BACKGROUND: Alcohol use disorder (AUD) is a debilitating physiological and psychiatric disorder which affects individuals globally. The current pharmacological interventions to treat AUD are limited, and hence there is an urgent need for a novel pharmacological therapy which can be effective and safe across the population.
OBJECTIVE: We aimed to investigate a novel neutral cannabinoid receptor-1 (CB1R) antagonist, AM6527, in several preclinical models of ethanol consumption using male and female C57BL6/J mice.
METHODS: Independent groups of male and female mice were subjected to repeated cycles of drinking in the dark (DID), or intermittent access to alcohol (IAA) procedures. Twenty minutes prior to ethanol access in each procedure, animals were treated with intraperitoneal injections of either 1, 3, and 10 mg/kg of AM6527 or its respective vehicle. Acamprosate (100, 200, 300, and 400 mg/kg) or its respective vehicle was used as a positive control. Separate groups of male mice were subjected to a chain schedule of ethanol reinforcement to gain access to ethanol wherein completion of a fixed interval (FI; 5 min) schedule (link 1: \"Seeking\") was reinforced with continuous access to ethanol (fixed ratio; FR1) for up to 1.8 g/kg (link 2: \"consumption\"). All the animals were treated with 1, 3, and 10 mg/kg of AM6527 or its respective vehicle 20 mins prior to the start of the FI chain of the procedure. Separately, AM6527 was also evaluated in male and female mice undergoing acute ethanol withdrawal following 8 weeks of intermittent or continuous access to 20% ethanol drinking.
RESULTS: In both DID and IAA procedures, AM6527 reduced ethanol consumption in a dose-related manner in both male and female mice. AM6527 produced no tolerance in the DID procedure; mice treated with 3 mg/kg of AM6527 for 3 weeks continuously drank significantly smaller amounts of ethanol as compared to vehicle-treated mice over a period of three DID cycles. Moreover, in the IAA procedure, AM6527 caused an increase in water intake over the 24-h period. Acamprosate transiently reduced ethanol intake in male mice in both the DID and the IAA procedures but failed to produce any significant effect in female mice. AM6527 also produced a decrease in the FI responding (\"ethanol seeking\") in animals trained to self-administer ethanol. Lastly, AM6527 mitigated neurological withdrawal signs, i.e., handling induced convulsions (HIC) in mice undergoing acute ethanol withdrawal.
CONCLUSIONS: Current findings support previous studies with CB1R neutral antagonist in reducing voluntary ethanol intake and seeking behavior. Based on results shown in this work, AM6527 can be developed as a first in class CB1R neutral antagonist to treat AUD in both males and females.

We tested the hypothesis that women may be more at risk of becoming dehydrated during physical work in the heat in the early follicular phase (EF), compared with the late follicular (LF) and mid-luteal (ML) phases of the menstrual cycle when allowed free access to drink. Twelve healthy, eumenorrheic, unacclimated women (26 ± 5 yr) completed three trials (EF, LF, and ML phases) involving 4 h of exposure to 33.8 ± 0.8 °C, 54 ± 1% relative humidity. Each hour, participants walked on a treadmill for 30 min at a rate of metabolic heat production of 338 ± 9 W. Participants drank a cool, flavor-preferred non-caloric sport drink ad libitum. Nude body weight was measured pre- and post-exposure, and percent changes in body weight loss were interpreted as an index of changes in total body water. Total fluid intake and urine output were measured and sweat rate was estimated from changes in body mass corrected for fluid intake and urine output. Fluid intake was not different between phases (EF: 1,609 ± 919 mL; LF: 1,902 ± 799 mL; ML: 1,913 ± 671; P = 0.202). Total urine output (P = 0.543) nor sweat rate (P = 0.907) differed between phases. Percent changes in body mass were not different between phases (EF: -0.5 ± 0.9%; LF: -0.3 ± 0.9%; ML: -0.3 ± 0.7%; P = 0.417). This study demonstrates that the normal hormonal fluctuations that occur throughout the menstrual cycle do not alter fluid balance during physical work in the heat.NEW & NOTEWORTHY The effect of the menstrual cycle on fluid balance during physical work in the heat when fluids are freely available is unknown. This study demonstrates that fluid balance is not modified in women across three distinct phases of the menstrual cycle during physical work in the heat These results indicate that when women have free access to cool fluid during physical work in the heat, they respond similarly across all three phases to maintain fluid homeostasis across the menstrual cycle.

