Blockade Of Oxytocin Receptors Research Articles

Estimation of udder emptying based on milk constituents of strip samples after milking

Milk ejection disorders were induced by oxytocin receptor blockade. We tested the hypothesis that the degree of udder emptying at incomplete milk ejection can be estimated based on the concentration of various milk constituents in different milk fraction samples. To induce different levels of spontaneous udder emptying (SUE) 10 Holstein dairy cows were milked either with or without i.v. injection of the oxytocin receptor blocking agent atosiban (ATO). In ATOearly, 12 µg/kg BW ATO was injected immediately before and in ATOlate directly after a 1 min manual udder preparation. The normal milking routine served as Control treatment. In all 3 treatments the udder was completely emptied by the i.v. injection of 10 IU oxytocin (OT) at the end of spontaneous milk flow. During all experimental milkings 4 milk samples were taken in all treatments: at the start of udder preparation (foremilk; FM), immediately after cessation of spontaneous milk flow and cluster detachment by hand stripping (strip milk; SM), from spontaneous removed milk in the bucket 1 (milk before OT; MBOT) and from the milk obtained after OT injection in the bucket 2 (milk after OT; MAOT). Fat, protein, lactose and electrolytes (Na, Cl and K) were measured in each milk sample. In addition, electrical conductivity (EC) was determined in parallel to continuous milk flow recording. The treatments induced individual degrees of SUE; therefore, the final evaluations of data were based on SUE classes instead of treatments. The most pronounced differences of milk constituents at different degrees of SUE were found for the milk fat content. The fat content of SM and MBOT remained almost unchanged up to 60% SUE, but was considerably higher if >80% of the milk was spontaneously removed. The concentrations of Na and Cl were highest and of K lowest if less than 20% on milk was received in the different samples. The EC was higher in SM and MBOT if <20% of milk was received. In conclusion, the blockade of the OT effect influences primarily the fat content, which confirmed an OT-induced fat secretion during milking. Similar effects are likely found in situations of disturbed milk ejections, caused by a lacking or reduced release of OT in response to different degrees of tactile udder stimulation. Our results show that the measurement of fat content and the EC in strip milk samples collected after cluster detachment can be used to estimate the completeness of udder emptying.

Titi monkey father-daughter bond-related behaviors explain stress response variability

Social interactions regulate our behavior and physiology, and strong social bonds can buffer us from stress. Coppery titi monkeys (Plecturocebus cupreus) are socially monogamous South American monkeys that display strong social bonds. Infants form selective bonds with their fathers, making them ideal for studying father-daughter bonds. We established a method for quantifying variability in expression of bond-related behaviors in females (n = 12), and the present study is the second to use this method for explaining titi monkey responses to behavioral tests. We also investigated how manipulations of oxytocin (OT) and vasopressin (AVP) influenced juvenile behavior and physiology. Subjects received acute intranasal treatments of saline, low/medium/high OT, low/high AVP, or OT receptor antagonist (OTA) prior to an acute social separation. General linear mixed-effects model results revealed fathers were significant behavioral and physiological stress buffers for their daughters, as evidenced by fewer distress vocalizations (p < 0.001), less locomotion (p < 0.001), and lower plasma cortisol (p < 0.001) in a social separation paradigm. Females vocalized less if they exhibited greater expression of bond-related behaviors with their fathers as infants (p = 0.01), and this stress-buffering effect remained even when the daughter was separated from the father (p = 0.001). While treatments did not alter behaviors, OTA treatment caused the largest rise in plasma cortisol (p < 0.001), suggesting blockade of OT receptors can inhibit fathers’ stress-buffering effects. Remarkably, females with greater expression of father-daughter bond-related behaviors exhibited an overall reduced physiological separation distress response (p = 0.04). Findings from the present study advance current knowledge of the neurobiological mechanisms foundational to female bonds and help inform how social disruptions may differently impact individuals based on expression of bond-related behaviors.

The role of the oxytocinergic system in the antidepressant-like effect of swimming training in male mice

Increasing evidence shows that higher physical activity such as running and swimming exercises is associated with decreased depression-related symptoms. However, underlying mechanisms are not fully understood. This study aimed to investigate whether oxytocinergic system can mediate the antidepressant effect of swimming exercises in mice. First, male NMRI mice were subjected to swimming training for eight weeks, then animals intraperitoneally received oxytocin antagonist (L-368899) 1 h before behavioral tests. We assessed anhedonia and social behavior and behavioral despair using the sucrose preference test, social interaction test, and tail suspension test. Oxytocin levels in the brain and serum were also measured. The results showed that swimming training decreased anhedonia and behavioral despair, whereas it increased social behavior and oxytocin levels in male mice. On the other hand, a subthreshold dose of oxytocin antagonist treatment in exercised mice prevented the antidepressant effect of swimming exercise via increased anhedonia and behavioral despair and decreased social behavior compared to the swimming training group. However, the blockade of oxytocin receptors did not affect oxytocin levels in exercised mice. Overall, these findings suggest that oxytocinergic system can play a role in mediating the antidepressant-like effect of swimming training in mice.

Effects of oxytocin receptor blockade on dyadic social behavior in monogamous and non-monogamous Eulemur

A prominent body of research spanning disciplines has been focused on the potential underlying role for oxytocin in the social signatures of monogamous mating bonds. Behavioral differences between monogamous and non-monogamous vole species, putatively mediated by oxytocinergic function, constitute a key source of support for this mechanism, but it is unclear to what extent this hormone–behavior linkage extends to the primate order. In a preregistered experiment, we test if oxytocin receptor blockade affects affiliative behavior in mixed-sex pairs of Eulemur, a genus of strepsirrhine primate containing both monogamous and non-monogamous species. Inconsistent with past studies in monogamous voles or monkeys, we do not find confirmatory evidence in Eulemur that monogamous pairs affiliate more than non-monogamous pairs, nor that oxytocin receptor blockade of one pair member selectively corresponds to reduced affiliative or scent-marking behavior in monogamous species. We do, however, find exploratory evidence of a pattern not previously investigated: simultaneously blocking oxytocin receptors in both members of a monogamous pair predicts lower rates of affiliative behavior relative to controls. Our study demonstrates the value of non-traditional animal models in challenging generalizations based on model organisms, and of methodological reform in providing a potential path forward for behavioral oxytocin research.

Leptin enhances social motivation and reverses chronic unpredictable stress-induced social anhedonia during adolescence

Social anhedonia, a loss of interest and pleasure in social interactions, is a common symptom of major depression as well as other psychiatric disorders. Depression can occur at any age, but typically emerges in adolescence or early adulthood, which represents a sensitive period for social interaction that is vulnerable to stress. In this study, we evaluated social interaction reward using a conditioned place preference (CPP) paradigm in adolescent male and female mice. Adolescent mice of both sexes exhibited a preference for the social interaction-associated context. Chronic unpredictable stress (CUS) impaired the development of CPP for social interaction, mimicking social anhedonia in depressed adolescents. Conversely, administration of leptin, an adipocyte-derived hormone, enhanced social interaction-induced CPP in non-stressed control mice and reversed social anhedonia in CUS mice. By dissecting the motivational processes of social CPP into social approach and isolation avoidance components, we demonstrated that leptin treatment increased isolation aversion without overt social reward effect. Further mechanistic exploration revealed that leptin stimulated oxytocin gene transcription in the paraventricular nucleus of the hypothalamus, while oxytocin receptor blockade abolished the leptin-induced enhancement of socially-induced CPP. These results establish that chronic unpredictable stress can be used to study social anhedonia in adolescent mice and provide evidence that leptin modulates social motivation possibly via increasing oxytocin synthesis and oxytocin receptor activation.

