Physiologic Determinants of Near-Infrared Spectroscopy-Derived Cerebral and Tissue Oxygen Saturation Measurements in Critically Ill Patients.

OBJECTIVES: Near-infrared spectroscopy (NIRS) is a potentially valuable modality to monitor the adequacy of oxygen delivery to the brain and other tissues in critically ill patients, but little is known about the physiologic determinants of NIRS-derived tissue oxygen saturations. The purpose of this study was to assess the contribution of routinely measured physiologic parameters to tissue oxygen saturation measured by NIRS. DESIGN: An observational sub-study of patients enrolled in the Role of Active Deresuscitation After Resuscitation-2 (RADAR-2) randomized feasibility trial. SETTING: Two ICUs in the United Kingdom. PATIENTS: Patients were recruited for the RADAR-2 study, which compared a conservative approach to fluid therapy and deresuscitation with usual care. Those included in this sub-study underwent continuous NIRS monitoring of cerebral oxygen saturations (SctO2) and quadriceps muscle tissue saturations (SmtO2). INTERVENTION: Synchronized and continuous mean arterial pressure (MAP), heart rate (HR), and pulse oximetry (oxygen saturation, Spo2) measurements were recorded alongside NIRS data. Arterial Paco2, Pao2, and hemoglobin concentration were recorded 12 hourly. Linear mixed effect models were used to investigate the association between these physiologic variables and cerebral and muscle tissue oxygen saturations. MEASUREMENTS AND MAIN RESULTS: Sixty-six patients were included in the analysis. Linear mixed models demonstrated that Paco2, Spo2, MAP, and HR were weakly associated with SctO2 but only explained 7.1% of the total variation. Spo2 and MAP were associated with SmtO2, but together only explained 0.8% of its total variation. The remaining variability was predominantly accounted for by between-subject differences. CONCLUSIONS: Our findings demonstrated that only a small proportion of variability in NIRS-derived cerebral and tissue oximetry measurements could be explained by routinely measured physiologic variables. We conclude that for NIRS to be a useful monitoring modality in critical care, considerable further research is required to understand physiologic determinants and prognostic significance.

Genome wide association joint analysis reveals 99 risk loci for pain susceptibility and pleiotropic relationships with psychiatric, metabolic, and immunological traits.

Chronic pain is at epidemic proportions in the United States, represents a significant burden on our public health system, and is coincident with a growing opioid crisis. While numerous genome-wide association studies have been reported for specific pain-related traits, many of these studies were underpowered, and the genetic relationship among these traits remains poorly understood. Here, we conducted a joint analysis of genome-wide association study summary statistics from seventeen pain susceptibility traits in the UK Biobank. This analysis revealed 99 genome-wide significant risk loci, 65 of which overlap loci identified in earlier studies. The remaining 34 loci are novel. We applied leave-one-trait-out meta-analyses to evaluate the influence of each trait on the joint analysis, which suggested that loci fall into four categories: loci associated with nearly all pain-related traits; loci primarily associated with a single trait; loci associated with multiple forms of skeletomuscular pain; and loci associated with headache-related pain. Overall, 664 genes were mapped to the 99 loci by genomic proximity, eQTLs, and chromatin interaction and ~15% of these genes showed differential expression in individuals with acute or chronic pain compared to healthy controls. Risk loci were enriched for genes involved in neurological and inflammatory pathways. Genetic correlation and two-sample Mendelian randomization indicated that psychiatric, metabolic, and immunological traits mediate some of these effects.

Three minutes of moderate-intensity stair walking improves glucose and insulin but not insulin sensitivity or total antioxidant capacity.