Debate continues over whether or not individuals with low total water intake (TWI) are in a chronic fluid deficit (i.e., low total body water) [1]. When women with habitually low TWI (1.6 ± 0.5 L/day) increased their fluid intake (3.5 ± 0.1 L/day) for 4 days 24-h urine osmolality decreased, but there was no change in body weight, a proxy for total body water (TBW) [2]. In a small (n = 5) study of adult men, there were no observable changes in TBW, as measured by bioelectrical impedance, after increasing TWI for 4 weeks [3]. However, body weight increased and salivary osmolality decreased indicating that the study may have been underpowered to detect changes in TBW. Further, no studies to date have measured changes in blood volume (BV) when TWI is increased.
Therefore, the purpose of this study was to identify individuals with habitually low fluid intake and determine if increasing TWI, for 14 days, resulted in changes in TBW or BV.
In order to identify individuals with low TWI, 889 healthy adults were screened. Participants with a self-reported TWI less than 1.8 L/day (men) or 1.2 L/day (women), and a 24-h urine osmolality greater than 800 mOsm were included in the intervention phase of the study. For the intervention phase, 15 participants were assigned to the experimental group and 8 participants were assigned to the control group. The intervention period lasted for 14 days and consisted of 2 visits to our laboratory: one before the intervention (baseline) and 14 days into the intervention (14-day follow-up). At these visits, BV was measured using a CO-rebreathe procedure and deuterium oxide (D2O) was administered to measure TBW. Urine samples were collected immediately prior, and 3-8 h after the D2O dose to allow for equilibration. Prior to each visit, participants collected 24-h urine to measure 24-h hydration status. After the baseline visit, the experimental group increased their TWI to 3.7 L for males and 2.7 L for females in order to meet the current Institute of Medicine recommendations for TWI.
Twenty-four-hour urine osmolality decreased (-438.7 ± 362.1 mOsm; p < 0.001) and urine volume increased (1,526 ± 869 mL; p < 0.001) in the experimental group from baseline, while there were no differences in osmolality (-74.7 ± 572 mOsm; p = 0.45), or urine volume (-32 ± 1,376 mL; p = 0.89) in the control group. However, there were no changes in BV (Fig. 1a) or changes in TBW (Fig. 1b) in either group.
Increasing fluid intake in individuals with habitually low TWI increases 24-h urine volume and decreases urine osmolality but does not result in changes in TBW or BV. These findings are in agreement with previous work indicating that TWI interventions lasting 3 days [2] to 4 weeks [3] do not result in changes in TBW. Current evidence would suggest that the benefits of increasing TWI are not related changes in TBW.

We investigated whether low arterial oxygen tension ([Formula: see text]) or hypoxia-induced plasma volume (PV) contraction, which reduces central blood volume (BV) and atrial distension, explain reduction in circulating atrial natriuretic peptide (ANP) after prolonged hypoxic exposure. Ten healthy males were exposed for 4 days to hypobaric hypoxia corresponding to an altitude of 3,500 m. PV changes were determined by carbon monoxide rebreathing. Venous plasma concentrations of midregional proANP (MR-proANP) were measured before and at the end of the exposure. At the latter time point, the measurement was repeated after 1) restoration of [Formula: see text] by breathing a hyperoxic gas mixture for 30 min and 2) restoration of BV by fluid infusion. Correspondingly, left ventricular end-diastolic volume (LVEDV), left atrial area (LAA), and right atrial area (RAA) were determined by ultrasound before exposure and both before and after fluid infusion at the end of the exposure. Hypoxic exposure reduced MR-proANP from 37.9 ± 18.5 to 24.5 ± 10.3 pmol/L (P = 0.034), LVEDV from 107.4 ± 33.5 to 91.6 ± 26.3 mL (P = 0.005), LAA from 15.8 ± 4.9 to 13.3 ± 4.2 cm2 (P = 0.007), and RAA from 16.2 ± 3.1 to 14.3 ± 3.5 cm2 (P = 0.001). Hyperoxic breathing did not affect MR-proANP (24.8 ± 12.3 pmol/L, P = 0.890). Conversely, fluid infusion restored LVEDV, LAA, and RAA to near-baseline values (108.0 ± 29.3 mL, 17.2 ± 5.7 cm2, and 17.2 ± 3.1 cm2, respectively, P > 0.05 vs. baseline) and increased MR-proANP to 29.5 ± 13.3 pmol/L (P = 0.010 vs. preinfusion and P = 0.182 vs. baseline). These findings support that ANP reduction in hypoxia is at least partially attributed to plasma volume contraction, whereas reduced [Formula: see text] does not seem to contribute.