Regular moderate exercise alleviates gastric oxidative damage in rats via the contribution of oxytocin receptors.

A moderate level of exercise has beneficial effects for the prevention of gastric ulcers. Although regular aerobic exercise was shown to elevate serum oxytocin levels and exogenously administered oxytocin exerts an anti-ulcer activity, the role of endogenous oxytocin in the gastroprotective effects of exercise has not yet been elucidated. We showed that increased anxiety and oxidative gastric damage induced by gastric ulcers were reversed in pre-exercised rats, while reduced hypothalamic oxytocin expression and decreased myenteric oxytocin receptor expression due to gastric ulcers were abolished by exercise. We also reported that the blockade of oxytocin receptors exaggerated gastric damage in exercised rats with ulcers. Our data establish that endogenous oxytocin is the key mediator in the beneficial effects of regular physical activity in alleviating gastric injury. Exercise increases serum oxytocin levels and exogenous oxytocin exerts an anti-ulcer activity; but the role of oxytocin in the protective effects of exercise against gastric ulcers has not yet been evaluated. This study was designed to investigate the impact of regular swimming exercise on oxidative gastric injury, and the role of oxytocin receptor activity in the anxiolytic and anti-inflammatory actions of exercise. Adult Wistar albino rats of both sexes performed swimming exercise (30min/day, 5days) or stayed sedentary. At the end of the 6-week exercise/sedentary protocol, rats were injected intraperitoneally with atosiban (0.1mg/kg/day) or saline for 4days. On the 5th day, under anaesthesia, acetic acid (ulcer) or saline (sham) was applied onto the gastric serosa and the treatments were continued. On the 9th day, anxiety levels were determined; gastric blood flow was measured, and blood, gastric and brain tissues were obtained. Induction of ulcers in sedentary rats increased anxiety and serum corticosterone levels; but reduced gastric blood flow and resulted in apoptosis and oxidative gastric damage with increased cytokine expressions. However, when ulcers were induced in pre-exercised rats, behavioural and biochemical alterations due to gastric damage were reversed. The inhibition of oxytocin receptors by atosiban exaggerated pro-inflammatory cytokine expressions and gastric lipid peroxidation in the stomachs of exercised rats with ulcers. When rats had regularly exercised prior to ulcer induction, reductions in the immunolabelling of hypothalamic oxytocin and myenteric oxytocin receptors were abolished, suggesting that exercise-induced alleviation of gastric injury may involve the reversal of down-regulated oxytocinergic activity.

Oxytocin Reduces Intravesical Pressure in Anesthetized Female Rats: Action on Oxytocin Receptors of the Urinary Bladder.

Urinary bladder dysfunction affects several people worldwide and shows higher prevalence in women. Micturition is dependent on the Barrington’s nucleus, pontine urine storage center and periaqueductal gray matter, but other brain stem areas are involved in the bladder regulation. Neurons in the medulla oblongata send projections to hypothalamic nuclei as the supraoptic nucleus, which synthetizes oxytocin and in its turn, this peptide is released in the circulation. We investigated the effects of intravenous injection of oxytocin (OT) on the urinary bladder in sham and ovariectomized rats. We also evaluated the topical (in situ) action of OT on intravesical pressure (IP) as well as the existence of oxytocin receptors in the urinary bladder. In sham female Wistar rats, anesthetized with isoflurane, intravenous infusion of OT (10 ng/kg) significantly decreased the IP (–47.5 ± 1.2%) compared to saline (3.4 ± 0.7%). Similar effect in IP was observed in ovariectomized rats after i.v. OT (–41.9 ± 2.9%) compared to saline (0.5 ± 0.6%). Topical administration (in situ) of 0.1 mL of OT (1.0 ng/mL) significantly reduced the IP (22.3.0 ± 0.6%) compared to saline (0.9 ± 0.7%). We also found by qPCR that the gene expression of oxytocin receptor is present in this tissue. Blockade of oxytocin receptors significantly attenuated the reduction in IP evoked by oxytocin i.v. or in situ. Therefore, the findings suggest that (1) intravenous oxytocin decreases IP due to bladder relaxation and (2) OT has local bladder effect, binding directly in receptors located in the bladder.

Impaired sex preference, but not social and social novelty preferences, following systemic blockade of oxytocin receptors in adult male mice

The hypothalamic neuropeptide oxytocin (OT) is a powerful modulator of mammalian social behavior and its administration was shown to affect various types of social interactions. However, systematic examinations of the role of endogenous OT release in social behavior have heretofore been done only using genetically modified animal models in which the genes encoding either OT or the OT receptor (OTR) were mutated. While such genetic manipulations revealed various behavioral deficits, these deficits may involve developmental or long-term processes and do not prove the participation of acute OT release in the impaired behavior. Here we used a battery of social discrimination tasks to evaluate the effects of acute systemic OTR blockade, using a non-peptide, orally active OTR antagonist (L368,899), on social behavior of adult male C57BL/6 J mice. We found no effect of the pharmacological manipulation on the social preference and social novelty preference behaviors. However, the preference of a male mouse for investigating a female conspecific more than a male (sex preference behavior), was lost by administration of the OTR antagonist. Finally, we found that blocking OTR activity before social defeat prevented the consequent loss of social preference, suggesting a role for OT in the acquisition of aversive social memory. Overall, our results suggest that OT plays a role in modulating the salience of social stimuli and facilitating their memory, as predicted by the social salience theory, rather than in regulating the internal motivation of the subject for social interactions.

The blockade of oxytocin receptors in the paraventricular thalamus reduces maternal crouching behavior over pups in lactating mice

Oxytocin (OT) systems contribute to the elicitation of stereotypic maternal behaviors. OT peptide-expressing neurons are predominantly localized in the hypothalamus, whereas OT receptor (OTR)-expressing neurons are widely distributed throughout the brain. Among those OTR-expressing regions, the paraventricular thalamus (PVT) consists of heterogeneous neuropeptide-responsive neurons critical for appetitive motivation, food intake control, and social behaviors; however, the precise distribution of OTR-expressing neurons within the PVT and whether these neurons are involved in maternal behaviors in mice are unknown. The distribution of OTR-expressing neurons was examined in an OTR-Venus transgenic line expressing a fluorescent protein controlled by the OTR promoter. The number of Venus expressing neurons was higher in the posterior PVT (pPVT) than in the anterior PVT (aPVT). When OTR-Venus dams were exposed to pups, the number of double-labelled neurons expressing both OTR-Venus and a marker of neuronal activity (c-Fos) was increased in the pPVT compared to non-exposed dams, while the aPVT remained unchanged. To investigate whether OT signaling in the pPVT is essential for maternal behaviors, an OT antagonist (OTA) was transiently or chronically infused into the pPVT of lactating dams during the postpartum period. Although the transient OTR blockade did not affect maternal behaviors, a chronic OTR blockade specifically reduced the duration of crouching behavior over pups. Taken together, these findings suggest that OTR-expressing neurons in the pPVT are involved in maternal crouching behavior.

