Quantization of Superflow Circulation and Magnetic Flux with a Tunable Offset

Quantization of superflow-circulation and of magnetic-flux are considered for systems, such as superfluid $^3$He-A and unconventional superconductors, having nonscalar order parameters. The circulation is shown to be the anholonomy in the parallel transport of the order parameter. For multiply-connected samples free of distributed vorticity, circulation and flux are predicted to be quantized, but generically to nonintegral values that are tunably offset from integers. This amounts to a version of Aharonov-Bohm physics. Experimental settings for testing these issues are discussed.Comment: 5 two-column pages, ReVTeX, figure available upon request (to [email protected]

EFFECTS OF DOPAMINE NOREPINEPHRINE, SEROTONIN AND ESTRADIOL-17-BETA ON SECRETION OF LUTEINIZING HORMONE AND PROLACTIN IN THE EWE.

Four studies were conducted to determine effects of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and estradiol-17(beta) on secretion of luteinizing hormone (LH) and prolactin (PRL) in ewes. In the first study, tonic and LHRH-induced secretion of LH was affected by intravenous infusion of DA, NE and 5-HT in a dose-dependent manner in ovariectomized ewes. Responses of LH to increasing doses of DA and 5-HT were biphasic and slopes of dose-response curves between catecholamines and 5-HT were opposite. Secretion of PRL was inhibited by DA and NE but not affected by 5-HT. In anestrous ewes no effects of DA, NE and 5-HT were noted on tonic secretion of LH. However, NE inhibited and 5-HT enhanced LHRH-induced release of LH, independent of the dose of NE or 5-HT infused. In anestrous ewes DA and NE inhibited secretion of PRL. In the second study, tonic secretion of LH was inhibited by DA and enhanced by 5-HT following induction of luteal regression with prostaglandin F(,2)(alpha). Neither DA nor 5-HT affected the pre-ovulatory surge of LH. Concentrations of estradiol-17(beta) in plasma were reduced by DA and this effect was reversed partially by 5-HT. In a third experiment, patterns of LH differed between acutely overiectomized ewes with implants of estradiol-17(beta) and ewes in which only the corpus luteum was removed. Following lutectomy a surge of PRL was associated with the preovulatory surge of LH. In ovariectomized ewes with implants of estradiol-17(beta), the magnitude of the surge of LH was less than that observed for lutectomized ewes; no surge of PRL accompanied the surge of LH. In the fourth study, treatment of ovariectomized ewes with estradiol-17(beta) during the summer increased the magnitude of the release of LH following LHRH. This increased release of LH was inhibited by para-chlorophenylalanine (PCPA), an inhibitor of 5-HT synthesis. The effect of PCPA was reversed partially by quipazine, an agonist of 5-HT. Treatment of non-estradiol-17(beta) treated ovariectomized ewes with quipazine or PCPA increased release of LH after LHRH. Key findings of these studies included: (1) in ovariectomized ewes response of LH to DA, NE and 5-HT was dose-dependent; (2) tonic secretion of LH was inhibited by DA and enhanced by 5-HT following prostaglandin F(,2)(alpha)-induced luteolysis; (3) ovarian secretions in addition to estradiol-17(beta) affected secretion of LH and PRL; and (4) enhanced release of LH after administration of LHRH in estradiol-17(beta)-treated ovariectomized ewes was mediated by 5-HT

Chronic administration of buprenorphine in combination with samidorphan produces sustained effects in olfactory bulbectomised rats and Wistar-Kyoto rats