UNASSIGNED: The concentration of fluid and its analysis in human skin is innately a challenge due to its continuous movement and involvement in maximum life processes. The concentration of the fluid gets affected by the diffusion of fluids through the skin, which acts as the main barrier between the human body and the external environment. Therefore, it becomes imperative to study the process and impact of the diffusion of fluids through the skin. The problem becomes more interesting when the human body is immersed in water.
UNASSIGNED: The present paper studies the change in the fluid distribution of human skin during its immersion in water of different temperatures. The application part of the paper visualizes various impaired vascular function and muscle soreness by water immersion during the physiotherapy treatment.
UNASSIGNED: A mathematical model based on the two-dimensional diffusion equation, along with appropriate boundary conditions, has been formulated. The maximum of the relevant parameters, such as fluid regulation, transfer coefficient, evaporation rate, etc., influencing the fluid distribution, have been incorporated. The model has been solved by variational finite element method, and numerical results have been obtained by the Crank-Nicholson scheme.
UNASSIGNED: The increase in fluid concentration due to treatment with cold and acute hot water immersion has been noted, and the role of water immersion in enhancing the recovery in exercise-induced muscular damage has been analyzed.
UNASSIGNED: The paper addressed the issue of rate of water diffusion through human skin, which otherwise couldn\'t be drawn from the analogy of gas diffusion through the membrane due to the variation in permeabilities of the two processes. The paper has applications in water immersion therapies and other activities like monitoring swimming induced pulmonary edema, etc.

In humans, hypohydration attenuates sweat secretion and attenuates whole-body heat loss, probably to mitigate further fluid losses and thereby support blood pressure regulation. Recently, however, we demonstrated that the hypohydration-mediated reduction in net whole-body heat exchange (evaporative heat loss - dry heat gain) was blunted in middle-aged compared to younger men during moderate exercise in dry heat; albeit, the underpinning mechanisms could not be determined. Here we evaluated the hypothesis that those findings stemmed from a diminished influence of extracellular hyperosmolality on net whole-body heat exchange in middle-aged-to-older compared to young men. Consistent with that hypothesis, extracellular hyperosmolality induced by an intravenous infusion of hypertonic saline (3% NaCl) reduced net heat exchange and augmented rectal temperature to a greater extent in the young compared to middle-aged-to-older men. Thus, age-related differences in the influence of hypohydration on thermoregulatory function appear to be due to blunted sensitivity to hyperosmolality with ageing.
We recently demonstrated that sweating-induced hypohydration attenuated whole-body heat dissipation to a greater extent in young compared to middle-aged men during exercise-heat stress. Here, we evaluated whether this divergent response stemmed from an attenuated influence of extracellular hyperosmolality on heat exchange with ageing. To achieve this, ten young (mean (SD): 25 (5) years) and ten middle-aged-to-older (61 (5) years) men completed two trials involving a 90-min intravenous infusion of isosmotic saline (0.9% NaCl; ISO) or hyperosmotic saline (3.0% NaCl; HYP) followed by 60 min of cycling at a fixed metabolic heat production of 250 W/m2 (∼50% peak aerobic power) in dry heat (40°C, ∼17% relative humidity). Whole-body net heat exchange (evaporative heat loss - dry heat gain) was measured via direct calorimetry. Rectal temperature was monitored continuously. Heat exchange was attenuated in HYP compared to ISO in the young (233 (20) vs. 251 (17) W/m2 ; P = 0.002) but not older group (229 (16) vs. 227 (20) W/m2 ; P = 0.621). Further, heat exchange was lower in the middle-aged-to-older vs. young men in ISO (P = 0.034) but not in HYP (P = 0.623). Similarly, end-exercise rectal temperature was greater in HYP relative to ISO in the young (38.3 (0.4)°C vs. 37.9 (0.3)°C; P = 0.015) but not the middle-aged-to-older men (38.3 (0.3)°C vs. 38.2 (0.2)°C; P = 0.652). Compared to the young, rectal temperature was greater in the middle-aged-to-older during ISO (P = 0.035) whereas no between-group difference was observed in HYP (P = 0.746). Our findings indicate that ageing blunts the effect of extracellular hyperosmolality on thermoregulatory function during exercise-heat stress.