BACKGROUND AND AIMS: This study examined the effect of moderate intensity stair stepping exercise on the glycemic response, and antioxidant capacity (TAC) during an oral glucose tolerance test (OGTT). METHODS AND RESULTS: Thirty participants (women = 12) completed 4 OGTTs during rest or stair walking bouts of 1, 3, and 10 min in a randomized order. Blood was collected at baseline and 30 min during the OGTTs and analyzed for glucose, insulin, TAC, and lactate. Glucose concentrations were decreased following the 10 min (-22.69 (-34.66 to -10.72) mg/dL, p < 0.002) and 3 min (-15.37 (-25.05 to -5.69) mg/dL, p < 0.004) bouts but not the 1 min bout (-6.18 (-19.54 to 7.18) mg/dL, p = 0.352). Insulin concentrations were decreased following the 10 min (-6.11 (-8.86 to -3.36 µIU/dL), p < 0.001) and 3 min (-2.589 (-4.54 to -0.63) µIU/dL, p < 0.012) bouts but not the 1 min bout (-0.37 (-1.87 to 1.13) µIU/dL, p = 0.616). Insulin sensitivity index values showed a significant increase in the 10-min trial (1.81 (0.03-3.58), p < 0.048), but not during the 3 min (0.65 (-0.66 to 1.96) p = 0.317) or 1 min trial (0.13 (-1.58 to 1.84) p = 0.878). There was no omnibus effect for trial in TAC (p = 0.132, η2 = 0.07). There was no interaction between trial and time for blood lactate (p = 0.621, η2 = 0.02). CONCLUSION: This study provides evidence bouts as short as 3 min decrease postprandial blood glucose and insulin levels but longer bouts are needed to affect insulin sensitivity.

The microbial gbu gene cluster links cardiovascular disease risk associated with red meat consumption to microbiota L-carnitine catabolism.

The heightened cardiovascular disease (CVD) risk observed among omnivores is thought to be linked, in part, to gut microbiota-dependent generation of trimethylamine-N-oxide (TMAO) from L-carnitine, a nutrient abundant in red meat. Gut microbial transformation of L-carnitine into trimethylamine (TMA), the precursor of TMAO, occurs via the intermediate γ-butyrobetaine (γBB). However, the interrelationship of γBB, red meat ingestion and CVD risks, as well as the gut microbial genes responsible for the transformation of γBB to TMA, are unclear. In the present study, we show that plasma γBB levels in individuals from a clinical cohort (n = 2,918) are strongly associated with incident CVD event risks. Culture of human faecal samples and microbial transplantation studies in gnotobiotic mice with defined synthetic communities showed that the introduction of Emergencia timonensis, a human gut microbe that can metabolize γBB into TMA, is sufficient to complete the carnitine → γBB → TMA transformation, elevate TMAO levels and enhance thrombosis potential in recipients after arterial injury. RNA-sequencing analyses of E. timonensis identified a six-gene cluster, herein named the γBB utilization (gbu) gene cluster, which is upregulated in response to γBB. Combinatorial cloning and functional studies identified four genes (gbuA, gbuB, gbuC and gbuE) that are necessary and sufficient to recapitulate the conversion of γBB to TMA when coexpressed in Escherichia coli. Finally, reanalysis of samples (n = 113) from a clinical, randomized diet, intervention study showed that the abundance of faecal gbuA correlates with plasma TMAO and a red meat-rich diet. Our findings reveal a microbial gene cluster that is critical to dietary carnitine → γBB → TMA → TMAO transformation in hosts and contributes to CVD risk.

Neurophysiological and transcriptomic predictors of chronic low back pain: Study protocol for a longitudinal inception cohort study.

Chronic low back pain is one of the most common, costly, and debilitating pain conditions worldwide. Increased mechanistic understanding of the transition from acute to chronic low back and identification of predictive biomarkers could enhance the clinical assessment performed by healthcare providers and enable the development of targeted treatment to prevent and/or better manage chronic low back pain. This study protocol was designed to identify the neurological and transcriptomic biomarkers predictive of chronic low back pain at low back pain onset. This is a prospective descriptive longitudinal inception cohort study that will follow 340 individuals with acute low back pain and 40 healthy controls over 2 years. To analyze the neurophysiological and transcriptomic biomarkers of low back pain, the protocol includes psychological and pain-related survey data that will be collected beginning within 6 weeks of low back pain onset (baseline, 6, 12, 24, 52 weeks, and 2 years) and remotely at five additional time points (8, 10, 16, 20 weeks, and 18 months). Quantitative sensory testing and collection of blood samples for RNA sequencing will occur during the six in-person visits. The study results will describe variations in the neurophysiological and transcriptomic profiles of healthy pain-free controls and individuals with low back pain who either recover to pain-free status or develop chronic low back pain.