Background: The combination of buprenorphine, a partial mu-opioid receptor agonist and a functional kappa-opioid receptor antagonist, with samidorphan, a functional mu-opioid receptor antagonist, is being developed as an adjunct therapy for major depressive disorder, in order to harness the mood-enhancing effects of opioids without unwanted side-effects such as a risk of addiction. Acute and subacute administration of the combination of buprenorphine and samidorphan is effective in reducing forced swim immobility in the Wistar-Kyoto rat, but the chronic effects have not been examined. Aims and methods: The purpose of this study was to assess if chronic (14-day) administration of buprenorphine (0.1 mg/kg, subcutaneous) alone or in combination with samidorphan (0.3 mg/kg, subcutaneous) maintains antidepressant-like activity in the olfactory bulbectomised rat model and the Wistar-Kyoto rat, two models that exhibit ongoing behavioural deficits in tests commonly used to study effects of antidepressants. Results: Olfactory bulbectomised-induced hyperactivity was attenuated by chronic administration of buprenorphine alone and in combination with samidorphan, to that of sham control activity levels. Neither buprenorphine nor samidorphan altered stress-associated defecation in sham or olfactory bulbectomised rats in the open field. In Wistar-Kyoto rats, buprenorphine alone significantly reduced forced swim immobility and increased locomotor activity three hours post-final dosing. Buprenorphine plus samidorphan significantly reduced forced swim immobility without changing locomotor activity at this time point. Buprenorphine alone also significantly reduced forced swim immobility 24 h post-final dosing. Conclusion: Chronic treatment of buprenorphine alone or buprenorphine plus samidorphan is effective in reversing behavioural deficits in distinct non-clinical paradigms. These non-clinical results complement the antidepressant effect of this combination observed in clinical studies.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by an Industry-Academia collaboration with funding and samidorphan provided by Alkermes Inc.peer-reviewe

Sex differences and similarities in depressive-and anxiety-like behaviour in the Wistar-Kyoto rat

Depression is a debilitating psychiatric disorder that is highly comorbid with anxiety. Depression is twice as prevalent in women as in men, however, females remain underrepresented in preclinical research. The stress hyper-responsive Wistar-Kyoto (WKY) rat displays hypolocotnotion in a novel aversive environment and depressive and anxiety-like behaviours, which have been mostly characterised in males. The current study characterised behaviour in male and female rats in a battery of behavioural paradigms. Adult male and female WKY rats were tested in the open field and forced swim tests (tests with a locomotor component); and the marble burying, novelty induced hypophagia and sucrose preference tests (tests with a minimal locomotor component) and 24 h home-cage locomotor activity was also monitored. The tests were compared against the Sprague-Dawley (SD) strain, a commonly used "control" strain.SD, but not WKY, females exhibited higher home-cage locomotor activity-compared to males. In the open field, WKY rats of both sexes exhibited a significant reduction in locomotor activity and increased anxiety-like behaviour as demonstrated by reduced time in the aversive inner zone of the open field, compared to SD counterparts. In the marble burying test, WKY females, but not males, exhibited a trend towards increased burying, indicative of anxiety-like/neophobic behaviour. In comparison, WKY males, but not females, exhibited enhanced novelty induced hypophagia, indicative of increased anxiety-like behaviour compared to SD rats. In the forced swim test, WKY rats of both sexes spent more time immobile compared with SD counterparts, indicating depressive-like behaviour. However, in comparison to SD rats, WKY males, but not females, exhibited anhedonic-like behaviour. In conclusion, WKY rats exhibit depressive-and anxiety-like behaviours that are complex and nuanced depending on the sex of the rat and testing conditions. This study supports the use of a varied test battery to fully characterise depression/anxiety-like behaviour in male and female rats. (C) 2016 Elsevier Inc. All rights reserved.This study was supported by an Industry-Academia collaboration with funding provided by Alkermes (RIN997). Financial sponsors had no role in the study design, collection, analysis or interpretation of data.peer-reviewe

Locomotor and anti-immobility effects of buprenorphine in combination with the opioid receptor modulator samidorphan in rats