The purpose of this review is to explore the parallel roles and interaction of hydrogen sulfide (H2S) and oxytocin (OT) in cardiovascular regulation and fluid homeostasis. Their interaction has been recently reported to be relevant during physical and psychological trauma. However, literature reports on H2S in physical trauma and OT in psychological trauma are abundant, whereas available information regarding H2S in psychological trauma and OT in physical trauma is much more limited. This review summarizes recent direct and indirect evidence of the interaction of the two systems and their convergence in downstream nitric oxide-dependent signaling pathways during various types of trauma, in an effort to better understand biological correlates of psychosomatic interdependencies.

OBJECTIVE: To investigate the roles that training load and environmental conditions have on fluid balance during a collegiate men\'s soccer preseason.
METHODS: Observational study.
METHODS: Twenty-eight male collegiate soccer players (mean±SD; age, 20±1.7y; body mass (BM), 79.9±7.3kg; height, 180.9±6.8cm; body fat, 12.7±3.1%; VO2max, 50.7±4.3ml·kg-1·min-1) participated in this study. Prior to (PRE) and following (POST) each team session, BM, percent BM loss (%BML) and hydration status was measured. Participants donned a heart rate and GPS enabled monitor to measure training load. For all team activities, ambient temperature (TAMB) and relative humidity (RH) were obtained from the nearest local weather station. Participants consumed 500mL of water as part of the team-based hydration strategy before and after training session. Stepwise linear regression was used to identify the variables that predicted %BML. Significance was set a-priori p<0.05.
RESULTS: Total distance covered predicted %BML during all preseason activities (r2=0.253, p<0.001), with TAMB and RH further adding to the model (r2=0.302, p<0.001). %BML never exceeded 2% of BM during any one session and daily variation in BM was <1% from baseline measures. Urine specific gravity was greater than 1.020 on 12/15days and UCOL was above 4 on 13/15days, indicating a state of hypohydration.
CONCLUSIONS: Total distance covered was the best predictor for the extent of body water losses during a collegiate preseason. While the team-based hydration strategy during preseason was successful in minimizing fluid losses during activity, participants arrived hypohydrated 80% of the time, necessitating a greater focus on daily fluid needs.

Ageing and hypohydration independently attenuate heat dissipation during exercise; however, the interactive effects of these factors remain unclear. We assessed the hypothesis that ageing suppresses hypohydration-induced reductions in whole-body heat loss during exercise in the heat.
On two occasions, eight young (mean [SD]: 24 [4] years) and eight middle-aged (59 [5] years) men performed 30-minute bouts of light (heat production of 175 W m-2 ) and moderate (275 W m-2 ) cycling (separated by 15-minute rest) in the heat (40°C, 15% relative humidity) when euhydrated and hypohydrated (~4% reduction in body mass). Heat production and whole-body net heat exchange (evaporative heat loss + dry heat gain) were measured via indirect and direct calorimetry (respectively) and heat storage was calculated via their temporal summation.
Net heat exchange was reduced, while heat storage was elevated, in the middle-aged men during moderate exercise when euhydrated (both P ≤ 0.01). In the young, evaporative heat loss was attenuated in the hypohydrated vs euhydrated condition during light (199 ± 6 vs 211 ± 10 W m-2 ; P ≤ 0.01) and moderate (287 ± 15 vs 307 ± 13 W m-2 ; P ≤ 0.01) exercise, but was similar in the middle-aged men, averaging 223 ± 6 and 299 ± 15 W m-2 , respectively, across conditions (both P ≥ 0.32). Heat storage was thereby exacerbated by hypohydration in the young (both P < 0.01) but not the middle-aged (both P ≥ 0.32) during both exercise bouts and, as a result, was similar between groups when hypohydrated (both P ≥ 0.50).
Hypohydration attenuates heat loss via sweating in young but not middle-aged men, indicating that ageing impairs one\'s ability to mitigate further sweat-induced fluid loss during hypohydration.