Exploring influences on adolescent diet and physical activity in rural Gambia, West Africa: food insecurity, culture and the natural environment.

OBJECTIVE: To explore, from the perspectives of adolescents and caregivers, and using qualitative methods, influences on adolescent diet and physical activity in rural Gambia. DESIGN: Six focus group discussions (FGD) with adolescents and caregivers were conducted. Thematic analysis was employed across the data set. SETTING: Rural region of The Gambia, West Africa. PARTICIPANTS: Participants were selected using purposive sampling. Four FGD, conducted with forty adolescents, comprised: girls aged 10-12 years; boys aged 10-12 years; girls aged 15-17 years, boys aged 15-17 years. Twenty caregivers also participated in two FGD (mothers and fathers). RESULTS: All participants expressed an understanding of the association between salt and hypertension, sugary foods and diabetes, and dental health. Adolescents and caregivers suggested that adolescent nutrition and health were shaped by economic, social and cultural factors and the local environment. Adolescent diet was thought to be influenced by: affordability, seasonality and the receipt of remittances; gender norms, including differences in opportunities afforded to girls, and mother-led decision-making; cultural ceremonies and school holidays. Adolescent physical activity included walking or cycling to school, playing football and farming. Participants felt adolescent engagement in physical activity was influenced by gender, seasonality, cultural ceremonies and, to some extent, the availability of digital media. CONCLUSIONS: These novel insights into local understanding should be considered when formulating future interventions. Interventions need to address these interrelated factors, including misconceptions regarding diet and physical activity that may be harmful to health.

Postprandial glucose response moderation by cardiorespiratory fitness following short exercise bouts.

BACKGROUND: Previous reports indicate that postprandial glucose (PPG) responses to exercise may depend on cardiorespiratory fitness (CRF), such that less fit individuals have greater reductions in PPG with exercise. Our aim was to investigate moderating effects of CRF on PPG response following exercise of progressively shorter durations and sedentary rest. METHODS: Thirty-four participants (14 female) completed a 75-g oral glucose tolerance test (OGTT) at seated rest. On three subsequent visits, participants completed additional OGTT with either 1, 3, or 10 minutes of stair-climbing. Fingerstick blood glucose measurements were taken every 15 minutes for 1 hour. CRF was determined using a treadmill ramp test. RESULTS: There was a main effect of condition F(3, 93)=13.07, P<0.001, ηp2=0.30. Stair-climbing reduced PPG iAUC compared to control by -3±27% (P=0.546), -11±29% (P=0.091), and -28±22% (P<0.000) for the 1, 3 and 10 min bouts, respectively. There was no trial by CRF interaction for glucose iAUC F(2.4, 73.8)=0.69, P=0.532, ηp2=0.02. Linear mixed model regression analysis revealed that CRF was not significantly associated with glucose iAUC, b=-14 (-45, 16), P=0.339. CONCLUSIONS: Contrary to previous reports CRF did not moderate PPG responses for either sedentary or exercise conditions in healthy men and women. Short, single-bout stair stepping exercise at a self-selected pace is equally efficient for all fitness levels.

Sex differences in postprandial glucose response to short bouts of exercise: A randomized controlled trial.

