordinate group-housed hamsters. Finally, examination of potential GABAA receptor subtype specificity revealed that social housing decreased the ratio of δ extrasynaptic to γ2 synaptic subunit GABAA receptor mRNA expression in the anterior dorsal lateral septum, while activation of δ extrasynaptic, but not γ2 synaptic, GABAA receptors in the dorsal lateral septum increased aggression. CONCLUSIONS: These data suggest that social experience can have profound effects on the neuronal mechanisms mediating aggression, especially in males, and that δ extrasynaptic GABAA receptors may be an important therapeutic target in disorders characterized by high levels of aggression.

Functional and neurochemical disruptions of brain hub topology in chronic pain.

A critical component of brain network architecture is a robust hub structure, wherein hub regions facilitate efficient information integration by occupying highly connected and functionally central roles in the network. Across a wide range of neurological disorders, hub brain regions seem to be disrupted, and the character of this disruption can yield insights into the pathophysiology of these disorders. We applied a brain network-based approach to examine hub topology in fibromyalgia, a chronic pain condition with prominent central nervous system involvement. Resting state functional magnetic resonance imaging data from 40 fibromyalgia patients and 46 healthy volunteers, and a small validation cohort of 11 fibromyalgia patients, were analyzed using graph theoretical techniques to model connections between 264 brain regions. In fibromyalgia, the anterior insulae functioned as hubs and were members of the rich club, a highly interconnected nexus of hubs. In fibromyalgia, rich-club membership varied with the intensity of clinical pain: the posterior insula, primary somatosensory, and motor cortices belonged to the rich club only in patients with the highest pain intensity. Furthermore, the eigenvector centrality (a measure of how connected a region is to other highly connected regions) of the posterior insula positively correlated with clinical pain and mediated the relationship between glutamate + glutamine (assessed by proton magnetic resonance spectroscopy) within this structure and the patient's clinical pain report. Together, these findings reveal altered hub topology in fibromyalgia and demonstrate, for the first time to our knowledge, a neurochemical basis for altered hub strength and its relationship to the perception of pain.

The WASh Trial: water-assisted sigmoidoscopy in the English Bowel Scope Screening Programme: study protocol for a randomized multicenter trial.

Background and study aims The English National Bowel Scope Screening Programme (BSSP) invites 55-year-olds for a one-off, unsedated flexible sigmoidoscopy (FSIG). Data from BSSP participant-reported experience studies shows 1 in 3 participants report moderate or severe discomfort. Water-assisted colonoscopy (WAS) may improve participants' comfort. The primary objective of this study is to ascertain if post-procedural participant-assessed pain is reduced in WAS compared with carbon dioxide (CO 2 ) insufflation, in invitees undergoing FSIG in BSSP. Patients and methods This is a multicenter, prospective, randomized, two-arm, single-blinded trial designed to evaluate the performance of WAS versus CO 2 insufflation in BSSP. Participants will be randomized to either CO 2 or WAS and will be asked to rate pain post-procedure. Key procedure-related data will be analyzed, including adenoma detection rates (ADR) and degree of sigmoid looping. A cost-effectiveness analysis of WAS versus CO 2 and a discrete choice experiment exploring preferences of participants for attributes of sigmoidoscopy will also be performed. Discussion This is the first trial in the United Kingdom (UK) to investigate the effects of WAS in a screening setting. If the trial shows WAS either reduces pain or increases ADR, this may result in a practice change to implement WAS in screening and non-screening endoscopic practice directly impacting on 256,000 people a year who will undergo BSSP FSIG by 2020. Trial funding came from National Institute for Health Research (NIHR) Research for Patient Benefit (RfPB) supported by the NIHR Clinical Research Network. The trial is actively recruiting. ID: 35866 ISRCTN: 81466870.

Illuminating the health and safety of luminol.

Luminol is a reagent that is used to enhance areas of non-visible bloodstaining and it is one of the most sensitive of such reagents available to the forensic scientist. However, its use, particularly within the UK and some other European countries, has been limited, predominantly due to concerns about the health and safety of the reagent. This paper reviews the literature currently available regarding the health and safety of luminol, and in the authors' view demonstrates that there are no significant health and safety concerns with the preparation of luminol solution and its application at the crime scene or in the laboratory, providing suitable precautions are taken.

Neurobiologic Features of Fibromyalgia Are Also Present Among Rheumatoid Arthritis Patients.