The ventromedial hypothalamic circuitry and male alloparental behaviour in a socially monogamous rodent species.

As prairie voles (Microtus ochrogaster) display spontaneous biparental care, and the ventromedial hypothalamus (VMH) has been implicated in reproductive behaviour, we conducted experiments to test the hypothesis that the VMH neurochemical circuitry is involved in alloparental behaviours in male prairie voles. We compared alloparental behaviours of adult, sexually naïve male and female voles-both displayed licking/grooming, huddling and retrieving behaviours towards conspecific pups. We also stained for the immediate-early gene encoded early growth protein Egr-1 in the vole brain. The pup-exposed animals showed levels of Egr-1 staining that was higher in the VMH but lower in the amygdala compared to animals exposed to a pup-sized piece of plastic (control). A retrograde tracer, Fluoro-Gold (FG), was injected into the VMH of male voles that were subsequently tested in the pup exposure or control condition. More FG/Egr-1 cells were detected for glutamatergic (GLU) staining in the ventral bed nucleus of the stria terminalis (BNSTv) and medial amygdala (MeA), whereas less FG/Egr-1 cells were stained for gamma-aminobutyric acid (GABA) in the MeA of the pup-exposed group compared to the control group. Further, the ratio of GLU:GABA expression in FG/Egr-1 projection neurons from both the BNSTv and MeA to the VMH was increased following pup exposure. Finally, pharmacological blockade of either dopamine D1 receptor or oxytocin receptor in the VMH impaired the onset of male alloparental behaviour. Together, these data suggest that the VMH may be involved in the onset of alloparental care and play a role in regulating social approach in male prairie voles.