OBJECTIVES: The objective of this study was to assess sex differences in PPG responses to short stair stepping bouts, and to describe their intensity and metabolic cost. DESIGN: Crossover trial. METHODS: 34 participants (age: 25.9±5.5y; women=14) underwent 4 oral glucose tolerance tests (OGTT) during rest or with stair-stepping bouts at self-selected, moderate pace for 1, 3, and 10min. Blood was collected every 15min during the OGTTs and assessed for glucose. Participants also underwent maximal aerobic capacity assessment. Expired gases were collected during capacity testing, and each stair-stepping bout. RESULTS: Normalized to body weight there was no significant interaction for sex with stair-stepping trials (p=0.445, ηp2=0.03), or time (p=0.069, ηp2=0.09), or trial by time (p=0.264, ηp2=0.04). Women had higher mean glucose values than men (15(CI=3, 27)%, p=0.015). iAUC also showed no interaction of sex*trial (p=0.059, ηp2=0.09). Women had higher iAUC values (meanΔ=-29(-48, -11)%, p=0.003). There was a main effect for trial with 10min showing the largest reduction from control for women (e.g. AUC -10(-6, -13)%, p<.001) and men (-8(2, 13)%, p=.010). Metabolic cost of the stair stepping bouts showed no interaction of sex*trial (p=0.715, ηp2=0.01) and no difference between sexes (meanΔ=-1.3(-5.9, 3.4)%, p=0.571). Intensity was higher for women for the 3min (60±11 vs. 48±9%VO2max, p=0.003) and 10min (67±8 vs. 54±12%VO2max, p=0.002) bouts. Moreover, both sexes underestimated the true intensity of stepping. CONCLUSIONS: Both sexes had similar responses to short bouts of exercise, which they perceived as less intense than indicated by objective assessment. Stair stepping reduces postprandial glucose response with similar effectiveness for both sexes. ClinicalTrials.gov Identifier: NCT03400774.

Reducing Glycemic Indicators with Moderate Intensity Stepping of Varied, Short Durations in People with Pre-Diabetes.

Investigate the effects of short duration stair climbing/descending at a self-selected pace on post-prandial glucose responses in adults. Thirty participants (10 female) completed 4 oral glucose tolerance tests on separate days. Following glucose consumption, participants underwent seated rest (control) or walked up/down 21 stairs at a self-selected comfortable pace for 10, 3, and 1min in randomized order. Blood glucose was measured by capillary sampling from finger sticks every 15min until values for all trials converged. Area under the curve (AUC) was calculated by trapezoidal rule. In addition, cardiometabolic measurements were taken during stair exercise with a mobile metabolic cart. Results are presented as mean (SD) unless stated otherwise. All stair-climbing trials reduced peak (30min) postprandial blood glucose levels compared to the control [(1 min = 12(31), p = 0.026; 3 min = -15(25), p = 0.003; 10 min = 35(32) mg/dL, p < 0.001]. At 45min, there were significant reductions only for the 3 and 10 min trials [13(29) and 23(31) mg/dL, p = 0.023 and < 0.001 respectively], but not the 1 min trial [6(33) mg/dL, p = 0.317]. There were significant differences in AUC compared to the control only for the 3 and 10min trials [502 (1141) and 866 (1123) mg/dL·min-1, p = 0.023 and < 0.000] but not for the 1min trial [353 (1265) mg/dL·min-1, p = 0.110]. Median (interquartile range) RPEs reported for the 1, 3, and 10min trials were 1.0 (1.5), 2.0(2), and 3.0 (2.0) respectively, while VO2 was n/a, 54(12), and 59(13)% of peak, respectively. Total metabolic cost was 1.4 (0.5), 4.0 (1.0), and 11.9 (2.1) L O2, respectively. A single 1min bout of low-moderate intensity stair stepping can significantly lower peak glucose concentration, with longer bouts being more effective.

Unpacking Sleep and Suicide in Older Adults in a Combined Online Sample.

OBJECTIVE: Duration of insomnia symptoms and nightmares are related to suicidal risk in young adults independent of current symptoms of insomnia, nightmares, anxiety, depression, and PTSD. However, this relation has yet to be examined among older adults, despite older adults being at higher risk of suicidal behavior. Further, the current study aims to replicate previous research among younger adults showing that insomnia symptoms and nightmares are associated with suicide risk independent of the interpersonal psychological theory of suicide (IPTS). METHODS: The present study utilized 167 participants age 55 and older obtained by combining two independent mTurk data collections of adults in the United States. RESULTS: In the current sample, duration of nightmares was associated with suicide risk in older adults independent of symptoms of current insomnia and nightmares, duration of insomnia, and symptoms of PTSD, anhedonia, and the IPTS. CONCLUSIONS: Our findings suggest that the duration of nightmares (i.e., how long someone has been experiencing nightmares) predict substantial variance in suicide risk among older adults in addition to the risk factors typically examined. Thus, assessment of sleep dysfunction is important when assessing suicide risk among older adults.

