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Acute myocarditis, also known as myocardial inflammation, is a self-limited condition caused by systemic infection with cardiotropic pathogens, primarily viruses, bacteria, or fungi. Despite significant research, inflammatory cardiomyopathy exacerbated by heart failure, arrhythmia, or left ventricular dysfunction and it has a dismal prognosis. In this study, we aimed to evaluate the therapeutic effect of yohimbine against lipopolysaccharide (LPS) induced myocarditis in rat model. The anti-inflammatory activity of yohimbine was assessed in in-vitro using RAW 264.7 and H9C2 cells. Myocarditis was induced in rats by injecting LPS (10 mg/kg), following the rats were treated with dexamethasone (2 mg/kg) or yohimbine (2.5, 5, and 10 mg/kg) for 12 h and their therapeutic activity was examined using various techniques. Yohimbine treatment significantly attenuated the LPS-mediated inflammatory markers expression in the in-vitro model. In-vivo studies proved that yohimbine treatment significantly reduced the LPS-induced increase of cardiac-specific markers, inflammatory cell counts, and pro-inflammatory markers expression compared to LPS-control samples. LPS administration considerably affected the ECG, RR, PR, QRS, QT, ST intervals, and hemodynamic parameters, and caused abnormal pathological parameters, in contrast, yohimbine treatment substantially improved the cardiac parameters, mitigated the apoptosis in myocardial cells and ameliorated the histopathological abnormalities that resulted in an improved survival rate. LPS-induced elevation of cardiac troponin-I, myeloperoxidase, CD-68, and neutrophil elastase levels were significantly attenuated upon yohimbine treatment. Further investigation showed that yohimbine exerts an anti-inflammatory effect partly by modulating the MAPK pathway. This study emphasizes yohimbine's therapeutic benefit against LPS-induced myocarditis and associated inflammatory markers response by regulating the MAPK pathway. [ABSTRACT FROM AUTHOR]

Studies have shown that dexmedetomidine (DEX, an a2-adrenoceptors agonist) provides a neuroprotective effect and influences blood glucose levels. Here, we evaluated the effect of prolonged treatment with low doses of DEX on the survival rate of dopaminergic (DAergic) neurons in the substantia nigra and also serum glucose levels in 6-hydroxydopamine (6-OHDA) – induced Parkinson's disease (PD) in the rat. The neurotoxin of 6-OHDA was injected into the medial forebrain bundle by stereotaxic surgery. DEX (25 and 50 µg/kg, i.p) and yohimbine, an a2-adrenoceptor antagonist (1 mg/kg, i.p) were administered before the surgery to the 13 weeks afterward. Apomorphine-induced rotational tests and blood sampling were carried out before the surgery and multiple weeks after that. Thirteen weeks after the surgery, the rats' brain was transcardially perfused to assess the survival rate of DAergic neurons using the tyrosine hydroxylase (TH) immunohistochemistry. DEX remarkably attenuated the severity of rotational behavior and reversed the progress of the PD. It also increased the number of TH-labeled neurons by up to 60%. The serum glucose levels in 6-OHDA-received rats did not change in the third and seventh weeks after the surgery but decreased significantly in the thirteenth week. Treatment with DEX prevented this decrement in glucose levels. On the other hand, Treatment with yohimbine did not affect PD symptoms and glucose levels. Our data indicate that DEX through neuroprotective activity attenuates the severity of 6-OHDA-induced PD in rats. DEX might also prevent hypoglycemia during the progress of the PD. [ABSTRACT FROM AUTHOR]