PC-FACS

PC-FACS (Fast Article Critical Summaries for Clinicians in Palliative Care) provides hospice and palliative care clinicians with concise summaries of the most important findings from more than 100 medical and scientific journals. If you have colleagues who would benefit from receiving PCFACS, please encourage them to join the AAHPM at aahpm.org. Comments from readers are welcomed at [email protected] . PC-FACS (Fast Article Critical Summaries for Clinicians in Palliative Care) provides hospice and palliative care clinicians with concise summaries of the most important findings from more than 100 medical and scientific journals. If you have colleagues who would benefit from receiving PCFACS, please encourage them to join the AAHPM at aahpm.org. Comments from readers are welcomed at [email protected] . Effects of Oxytocin Aid in Dying for Patients with ALS Prescribing Inappropriate Medications Hospice Use Outcomes in Advanced Heart Failure Ethics in Decision-Making Nudges Probiotics in Treating Diarrhea Oxytocin has antinociceptive properties.1 How does the oxytocin system influence nociceptive hypersensitivity? This study tested whether the endogenous analgesic effect of oxytocin (through an action on the nociceptive system) is altered by early life stress, possibly contributing to long-term consequences on pain response. A rat model of neonatal maternal separation (NMS) was used, which induces long-term consequences on brain functions including chronic stress, anxiety, altered social behavior, and visceral hypersensitivity. Adult NMS rats were hypersensitive to noxious mechanical/thermal stimuli and inflammatory pain. Oxytocin receptor-mediated stress-induced analgesia and oxytocin antihyperalgesia after carrageenan inflammation were unobserved. These alterations were partially rescued via intraperitoneal daily injection during NMS with oxytocin or its downstream second messenger allopregnanolone. Epigenetic involvement in these alterations was confirmed because neonatal treatment with a histone deacetylase inhibitor normalized nociceptive sensitivities and restored oxytocin receptor-mediated stress-induced analgesia and endogenous antihyperalgesia (all P<.001). This study tested whether pain recovery in rats postsurgery could be reversed by antagonism of spinal oxytocin or vasopressin receptors. Male and female rats underwent partial spinal nerve ligation (PSNL). Effects of nonselective and selective oxytocin and vasopressin 1A receptor antagonists on mechanical hypersensitivity during recovery were assessed. Oxytocin immunoreactivity in the spinal cord (SC) dorsal horn and oxytocin-binding receptor mRNA expression in dorsal root ganglia and SC were measured. Post-PSNL in both sexes: oxytocin or vasopressin 1A receptor blockade increased mechanical hypersensitivity (P<.0025); SC oxytocin levels (P<.05) and oxytocin and vasopressin 1A receptor expression increased (P<.05). Oxytocin, a peptide hormone, traditionally has been known to play a role in social bonding, sexual reproduction, and childbirth. The oxytocin system is intertwined with the hypothalamic-pituitary stress axis; autonomic nervous system; neurotransmitters such as dopamine, serotonin, and GABA/glutamate; and the immune system. Recently, researchers have identified an oxytocin analgesic system that limits inflammatory sensitization2 and neuropathic pain3 and is altered by early life stress4. In NMS rodents, a well-established model of early life stress, a histone deacetylase inhibitor (SAHA) prevented visceral5, mechanical, and thermal hypersensitivity. In the future, patients with stress-induced alterations in pain circuits may be “rescued” by restoring the oxytocin analgesic system or by reversing the long-term epigenetic changes triggered by early life stress or trauma. Research on oxytocin highlights the impact of early life stress on a patient’s ability to process painful stimuli, which could potentially contribute to pain-related comorbidities such as anxiety and depression. In addition, individual variation of the endogenous oxytocin system based on genetic disposition and environmental influences has been implicated in vulnerability to addiction6, which is a growing epidemic in our country. The palliative care principle of treating pain and suffering of the patient and addressing the needs of the family, especially children, may have longitudinal impact on processing pain and coping with stress. Oxytocin provides antinociception, centrally mediated at the level of the spinal cord and peripherally at the dorsal root ganglion7, resulting in decreased sensitivity to noxious mechanical/thermal stimuli and quicker recovery from surgical nerve injury. Rony Dev, DO, Department of Symptom Control and Palliative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX Melchior M, Juif PE, Gazzo G, et al. Pharmacological rescue of nociceptive hypersensitivity and oxytocin analgesia impairment in a rat model of neonatal maternal separation. Pain. 2018;159(12):2630-2640. 1.Poisbeau P, Grinevich V, Charlet A. Oxytocin signaling in pain: cellular, circuit, system, and behavioral levels. Curr Top Behav Neurosci. 2018;35:193-212.2.Eliava M, Mechior M, Knobloch-Bollmann HS, et al. A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and inflammatory pain processing. Neuron. 2016;89(6):1291-1304.3.Martinez-Lorenzana G, Espinoza-Lopez L, Carranza M, et al. PVN electrical stimulation prolongs withdrawal latencies and releases oxytocin in cerebrospinal fluid, plasma, and spinal cord tissue in intact and neuropathic rats. PAIN. 2008;140(2):265-273.4.Juif PE, Salio C, Zell V, et al. Peripheral and central alterations affecting spinal nociceptive processing and pain at adulthood in rats exposed to neonatal maternal deprivation. Eur J Neurosci. 2016;44(3):1952-1962.5.Moloney RD, Stilling RM, Dinan TG, Cryan JF. Early-life stress-induced visceral hypersensitivity and anxiety behavior is reversed by histone deacetylase inhibition. Neurogastrenerol Motil. 2015;27(12):1831-1836.6.Buisman-Pijlman FT, Sumracki NM, Gordon JJ, Hull PR, Carter CS, Tops M. Individual differences underlying susceptibility to addiction: role for the endogenous oxytocin system. Pharmacol Biochem Behav. 2014;119:22-38.7.Moreno-Lopez Y, Martinez-Lorenzana G, Condes-Lara M, Rojas-Piloni G. Identification of oxytocin receptor in the dorsal horn and nociceptive dorsal root ganglion neurons. Neuropeptides. 2013;47(2):117-123. Death with dignity (DWD) legislation excludes patients with amyotrophic lateral sclerosis (ALS) because the drug must be self-ingested and the alternative (euthanasia) is illegal.1,2 What constitutes an ethical framework for physicians faced with difficult end-of-life situations? This essay defines relevant terms raised by the case of a dying patient in Washington who cannot self-administer a lethal prescription. Donald’s ALS has progressed; he uses a wheelchair and cannot use his hands for even simple tasks. His declining respiratory function remains intact, but his swallowing is deteriorating. Donald tells his palliative care (PC) physician, Dr. S, he wishes to end his life. In physician aid-in-dying (PAD), physicians prescribe lethal drugs that their patients self-administer, whereas in euthanasia (illegal in the United States), physicians themselves administer lethal drugs. Because of Donald’s inability to self-administer, Donald cannot take advantage of Washington’s DWD law. When patients request PAD in states that allow PAD, the authors suggest these steps for physicians: (1) explore the patient’s motivations (identify/treat/refer for any psychiatric conditions); (2) obtain the patient’s informed consent (explain the alternatives [PC], and consider the patient’s decision-making capacity); (3) after learning what brings meaning to the patient’s life, discuss prognosis and define goals of care; (4) discuss alternatives (eg, PC, stopping eating/drinking, life-sustaining treatment withdrawal), and ensure the patient is not seeking PAD for lack of financial resources. As a way around physical limitations, if the patient still wants PAD, the family could prepare the drug and place it in the patient’s mouth; the patient would subsequently move his or her head or push the syringe into his or her mouth. Patients with progressive neurological illnesses may be referred to PC teams for symptom management, clarifying goals of care, and advance care planning. In areas where aid-in-dying (AID) is legal, it may be part of the broad discussion with the PC team. PC may be provided during the waiting periods required in most jurisdictions that currently have legal AID. This case study provides a framework for considering how to respond when encountering these situations. Some of the suggestions in this article are ethically and legally controversial and should be considered very carefully and with appropriate guidance. PC clinicians will need to develop an approach to the care of patients who wish for AID but do not qualify under the law. Even in areas where AID is legal, some terminally ill patients, especially those with progressive neurological conditions, who might want to utilize AID will be unable to do so legally. Beth Popp, MD HMDC FAAHPM FACP, Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY Craig A, Dzeng E. How should physicians care for dying patients with amyotrophic lateral sclerosis? AMA J Ethics. 