Weight management practices among heart and vascular health care providers in an ambulatory setting.

In this study, health care providers' assessment, intervention practices, and perceived barriers to weight management approaches in an ambulatory adult heart and vascular setting are reported. Their knowledge of the National Institutes of Health National Heart, Lung and Blood Institute's The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults are also described.

A critical review of the impact of continuing breastfeeding education provided to nurses and midwives.

This review of 15 studies from nine different countries analyzes the practice of continuing education on breastfeeding for health professionals, with a specific focus on nurses and midwives. Continuing breastfeeding education improves the knowledge, clinical skills and practices, and counseling skills of nurses and midwives, and it improves the Baby-Friendly Hospital Initiative compliance of institutions. Education of any duration is beneficial; however, findings support the recommendation of the World Health Organization that at least 18 hours' education for all health professionals who advise pregnant women and mothers should be undertaken.

Sympathetic response to insulin is mediated by melanocortin 3/4 receptors in the hypothalamic paraventricular nucleus.

Hyperinsulinemia increases sympathetic nerve activity and contributes to cardiovascular dysfunction in obesity and diabetes. Neurons of the hypothalamic paraventricular nucleus (PVN) regulate sympathetic nerve activity through mono- and poly-synaptic connections to preganglionic neurons in the spinal cord. The purpose of the present study was to determine whether PVN neurons mediate the sympathetic response to insulin. Hyperinsulinemic-euglycemic clamps were performed in α-chloralose-anesthetized, male Sprague-Dawley rats (280-420 g) by an infusion of insulin (3.75 mU/kg per min) and 50% dextrose (0.75-2.0 mL/h) for 120 minutes. At 90 minutes, insulin significantly increased lumbar sympathetic nerve activity without any change in renal sympathetic nerve activity, heart rate, or blood glucose levels. Inhibition of the PVN with bilateral injection of the GABA(A) receptor agonist muscimol completely reversed the sympathoexcitatory response. However, direct injection of insulin into the PVN did not alter lumbar sympathetic nerve activity, and thereby suggests that insulin activates neurons upstream of the PVN. Interestingly, the sympathetic response to insulin was eliminated by PVN injection of the melanocortin 3/4 receptor antagonist SHU9119, but was unaffected by the angiotensin II type 1 receptor antagonist losartan. A final set of experiments suggests activation of PVN neurons during hyperinsulinemia increases glutamatergic drive to the rostral ventrolateral medulla. Collectively, these findings indicate that insulin activates a melanocortin-dependent pathway to the PVN that increases glutamatergic drive to the rostral ventrolateral medulla and alters cardiovascular function.

Disruption of human plasma high-density lipoproteins by streptococcal serum opacity factor requires labile apolipoprotein A-I.

Human plasma high-density lipoproteins (HDL), the primary vehicle for reverse cholesterol transport, are the target of serum opacity factor (SOF), a virulence determinant of Streptococcus pyogenes that turns serum opaque. HDL comprise a core of neutral lipidscholesteryl esters and some triglyceridesurrounded by a surface monolayer of cholesterol, phospholipids, and specialized proteins [apolipoproteins (apos) A-I and A-II]. A HDL is an unstable particle residing in a kinetic trap from which it can escape via chaotropic, detergent, or thermal perturbation. Recombinant (r) SOF catalyzes the transfer of nearly all neutral lipids of approximately 100,000 HDL particles (D approximately 8.5 nm) into a single, large cholesteryl ester-rich microemulsion (CERM; D > 100 nm), leaving a new HDL-like particle [neo HDL (D approximately 5.8 nm)] while releasing lipid-free (LF) apo A-I. CERM formation and apo A-I release have similar kinetics, suggesting parallel or rapid consecutive steps. By using complementary physicochemical methods, we have refined the mechanistic model for HDL opacification. According to size exclusion chromatography, a HDL containing nonlabile apo A-I resists rSOF-mediated opacification. On the basis of kinetic cryo-electron microscopy, rSOF (10 nM) catalyzes the conversion of HDL (4 microM) to neo HDL via a stepwise mechanism in which intermediate-sized particles are seen. Kinetic turbidimetry revealed opacification as a rising exponential reaction with a rate constant k of (4.400 +/- 0.004) x 10(-2) min(-1). Analysis of the kinetic data using transition state theory gave an enthalpy (DeltaH()), entropy (DeltaS(++)), and free energy (DeltaG()) of activation of 73.9 kJ/mol, -66.87 J/K, and 94.6 kJ/mol, respectively. The free energy of activation for opacification is nearly identical to that for the displacement of apo A-I from HDL by guanidine hydrochloride. We conclude that apo A-I lability is required for HDL opacification, LF apo A-I desorption is the rate-limiting step, and nearly all HDL particles contain at least one labile copy of apo A-I.

Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] administered acutely or chronically at doses occupying central CRF1 receptors in rats.

Corticotropin-releasing factor(1) (CRF(1)) antagonists may be effective in the treatment of anxiety disorders with fewer side effects compared with classic benzodiazepines. The behavioral effects of DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] and its effects on the hypothalamic-pituitary-adrenal (HPA) axis were related to its levels in plasma and estimated occupancy of central CRF(1) receptors. DMP904 (10-30 mg/kg, p.o.) and alprazolam (10 mg/kg, p.o.) increased time spent in open arms of an elevated-plus maze. In addition, acutely or chronically (14 days) administered DMP904 (1.0-30 mg/kg, p.o.) and acute alprazolam (1.0-3.0 mg/kg, p.o.) significantly reduced exit latency in the defensive withdrawal model of anxiety in rats, suggesting that tolerance may not develop to the anxiolytic-like effects of DMP904 in this model of anxiety. Acutely, DMP904 reversed the stress-induced increase in plasma corticosterone levels in defensive withdrawal at doses of 3.0 mg/kg and higher. These doses also resulted in levels of DMP904 in plasma similar to (for anxiolytic-like effects) or 4-fold higher (for effects on the HPA axis) than the in vitro IC(50) value for binding affinity at CRF(1) receptors and greater than 50% occupancy of CRF(1) receptors. Unlike alprazolam, DMP904 did not produce sedation, ataxia, or chlordiazepoxide-like subjective effects (as measured by locomotor activity, rotorod performance, and chlordiazepoxide discrimination assays, respectively) at doses at least 3-fold higher than anxiolytic-like doses. In conclusion, anxiolytic-like effects and effects on the stress-activated HPA axis of DMP904 in the defensive withdrawal model of anxiety required 50% or greater occupancy of central CRF(1) receptors. This level of CRF(1) receptor occupancy resulted in fewer motoric side effects compared with classic benzodiazepines.

Receptor occupancy of nonpeptide corticotropin-releasing factor 1 antagonist DMP696: correlation with drug exposure and anxiolytic efficacy.

4-(1,3-Dimethoxyprop-2-ylamine)-2,7-dimethyl-8-(2,4-dichlorophenyl)-pyrazolo[1,5-a]-1,3,5-triazine (DMP696) is a highly selective and potent, nonpeptide corticotropin-releasing factor 1 (CRF(1)) antagonist. In this study, we measured in vivo CRF(1) receptor occupancy of DMP696 by using ex vivo ligand binding and quantitative autoradiography and explored the relationship of receptor occupancy with plasma and brain exposure and behavioral efficacy. In vitro affinity (IC(50)) of DMP696 to brain CRF(1) receptors measured using the brain section binding autoradiography in this study is similar to that assessed using homogenized cell membrane assays previously. The ex vivo binding assay was validated by demonstrating that potential underestimation of receptor occupancy with this procedure could be minimized by identifying an appropriate in vitro incubation time (40 min) based upon the dissociation kinetics of DMP696. Orally administrated DMP696 dose dependently occupied CRF(1) receptors in the brain, with ~60% occupancy at 3 mg/kg. In the defensive withdrawal test of anxiety, this dose of DMP696 produced approximately 50% reduction in the exit latency. The time course of plasma and brain drug levels paralleled that of receptor occupancy, with peak exposure at 90 min after dosing. The plasma-free concentration of DMP696 corresponding to 50% CRF(1) receptor occupancy (in vivo IC(50), 1.22 nM) was similar to the in vitro IC(50) (~1.0 nM). Brain concentrations of DMP696 were over 150-fold higher than the plasma-free levels. In conclusion, doses of DMP696 occupying over 50% brain CRF(1) receptors are consistent with doses producing anxiolytic efficacy in the defense withdrawal test of anxiety, and the IC(50) value estimated in vivo based on plasma-free drug concentrations is consistent with the in vitro IC(50) value.