Modulation of the opioid system has re-emerged as a potential therapeutic avenue for treating depression, with efficacy of a fixed-dose combination of buprenorphine (BUP), a partial mu-opioid receptor (MOR) agonist and kappa-opioid receptor (KOR) antagonist, and samidorphan (SAM), a potent MOR antagonist, as an adjuvant treatment in patients with major depressive disorder (MDD). To advance understanding of the mechanism of action underlying this combination, we examined BUP, SAM and their combination in a series of rat behavioural assays. We examined effects on locomotor activity in Sprague Dawley (SD) rats over an extended period of time in a home-cage tracking system, and behavioural despair (immobility) in the forced swim test (FST), a commonly-used test to study antidepressants, in SD and Wistar-Kyoto (WKY) rats. Strain differences in opioid receptor and prepropeptide mRNA expression in the brain (prefrontal cortex, amygdala, hippocampus and striatum) were examined using qRT-PCR. BUP produced locomotor hyperactivity in SD rats from 2 to 6 h following administration, which was attenuated by SAM. In SD rats, a low, but not a high, dose of SAM in combination with BUP counteracted swim-stress induced immobility. This effect was not seen with BUP alone. In contrast, BUP alone reduced immobility in WKY rats, and this effect was enhanced by a low, but not high, dose of SAM. In WKY rats, MOR mRNA expression was higher in the hippocampus and lower in the striatum vs. SD rats. KOR mRNA expression was higher in the amygdala and nociceptin receptor (NOP) mRNA expression was lower in the hippocampus vs. SD rats. Differences in opioid receptor expression may account for the differential behavioural profile of WKY and SD rats. In summary, administration of BUP, a MOR receptor agonist together with a MOR opioid-receptor antagonist, SAM, reduces behavioural despair in animal models traditionally used to study effects of antidepressants.This study was supported by an Industry-Academia collaboration with funding and samidorphan provided by Alkermes Inc; and a Strategic Partnership Programme Grant from Science Foundation Ireland and Alkermes Inc (14/SPP/B3051).peer-reviewed2019-12-1

Chronic administration of buprenorphine in combination with samidorphan produces sustained effects in olfactory bulbectomised rats and Wistar-Kyoto rats

Background: The combination of buprenorphine, a partial mu-opioid receptor agonist and a functional kappa-opioid receptor antagonist, with samidorphan, a functional mu-opioid receptor antagonist, is being developed as an adjunct therapy for major depressive disorder, in order to harness the mood-enhancing effects of opioids without unwanted side-effects such as a risk of addiction. Acute and subacute administration of the combination of buprenorphine and samidorphan is effective in reducing forced swim immobility in the Wistar-Kyoto rat, but the chronic effects have not been examined. Aims and methods: The purpose of this study was to assess if chronic (14-day) administration of buprenorphine (0.1 mg/kg, subcutaneous) alone or in combination with samidorphan (0.3 mg/kg, subcutaneous) maintains antidepressant-like activity in the olfactory bulbectomised rat model and the Wistar-Kyoto rat, two models that exhibit ongoing behavioural deficits in tests commonly used to study effects of antidepressants. Results: Olfactory bulbectomised-induced hyperactivity was attenuated by chronic administration of buprenorphine alone and in combination with samidorphan, to that of sham control activity levels. Neither buprenorphine nor samidorphan altered stress-associated defecation in sham or olfactory bulbectomised rats in the open field. In Wistar-Kyoto rats, buprenorphine alone significantly reduced forced swim immobility and increased locomotor activity three hours post-final dosing. Buprenorphine plus samidorphan significantly reduced forced swim immobility without changing locomotor activity at this time point. Buprenorphine alone also significantly reduced forced swim immobility 24 h post-final dosing. Conclusion: Chronic treatment of buprenorphine alone or buprenorphine plus samidorphan is effective in reversing behavioural deficits in distinct non-clinical paradigms. These non-clinical results complement the antidepressant effect of this combination observed in clinical studies.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by an Industry-Academia collaboration with funding and samidorphan provided by Alkermes Inc