2018;20(8):E690-E698. 1.Wash Rev Code ch 70.245 (2008).2.Emanuel EJ, Daniels ER, Fairclough DL, Clarridge BR. The practice of euthanasia and physician-assisted suicide in the United States: adherence to proposed safeguards and effects on physicians. JAMA. 1998;280(6):507-513. About 29% of Medicare beneficiaries aged ≥65 years filled a prescription in 2015 for medication included in the American Geriatrics Society Beers Criteria list of drugs to avoid.1 Can an educational intervention reduce inappropriate prescribing? This cluster randomized trial assessed the effectiveness of a consumer-targeted, pharmacist-led educational intervention on the discontinuation of inappropriate medication among community-dwelling older adults. Community pharmacists in Quebec, Canada were recruited (2014-2017). Patients aged ≥65 years, who were prescribed 1 of 4 Beers Criteria medications (sedative-hypnotics, glyburide, or nonsteroidal antiinflammatory drugs), were recruited from 69 community pharmacies. Intervention-group pharmacists were encouraged to send patients an educational deprescribing brochure parallel to sending their physicians an evidence-based pharmaceutical opinion to recommend deprescribing. Control-group pharmacists provided usual care. Patients, physicians, pharmacists, and evaluators were blinded to outcome assessment. Analysis (intention-to-treat) included generalized estimating equations. Among 489 patients (mean [range] age 75 [66–96] years; 66% women, 23% aged ≥80 years, and 27% meeting criteria for frailty), 89% completed the trial (n=219 intervention [34 pharmacies] vs. n=218 control [35 pharmacies]). At 6 months, 43% of intervention patients no longer filled prescriptions for inappropriate medication, vs. 12% of control (risk difference [RD]=31% [95% CI, 23%–38%]). Discontinuation of inappropriate medication occurred among 43% (vs. 9.0%) of sedative-hypnotic drug users (RD=34% [25%–43%]), 31% (vs. 14%) of glyburide users (RD=17% [2%–31%]), and 58% (vs. 22%) of nonsteroidal antiinflammatory drug users (RD=35% [10%–55%]; P for interaction=.09). No hospitalization-requiring adverse events were reported, however, 38% of patients who attempted to taper sedative-hypnotics reported withdrawal symptoms. Older adults are at risk of polypharmacy. This is especially true in the last stages of life when new medications are prescribed to manage symptoms while chronic preventive medications often are also continued.2,3 This study demonstrates that a pharmacist-initiated effort to educate patients and their physicians about medication risks can lead to a decrease in prescriptions. It adds to the body of literature that indicates that directly involving patients in decision-making processes to deprescribe can improve deprescription rates. To expand upon this research for a palliative care population, it may be worth exploring the role of pharmacists in providing education not just on potentially harmful medications but also on re-evaluating medications that are unlikely to benefit patients, such as statins for primary prevention in the last year of life or cholinesterase inhibitors in advanced dementia. Pharmacist-led educational intervention has the ability to reduce prescription of potentially harmful medications. Evie Kalmar, MD MS, and Eric Widera, MD; University of California, San Francisco, CA Martin P, Tamblyn R, Benedetti A, Ahmed S, Tannenbaum C. Effect of a pharmacist-led educational intervention on inappropriate medication prescriptions in older adults: the D-PRESCRIBE randomized clinical trial. JAMA. 2018;320(18):1889-1898. 1.Patel R, Zhu L, Sohal D, et al. Use of 2015 Beers Criteria medications by older Medicare beneficiaries. Consult Pharm. 2018;33(1):48-54.2.McNeil MJ, Kamal AH, Kutner JS, Ritchie CS, Abernethy AP. The burden of polypharmacy in patients near the end of life. J Pain Symptom Manage. 2016;51(2):178-183.3.Morin L, Vetrano DL, Rizzuto D, Calderón-Larrañaga A, Fastbom J, Johnell K. Choosing wisely? Measuring the burden of medications in older adults near the end of life: nationwide, longitudinal cohort study. Am J Med. 2017;130(8):927-936. Median survival among Medicare beneficiaries hospitalized with heart failure (HF) is only 2.1 years.1,2 What is the state of hospice care for older patients hospitalized with HF? This observational cohort study assessed rates of discharge to hospice, posthospice rehospitalization, and in-hospice survival in patients following hospital discharge. Patients (aged ≥65 years) in the Get With The Guidelines–Heart Failure3 registry linked to Medicare claims data, who were discharged alive from the hospital (2005-2014), were analyzed. Patients with HF discharged to hospice (group A) were compared against patients with advanced HF (based on predefined clinical criteria) who were not discharged to hospice (group B) and other patients with HF in the registry (group C). Pearson χ2, Kruskal-Wallis, and log-rank tests were used as well as Cox and Fine-Gray models. In this study, 121,990 patients (438 sites) were included. Three point eight percent were A (median age 86 [IQR=80–90] years; 56% female), 3.6% were B (78 [72–84]; 34%), and 93% were C (81 [74–87]; 55%; all P<.001). Group A were more symptomatic, more likely white, and had received higher education than B or C (P<.001). Hospice discharges increased 2%–4.9% (2005-2014). The median survival time in A was 11 (IQR=3–63) days, vs. B=318 (78–1105) and C=754 (221–1868; all P<.001). Thirty-four percent (vs. 12%) of patients discharged to hospice facilities (vs. home hospice) died in <72 hours (P<.001); 15% discharged from hospice lived ≥6 months. Among hospitals with >25 hospice discharges, the median discharge rate was 3.5% (IQR=2%–5.7%). Readmission at 30 days was 4.1% in A, vs. B=27% and C=22% (P<.001). Non-white race and younger age were the strongest readmission-from-hospice predictors. This large study contains good and bad news. Hospice use for patients discharged from the hospital with advanced HF increased from 2% to almost 5% over a decade, but median survival remains short: 11 days for all discharged to hospice and only 5 days for those discharged to a facility. The comparator cohort with advanced HF survived for almost a year. This short survival, whether due to very late referrals of those “already-dying” to hospice or hospices’ difficulties managing heart failure symptoms in such a way that allows additional longevity, may serve to reinforce to HF clinicians that hospice is for acutely dying patients for whom there is nothing more to do. For patients with advanced HF, hospice use is increasing; however, patients discharged with hospice support die much faster than comparator patients who do not receive hospice care. Christopher A. Jones, MD MBA HMDC FAAHPM, Perelman School of Medicine and the Palliative and Advanced Illness Research Center at the University of Pennsylvania, Philadelphia, PA Warraich HJ, Xu H, DeVore AD, et al. Trends in hospice discharge and relative outcomes among Medicare patients in the Get With The Guidelines–Heart Failure registry. JAMA Cardiol. 2018;3(10):917-926.1.Shah KS, Xu H, Matsouaka RA, et al. Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. J Am Coll Cardiol. 2017;70(20):2476-2486.2.Gupta A, Allen LA, Bhatt DL, et al. Association of the hospital readmissions reduction program implementation with readmission and mortality outcomes in heart failure. JAMA Cardiol. 2018;3(1):44-53.3.Smaha LA; American Heart Association. The American Heart Association Get With The Guidelines program. Am Heart J. 2004;148(5, Suppl):S46-S48. “Nudges” (physician communication techniques that influence patients' choices) may assist patients in making decisions.1 Are nudges ethical/appropriate in medical decision making? This study assessed whether stakeholders (physicians and laypersons without clinical training) consider nudges ethical/appropriate in medical decision making. Resident physicians and Mechanical Turk workers (nonclinicians) completed an electronic survey consisting of two decision-making vignettes (V1=hospice-endorsing; V2=chemotherapy-endorsing) describing patients deciding between chemotherapy and hospice care for incurable cancer. Two attributes of each vignette varied randomly among participants: (1) whether or not the patient's decision was influenced by a mistaken judgment (bias) and (2) whether or not the physician nudged the patient (eg, information framing and social comparisons). Participants reported the extent to which the communication was ethical/appropriate and desirable. MANOVA analyses were performed. Nonclinicians (n=336) were mean (SD) age 32 (10) years, 64% female, and 78% white. Physicians (n=89) were mean age 30 (2) years, 38% female, and 62% white. Physicians and nonclinicians perceived using nudges more positively than not using them, regardless of an initial patient bias (nudge effect: V1: F[8, 78]=16.09, V2: F[8, 78]=7.42; V1: F[8, 325]=16.10, V2: F[8, 325]=33.81, respectively [all P<.001]). In V1, nonclinicians evaluated patients' autonomy the same, regardless of nudge presence/absence, and physicians evaluated communications as more acceptable/trustworthy if bias was absent (bias effect: F[8, 78]=2.15, P=.04). Contrary to nonclinicians, physicians viewed the V1 (vs. V2) nudge more favorably. Physicians evaluated V1 nudges more positively than nonclinicians (V1: F[8, 203]=2.16,P=.032). Nonclinicians evaluated V2 nudges more positively than physicians (V2: F[8, 201]=3.25, P=.002). This study is the first to examine ethical concerns about nudges in preference-sensitive, end-of-life decisions. The findings suggest that both clinicians and nonclinicians view nudges as ethical and appropriate, even if there was no evidence that the patient had a bias in initial judgement. The fact that clinicians evaluated the nudge endorsing hospice care more favorably, while nonclinicians evaluated the nudge endorsing chemotherapy more favorably, suggests that individuals support nudges more when they are consistent with their views. Findings should be interpreted in light of the study design, which used hypothetical vignettes. Future research should collect data among people actually dealing with these decisions. This study provides preliminary evidence that both clinicians and nonclinicians view nudges as ethical in the context of treatment decisions at the end of life. Laura Porter, PhD, Duke University Medical Center, Durham, NC Fridman I, Hart JL, Yadav KN, Higgins ET. Perspectives on using decision-making nudges in physician-patient communications. PLoS One. 2018;13(9):e0202874. 