The anxiolytic CRF(1) antagonist DMP696 fails to function as a discriminative stimulus and does not substitute for chlordiazepoxide in rats.

RATIONALE: Compounds with a mechanism of action different from benzodiazepines may retain the anxiolytic effects of benzodiazepines with fewer side effects. CRF(1) antagonists have anxiolytic-like effects but may have different discriminative stimulus (DS) effects compared with benzodiazepines. OBJECTIVE: The present study evaluated the similarity of DS effects of a CRF(1) antagonist DMP696 to the benzodiazepine chlordiazepoxide and the ability of DMP696 to produce DS effects on its own using drug discrimination procedures, as well as its anxiolytic-like effects after acute or chronic administration. METHODS: Rats were trained to discriminate chlordiazepoxide (5.0 mg/kg, IP, 30 min prior to session) from vehicle under a fixed-ratio 10 schedule of food reinforcement and drug- or vehicle-lever selection following administration of DMP696 was determined. The effects of DMP696 on latency to exit a dark chamber (defensive withdrawal model of anxiety) were used as an index of anxiolytic-like activity. RESULTS: In chlordiazepoxide-trained rats, DMP696 (1.0-100 mg/kg, PO) resulted in most of the animals selecting the vehicle lever, as did another anxiolytic, the 5-HT(1A) partial agonist buspirone (0.3-10 mg/kg, IP). DMP696 reduced exit latency in defensive withdrawal at 10 mg/kg administered either acutely or chronically for 14 days. Thus, the doses of DMP696 studied in drug discrimination were up to 10-fold higher than those active in the anxiety model. In addition, DMP696 (10-60 mg/kg, PO) could not be established as a DS under the conditions used in this study. In a subsequent study, chlordiazepoxide was established as a DS in these same animals. CONCLUSIONS: Lack of substitution of DMP696 for the chlordiazepoxide DS in rats and its inability to acquire DS properties suggest that the DS effects of DMP696 differ from those of benzodiazepines.

The CRF(1) receptor antagonist DMP696 produces anxiolytic effects and inhibits the stress-induced hypothalamic-pituitary-adrenal axis activation without sedation or ataxia in rats.

RATIONALE: CRF(1) antagonists may be effective in the treatment of anxiety disorders while having fewer side effects compared with classical benzodiazepines. OBJECTIVES: The effects of a small molecule selective CRF(1) antagonist DMP696 on anxiety-like behaviors and stress-induced increases in corticosterone in rats exposed to a novel environment and on locomotor activity and motor coordination were determined in rats. These effects of DMP696 were compared with those produced by the classical benzodiazepine chlordiazepoxide (CDP). METHODS: DMP696 or CDP were administered PO, 60 minutes before behavioral testing in rats. Their effects on latency to exit a dark chamber and stress-induced increase in corticosterone in the Defensive Withdrawal test (an animal model of anxiety), locomotor activity, and rotorod performance (measure of ataxia) were determined. RESULTS: DMP696 significantly reduced exit latency and reversed the stress-induced increase in corticosterone in the Defensive Withdrawal test at doses of 3.0-10 mg/kg and higher. In contrast, CDP significantly decreased exit latency at 10 and 30 mg/kg, but not at 100 mg/kg, due to concurrent non-specific side effects. Unlike DMP696, CDP had no effect on the stress-induced increase in corticosterone at lower doses, but resulted in a significant increase at higher doses. DMP696 did not reduce locomotor activity or impair motor coordination at doses up to 30-fold higher than doses effective in the Defensive Withdrawal model. In contrast, CDP produced significant sedation and ataxia at the same doses that were effective in reducing exit latency. CONCLUSIONS: These data suggest that the CRF(1) antagonist DMP696 might retain the therapeutic benefits of classical benzodiazepines but have fewer motoric side effects.