OBJECTIVE: Many patients with rheumatoid arthritis (RA) report pain despite excellent control of inflammation with immunotherapies. Variable degrees of coexisting fibromyalgia (FM) may explain this disparity. FM has been characterized by aberrant brain functional connectivity, especially between the default mode network (DMN) and insula. We undertook this study to test the hypothesis that RA patients with the highest 2011 American College of Rheumatology FM survey criteria scores-a continuous measure of the degree of FM also known as "fibromyalgianess" (FMness)-would demonstrate functional connectivity abnormalities similar to those in FM. METHODS: RA patients underwent an 11-minute functional connectivity magnetic resonance imaging (MRI) brain scan and a clinical evaluation which included a measure of FMness. Brain networks were isolated from functional connectivity MRI data. Individual patient network-to-whole brain connectivity analyses were then conducted, followed by group-level regression, which correlated the connectivity of each network with FMness. Results were significant on the cluster level with a family-wise error (FWE) rate P value less than 0.05 derived from an uncorrected voxel-level P value less than 0.001. RESULTS: A total of 54 patients participated (mean age 54.9 years, 75.9% women, mean FMness score 13.2 [range 1-29]). From the whole brain analyses, a single significant positive correlation between DMN connectivity to the left mid/posterior insula and FMness (r = 0.58, FWE-corrected P = 0.001) was demonstrated. CONCLUSION: RA patients who have increased levels of FMness appear to share neurobiologic features consistently observed in FM patients. This study is the first to provide neuroimaging evidence that RA is a mixed pain state, with many patients' symptoms being related to the central nervous system rather than to classic inflammatory mechanisms.

A multi-modal MRI study of the central response to inflammation in rheumatoid arthritis.

It is unknown how chronic inflammation impacts the brain. Here, we examined whether higher levels of peripheral inflammation were associated with brain connectivity and structure in 54 rheumatoid arthritis patients using functional and structural MRI. We show that higher levels of inflammation are associated with more positive connections between the inferior parietal lobule (IPL), medial prefrontal cortex, and multiple brain networks, as well as reduced IPL grey matter, and that these patterns of connectivity predicted fatigue, pain and cognitive dysfunction. At a second scan 6 months later, some of the same patterns of connectivity were again associated with higher peripheral inflammation. A graph theoretical analysis of whole-brain functional connectivity revealed a pattern of connections spanning 49 regions, including the IPL and medial frontal cortex, that are associated with peripheral inflammation. These regions may play a critical role in transducing peripheral inflammatory signals to the central changes seen in rheumatoid arthritis.

Activation of oxytocin receptors, but not arginine-vasopressin V1a receptors, in the ventral tegmental area of male Syrian hamsters is essential for the reward-like properties of social interactions.

Social reward plays a fundamental role in shaping human and animal behavior. The rewarding nature of many forms of social behavior including sexual behavior, parental behavior, and social play has been revealed using well-established procedures such as the conditioned place preference test. Many motivated social behaviors are regulated by the nonapeptides oxytocin (OT) and arginine vasopressin (AVP) through their actions in multiple brain structures. Interestingly, there are few data on whether OT or AVP might contribute to the rewarding properties of social interaction by their actions within brain structures that play a key role in reward mechanisms such as the ventral tegmental area (VTA). The goal of the present study was to investigate the role of OT and AVP in the VTA in regulating the reward-like properties of social interactions. Social interactions between two male hamsters reduced a spontaneous place avoidance in hamsters injected with saline control. Interestingly, however, OT and AVP injected into the VTA induced a significant two-fold reduction in place avoidance for the social interaction chamber when compared to control injections of vehicle. Finally, because OT and AVP can act on each other's receptors to influence social behavior, we also injected highly selective OTR and V1aR agonists and antagonists to determine whether OT or AVP V1a receptors were responsible for mediating the effects of these neuropeptides on social reward. Our results not only demonstrated that OT and AVP activate OTRs and not V1aRs to mediate social reward, they also demonstrated that the activation of OT receptors in the VTA is essential for the expression of the rewarding properties of social interactions.

Oxytocin induces social communication by activating arginine-vasopressin V1a receptors and not oxytocin receptors.

Arginine-vasopressin (AVP) and oxytocin (OT) and their receptors are very similar in structure. As a result, at least some of the effects of these peptides may be the result of crosstalk between their canonical receptors. The present study investigated this hypothesis by determining whether the induction of flank marking, a form of social communication in Syrian hamsters, by OT is mediated by the OT receptor or the AVP V1a receptor. Intracerebroventricular (ICV) injections of OT or AVP induced flank marking in a dose-dependent manner although the effects of AVP were approximately 100 times greater than those of OT. Injections of highly selective V1a receptor agonists but not OT receptor agonists induced flank marking, and V1a receptor antagonists but not OT receptor antagonists significantly inhibited the ability of OT to induce flank marking. Lastly, injection of alpha-melanocyte-stimulating hormone (α-MSH), a peptide that stimulates OT but not AVP release, significantly increased odor-induced flank marking, and these effects were blocked by a V1a receptor antagonist. These data demonstrate that OT induces flank marking by activating AVP V1a and not OT receptors, suggesting that the V1a receptor should be considered to be an OT receptor as well as an AVP receptor.