1.Fridman I, Scherr KA, Glare PA, Higgins ET. Using a non-fit message helps to de-intensify negative reactions to tough advice. Pers Soc Psychol Bull. 2016;42(8):1025-1044. The incidence of diarrhea during chemotherapy/radiotherapy is 50%–80%.1 Can probiotics prevent/reduce chemotherapy/radiotherapy–induced diarrhea? This meta-analysis evaluated the effectiveness of probiotics for prevention/treatment of diarrhea related to radiotherapy (with/without chemotherapy) or chemotherapy alone in adults with cancer. The Cochrane Central Register of Controlled Trials (2017), MEDLINE (1946-2017), and Embase (1980-2017) were searched. Two authors independently selected randomized controlled trials, extracted data, and assessed bias. Random-effects models were used. For prevention of radiotherapy (with/without chemotherapy)-induced diarrhea, authors identified five placebo-controlled studies (n=926): for any diarrhea, risk ratios (RRs) ranged from 0.35 (95% CI=0.26–0.47) to 1 (0.94–1.06; three studies; low-certainty evidence); a beneficial effect of probiotics on quality-of-life could not be demonstrated/refuted (two; low certainty). For probiotic users, time-to-rescue medication was 36 hours longer in 1 study (34.7–37.3), but 1 reported no difference (moderate certainty). Three placebo-controlled studies addressed chemotherapy-induced diarrhea prevention (not quality of life/time to rescue): for any diarrhea, pooled RR=0.59 (0.36–0.96; two; n=106; low certainty); for all other outcomes, a beneficial effect of probiotics could not be demonstrated/refuted (one-two; n=46–106; low certainty). Three studies compared probiotics with another intervention for radiotherapy (with/without chemotherapy)-induced diarrhea (not quality of life/time to rescue): one (n=21) reported less diarrhea when providing dietary counseling (RR=0.30, 0.11–0.81; very low certainty); in another (n=148), diarrhea occurred less often with probiotics vs. guar gum (odds ratio [OR]=0.38, 0.16-0.89; low certainty); and two (n=63) found less need for rescue in probiotics (RR=0.44, 0.22–0.86; very low certainty). One placebo-controlled study (n=205) addressed radiotherapy-induced diarrhea treatment and could not demonstrate/refute a beneficial effect on average diarrhea grade, time to rescue (13 hours longer for probiotics, -0.9–26.9 hours), or need for rescue (RR=0.74, 0.53–1.03; moderate certainty). Diarrhea is a very common and troublesome side effect of radiation and/or chemotherapy that adversely affects cancer patients’ quality of life and may be difficult to control. Probiotics are live microorganisms thought to work by stimulating the proliferation of bowel epithelial cells and thus aiding in repair of damaged mucosa. The question whether probiotics are helpful in prevention or treatment of radiotherapy- or chemotherapy-induced diarrhea remains largely unanswered, as only low- or very low-certainty evidence currently exists.2-5 All studies were found to be underpowered and heterogeneous in populations and strain(s) of probiotics used. However, probiotics appear to be safe and some studies found them to be beneficial. Future well-designed studies are necessary. Probiotics should not yet be routinely considered for the prevention or treatment of chemotherapy- or radiotherapy-related diarrhea in people with cancer. Jennifer Pruskowski, PharmD BCPS BCGP CPE, UPMC Palliative and Supportive Institute, Pittsburgh, PA Wei D, Heus P, van de Wetering FT, van Tienhoven G, Verleye L, Scholten RJ. Probiotics for the prevention or treatment of chemotherapy or radiotherapy-related diarrhoea in people with cancer. Cochrane Database Syst Rev. 2018;8:CD008831. 1.Sanguineti G, Endres EJ, Parker BC, et al. Acute toxicity of whole-pelvis IMRT in 87 patients with localized prostate cancer. Acta Oncol. 2008;47(2):301-310.2.Fuccio L, Guido A, Eusebi LH, et al. Effects of probiotics for the prevention and treatment of radiation-induced diarrhea. J Clin Gastroenterol. 2009;43(6):506-513.3.Redman MG, Ward EJ, Phillips RS. The efficacy and safety of probiotics in people with cancer: a systematic review. Ann Oncol. 2014;25(10):1919-1929.4.Wang YH, Yao N, Wei KK, et al. The efficacy and safety of probiotics for prevention of chemoradiotherapy-induced diarrhea in people with abdominal and pelvic cancer: a systematic review and meta-analysis. Eur J Clin Nutr. 2016;70(11):1246-1253.5.Liu MM, Li ST, Shu Y, Zhan HQ. Probiotics for prevention of radiation-induced diarrhea: a meta-analysis of randomized controlled trials. PLoS ONE. 2017;12(6):e0178870. PC-FACS Feedback We appreciate your feedback. Help us help you—send your comments to [email protected] . PC-FACS was created in 2005 by Founding Editor-in-Chief Amy P. Abernethy, MD, PhD, FACP, FAAHPM. The Academy is deeply grateful to Dr. Abernethy for creating this important publication and for her many contributions to the field of hospice and palliative medicine. PC-FACS is edited by Editor-in-Chief, Mellar P. Davis, MD, FCCP, FAAHPM, of the Geisinger Health System, and Associate Editor-in-Chief, Robert M. Arnold, MD, FAAHPM, of the University of Pittsburgh Medical Center. All critical summaries are written by Jeff Fortin, MD. AAHPM thanks the following PC-FACS Editorial Board members for their review of the critical summaries and preparation of the commentaries: Editorial Leadership Mellar P. Davis, MD, FCCP, FAAHPM, Editor-in-Chief Robert M. Arnold, MD, FAAHPM, Associate Editor-in-Chief Basic Science Rony Dev, DO, MS, FACP, FAAHPM, Senior Section Editor Amy L. Davis, DO, MS, FACP, FAAHPM Rosene Pirrello, RPh Jacob Strand, MD Bioethics, Humanities, and Spirituality Jessica A. Moore, DHCE, MA, Senior Section Editor Timothy Mark Corbett, MD, MA, HMDC, FAAHPM Adam Marks, MD Beth Popp, MD, HMDC, FAAHPM, FACP Erin Zahradnik, MD Geriatrics and Care Transitions Eric Widera, MD, FAAHPM, Senior Section Editor Gouri Bhattacharyya, MD, MRCP David B. Brecher, MD, FAAFP, FAAHPM Elizabeth Chuang, MD, MPH Catherine Bree Johnston, MD, MPH Hospice, Hospice and Palliative Medicine Interface, and Regulatory Issues Joel S. Policzer, MD, FACP, FAAHPM, Senior Section Editor Christopher Jones, MD, FAAHPM Nina O’Connor, MD Renato Samala, MD, FACP Pediatrics Robert C. Macauley, MD, FAAP, FAAHPM, Senior Section Editor Christopher A. Collura, MD Sue Sreedhar Kevin Madden, MD Rachel Thienprayoon, MD Psychosocial Ronit Elk, PhD, Senior Section Editor Dan Handel, MD Laura Porter, PhD Karen Ogle, MD, FAAHPM Abby R. Rosenberg, MD, MS, FAAP Symptom Assessment and Management Marcin Chwistek, MD, FAAHPM, Senior Section Editor Dulce M. Cruz Oliver, MD, CMD, FAAHPM, AGSF Giovanni Elia, MD, FAAHPM Jennifer Pruskowski, PharmD, BCPS, BCGP, CPE Jason A. Webb, MD Medical Writers Jeff M. Fortin, PhD (September 2016-present) Lana Christian, MS (August 2015-August 2016) Moses Sandrof (October 2014-July 2015) Jane Wheeler (July 2005-September 2014) AAHPM Staff Laura Davis, CAE, Director, Marketing and Membership Allison Lundberg, Manager, Marketing and Membership Andie Bernard, Managing Editor AAHPM Publications Committee (Joanne Wolfe, MD, chair) The views expressed herein are those of the individual authors and are not necessarily those of the Academy. Information included herein is not medical advice and is not intended to replace the judgment of a practitioner with respect to particular patients, procedures or practices. To the extent permissible under applicable laws, the Academy disclaims responsibility for any injury and / or damage to persons or property as a result of any actual or alleged libelous statements, infringement of intellectual property or other proprietary or privacy rights, or from use or operation of any ideas, instructions, procedures, products or methods contained in this publication. American Academy of Hospice and Palliative Medicine 8735 W. Higgins Road, Suite 300 Chicago, IL 60631, USA Phone: 847-375-4712 Fax: 877-734-8671 E-mail: [email protected] Website: www.aahpm.org

Critical roles of serotonin-oxytocin interaction during the neonatal period in social behavior in 15q dup mice with autistic traits

Disturbance of neurotransmitters and neuromodulators is thought to underlie the pathophysiology of autism spectrum disorder (ASD). Studies of 15q dup mouse models of ASD with human 15q11–13 duplication have revealed that restoring serotonin (5-HT) levels can partially reverse ASD-related symptoms in adults. However, it remains unclear how serotonin contributes to the behavioral symptoms of ASD. In contrast, oxytocin (OXT) has been found to involve social and affiliative behaviors. In this study, we examined whether serotonin-OXT interaction during the early postnatal period plays a critical role in the restoration of social abnormality in 15q dup mice. OXT or the 5-HT1A receptor agonist 8OH-DPAT treatment from postnatal day 7 (PD7) to PD21 ameliorated social abnormality in the three-chamber social interaction test in adult 15q dup mice. The effect of 8OH-DPAT was inhibited by blockade of OXT receptors in 15q dup mice. Thus, serotonin-OXT interaction via 5-HT1A receptors plays a critical role in the normal development of social behavior in 15q dup mice. Therefore, targeting serotonin-OXT interaction may provide a novel therapeutic strategy for treatment of ASD.

Oxytocin receptor antagonist atosiban impairs consolidation, but not reconsolidation of contextual fear memory in rats

There is increasing evidence that oxytocin is involved in learning and memory process. This study investigated the effects of blockade of oxytocin receptors using the selective oxytocin receptor antagonist atosiban (ATO) on contextual fear memory consolidation and reconsolidation in male rats. Post-training injections of different doses of ATO (1, 10, 100 or 1000 µg/kg) impaired the 48 h retention performance in a dose-dependent manner. The same doses of ATO following memory reactivation did not impair subsequent expression of contextual fear memories which formed under low or high shock intensities and tested 24 h or one week following memory reactivation. Also, no effect was found when ATO was administrated in the absence of memory reactivation. Our finding is the first report that indicates endogenous oxytocin released during training play an important role in the consolidation, but not reconsolidation of contextual fear memory in rats.

Intragastric preloads of l-tryptophan reduce ingestive behavior via oxytocinergic neural mechanisms in male mice

Human and laboratory animal studies suggest that dietary supplementation of a free essential amino acid, l-tryptophan (TRP), reduces food intake. It is unclear whether an acute gastric preload of TRP decreases consumption and whether central mechanisms underlie TRP-driven hypophagia. We examined the effect of TRP administered via intragastric gavage on energy- and palatability-induced feeding in mice. We sought to identify central mechanisms through which TRP suppresses appetite. Effects of TRP on consumption of energy-dense and energy-dilute tastants were established in mice stimulated to eat by energy deprivation or palatability. A conditioned taste aversion (CTA) paradigm was used to assess whether hypophagia is unrelated to sickness. c-Fos immunohistochemistry was employed to detect TRP-induced activation of feeding-related brain sites and of oxytocin (OT) neurons, a crucial component of satiety circuits. Also, expression of OT mRNA was assessed with real-time PCR. The functional importance of OT in mediating TRP-driven hypophagia was substantiated by showing the ability of OT receptor blockade to abolish TRP-induced decrease in feeding. TRP reduced intake of energy-dense standard chow in deprived animals and energy-dense palatable chow in sated mice. Anorexigenic doses of TRP did not cause a CTA. TRP failed to affect intake of palatable yet calorie-dilute or noncaloric solutions (10% sucrose, 4.1% Intralipid or 0.1% saccharin) even for TRP doses that decreased water intake in thirsty mice. Fos analysis revealed that TRP increases activation of several key feeding-related brain areas, especially in the brain stem and hypothalamus. TRP activated hypothalamic OT neurons and increased OT mRNA levels, whereas pretreatment with an OT antagonist abolished TRP-driven hypophagia. We conclude that intragastric TRP decreases food and water intake, and TRP-induced hypophagia is partially mediated via central circuits that encompass OT.

Insular cortex mediates approach and avoidance responses to social affective stimuli.

Social animals detect the affective states of conspecifics and utilize this information to orchestrate social interactions. In a novel social affective preference text in which experimental adult male rats could interact with either naive or stressed conspecifics, the experimental rats either approached or avoided the stressed conspecific, depending upon the age of the conspecific. Specifically, experimental rats approached stressed juveniles but avoided stressed adults. Inhibition of insular cortex, which is implicated in social cognition, and blockade of insular oxytocin receptors disrupted the social affective behaviors. Oxytocin application increased intrinsic excitability and synaptic efficacy in acute insular cortex slices, and insular oxytocin administration recapitulated the behaviors observed toward stressed conspecifics. Network analysis of Fos immunoreactivity in 29 regions identified functional connectivity between insular cortex, prefrontal cortex, amygdala and the social decision-making network. These results implicate insular cortex as a key component in the circuit underlying age-dependent social responses to stressed conspecifics.

Differential activation of arginine-vasopressin receptor subtypes in the amygdaloid modulation of anxiety in the rat by arginine-vasopressin.

The amygdala plays a paramount role in the modulation of anxiety and numerous studies have shown that arginine vasopressin (AVP) elicits anxiogenic effects following either its systemic or septal administration. The aim of this paper was to study the involvement of vasopressinergic neurotransmission in the amygdaloid modulation of unconditioned anxiety and to ascertain whether or not AVP receptor subtypes may have a differential role in this modulation. Anxiety behavior was evaluated both in Shock-Probe Burying Test and Light-Dark Box following the bilateral microinfusion of AVP alone or AVP together with either AVP 1a or AVP 1b receptor antagonists into the central amygdala (CeA). AVP microinfusion elicited at low (1ng/side) but not at high doses (10ng/side) anxiogenic-like responses in the Shock-Probe Burying Test but not in the Light-Dark Box. SSR149415, an AVP 1b antagonist unlike Manning compound, an AVP 1a antagonist, fully prevented AVP effects in the Shock-Probe Burying Test when it was administered simultaneously with AVP. In addition, oxytocin receptor blockade also failed to affect AVP effects. No effects of any AVP antagonist by itself were observed in both anxiety paradigms. Our results indicate that AVP 1b receptor contribute to the amygdaloid modulation of anxiety at least in the context of the Shock-Probe Burying Test since no effects were noticed in the Light-Dark Box. It remains to the future to ascertain whether AVP receptor subtypes have indeed differential actions either in the modulation of global or specific features of unconditioned anxiety.

Role of the oxytocin system in amygdala subregions in the regulation of social interest in male and female rats

We previously found that oxytocin (OT) receptor (OTR) binding density in the medial amygdala (MeA) correlated positively with social interest (i.e., the motivation to investigate a conspecific) in male rats, while OTR binding density in the central amygdala (CeA) correlated negatively with social interest in female rats. Here, we determined the causal involvement of OTR in the MeA and CeA in the sex-specific regulation of social interest in adult rats by injecting an OTR antagonist (5ng/0.5μl/side) or OT (100pg/0.5μl/side) before the social interest test (4-min same-sex juvenile exposure). OTR blockade in the CeA decreased social interest in males but not females, while all other treatments had no behavioral effect. To further explore the sex-specific involvement of the OT system in the CeA in social interest, we used in vivo microdialysis to determine possible sex differences in endogenous OT release in the CeA during social interest. Interestingly, males and females showed similar levels of extracellular OT release at baseline and during social interest, suggesting that factors other than local OT release mediate the sex-specific role of CeA-OTR in social interest. Moreover, we found a positive correlation between CeA-OT release and social investigation time in females. This was further reflected by reduced CeA-OT release during social interest in females that expressed low compared to high social interest. We discuss the possibility that this reduction in OT release may be a consequence, rather than a cause, of exposure to a social stimulus. Overall, our findings show for the first time that extracellular OT release in the CeA is similar between males and females and that OTR in the CeA plays a causal role in the regulation of social interest toward juvenile conspecifics in males.

Lu pour vous

Oxytocin (OT) systems contribute to the elicitation of stereotypic maternal behaviors. OT peptide-expressing neurons are predominantly localized in the hypothalamus, whereas OT receptor (OTR)-expressing neurons are widely distributed throughout the brain. Among those OTR-expressing regions, the paraventricular thalamus (PVT) consists of heterogeneous neuropeptide-responsive neurons critical for appetitive motivation, food intake control, and social behaviors; however, the precise distribution of OTR-expressing neurons within the PVT and whether these neurons are involved in maternal behaviors in mice are unknown. The distribution of OTR-expressing neurons was examined in an OTR-Venus transgenic line expressing a fluorescent protein controlled by the OTR promoter. The number of Venus expressing neurons was higher in the posterior PVT (pPVT) than in the anterior PVT (aPVT). When OTR-Venus dams were exposed to pups, the number of double-labelled neurons expressing both OTR-Venus and a marker of neuronal activity (c-Fos) was increased in the pPVT compared to non-exposed dams, while the aPVT remained unchanged. To investigate whether OT signaling in the pPVT is essential for maternal behaviors, an OT antagonist (OTA) was transiently or chronically infused into the pPVT of lactating dams during the postpartum period. Although the transient OTR blockade did not affect maternal behaviors, a chronic OTR blockade specifically reduced the duration of crouching behavior over pups. Taken together, these findings suggest that OTR-expressing neurons in the pPVT are involved in maternal crouching behavior.

Endocannabinoid signaling mediates oxytocin-driven social reward

Marijuana exerts profound effects on human social behavior, but the neural substrates underlying such effects are unknown. Here we report that social contact increases, whereas isolation decreases, the mobilization of the endogenous marijuana-like neurotransmitter, anandamide, in the mouse nucleus accumbens (NAc), a brain structure that regulates motivated behavior. Pharmacological and genetic experiments show that anandamide mobilization and consequent activation of CB1 cannabinoid receptors are necessary and sufficient to express the rewarding properties of social interactions, assessed using a socially conditioned place preference test. We further show that oxytocin, a neuropeptide that reinforces parental and social bonding, drives anandamide mobilization in the NAc. Pharmacological blockade of oxytocin receptors stops this response, whereas chemogenetic, site-selective activation of oxytocin neurons in the paraventricular nucleus of the hypothalamus stimulates it. Genetic or pharmacological interruption of anandamide degradation offsets the effects of oxytocin receptor blockade on both social place preference and cFos expression in the NAc. The results indicate that anandamide-mediated signaling at CB1 receptors, driven by oxytocin, controls social reward. Deficits in this signaling mechanism may contribute to social impairment in autism spectrum disorders and might offer an avenue to treat these conditions.

Effects of Combined Oxytocin Receptor (OTR) with Vasopressin Receptor (V1aR or V1bR) Blockade within Paraventricular Nucleus (PVN) on Neurocardiovascular Responses

Vasopressin (VP) released from dendrites of magnocellular neurons within PVN may influence systemic hemodynamics and sympathetic nerve activity. PVN neurons possess all three receptor subtypes: V1aR, V1bR and OTR. We have shown that inhibition of any one of these receptors alone dose dependently blocks the rise in MAP and reflex changes in heart rate (HR) and renal sympathetic nerve activity (RSNA) with injection of VP into PVN. Here we test the hypothesis that a subthreshold dose of OTR antagonist combined with either subthreshold V1aR or V1bR blockers within PVN will result in additive inhibition of hemodynamic and RSNA changes induced by 100 ng VP into PVN. Male Sprague Dawley rats were instrumented and studies performed in awake unrestrained rats 24 ‐ 48 hr after recovery from anesthesia. Baseline parameters did not differ. VP increased MAP by 18.2 ± 3.1 mmHg (P &lt; 0.001) while HR and RSNA decreased 33 ± 14 bpm and 13.6 ±10.6 %baseline, respectively (P &lt;0.05). The response to combined subthreshold inhibitory doses of (d(CH₂)₅¹,Tyr(Me)²,Arg⁸)‐Vasopressin (V1aR, 20 ng), nelivaptan (V1bR, 0.5 ng) and (d(CH₂)₅¹,Tyr(Me)²,Thr⁴,Orn⁸,des‐Gly‐NH₂⁹)‐Vasotocin (OTR, 1 ng) attenuated the rise in MAP by 43% as well as the reflex changes in HR and RSNA. Neither V1aR+OTR blockade nor V1bR+ OTR blockade resulted in greater blockade of the responses (45% and 49%, respectively. Vehicle did not block any responses. These findings suggest that V1aR, V1bR and OTR activated pathways share intracellular and/or neural pathways that regulate system hemodynamics and sympathoexcitatory responses to VP within the PVN.