Plants are a priceless and vital resource that give us medicine, food, fibre, and all other necessities. The evergreen shrub, Rauwolfia serpentina (L.) Benth. ex Kurz., also known as Indian snakeroot, sarpagandha is a member of the Apocynaceae family. Rauwolfia serpentina has fewer negative effects and an abundance of phytochemicals in the roots and leaves of the plant, it shows a wide range of therapeutic activity. With the goal of developing a densitometric high-performance thin-layer chromatography (HPTLC) method, in order to quantify Yohimbine hydrochloride in Rauwolfia roots, it will help to insure the collection and harvesting time. The five distinct brands of market Rauwolfia root samples are compared with in-house samples prepared in the laboratory. The silica gel 60 F254 high-performance thin-layer chromatography plates were used with toluene, Toluene : Ethyl acetate : Diethylamine (7:1.5:1.5 v/v/v) as a mobile phase. The validation parameters for the developed method were carried out as per the International Conference on Harmonisation (ICH) guideline Q2 (R1). The calibration curve was found to be linear over a range of 1-7 μg/spot for yohimbine. The method involves densitometric detection at 280 nm. The relative standard deviations (RSD) for precision were found to be lower than 2% for both analytes. Percent recoveries for accuracy were performed and found to be 98.5-99.98% for yohimbine, The LOD and LOQ for Yohimbine were 0.08 μg/ml and 0.24 μg/ml, respectively. Validation parameters were carried out as per International Conference on Harmonisation (ICH) guideline Q2 (R1). The Rf value of 0.64 have been observed for Yohimbine. This HPTLC densitometric method is highly suitable for the analysis of Yohimbine present in the dosage of marketed herbal products of sarpagandha root without any interference. [ABSTRACT FROM AUTHOR]

Background: The human stress response is characterized by increases in neuromodulators, including norepinephrine (NE) and cortisol. Both neuromodulators can enter the brain and affect neurofunctional responses. Two brain areas associated with stress are the amygdala and the hippocampus. The precise influence of NE and cortisol on the amygdala and hippocampal resting state functional connectivity (RSFC) is poorly understood. Aims: To investigate the influence of NE and cortisol on the amygdala and hippocampal RSFC. Methods: We recruited 165 participants who received 10 mg yohimbine and/or 10 mg hydrocortisone in a randomized, placebo-controlled design. With seed-based analyses, we compared RSFC of the hippocampus and amygdala separately between the three groups that received medication versus placebo. Results: We found no differences between yohimbine and placebo condition or between hydrocortisone and placebo condition regarding amygdala or hippocampal FC. Compared with placebo, the yohimbine/hydrocortisone condition showed increased amygdala and hippocampal RSFC with the cerebellum. Also, they had increased hippocampal RSFC with the amygdala and cerebral white matter. Discussion: The group with elevated NE and cortisol showed significantly increased RSFC between the amygdala, hippocampus, and cerebellum compared to placebo. These three brain areas are involved in associative learning and emotional memory, suggesting a critical role for this network in the human stress response. Our results show that NE and cortisol together may influence the strength of this association. Compared to placebo, we found no differences in the groups receiving only one medication, suggesting that increasing one neuromodulator alone may not induce differences in neurofunctional responses. The study procedure has been registered at clinicaltrials.gov (ID: NCT04359147). [ABSTRACT FROM AUTHOR]

There are many indole alkaloids that contain diverse functional groups attached to the benzene ring on the indole core. Promising biological activities of these alkaloids have been reported. Herein, we report the indole C5‐selective bromination of indolo[2,3‐a]quinolizidine alkaloids by adding nearly equimolar amounts of Br3 ⋅ PyH and HCl in MeOH. The resulting reaction plausibly proceeds through an indoline intermediate by the nucleophilic addition of MeOH to the C3‐brominated indolenine intermediate. Data support the intermediacy of a C3‐, C5‐dibrominated indolenine intermediate as a brominating agent. These conditions demonstrate excellent selectivity for indole C5 bromination of natural products and their derivatives. Thus, these simple, mild, and metal‐free conditions allow for selective, late‐stage bromination followed by further chemical modifications. The utility of the brominated product prepared from naturally occurring yohimbine was demonstrated through various derivatizations, including a bioinspired heterodimerization reaction. [ABSTRACT FROM AUTHOR]

In contrast to cats and dogs, here we report that the α2-adrenergic receptor antagonist yohimbine is emetic and corresponding agonists clonidine and dexmedetomidine behave as antiemetics in the least shrew model of vomiting. Yohimbine (0, 0.5, 0.75, 1, 1.5, 2, and 3 mg/kg, i.p.) caused vomiting in shrews in a bell-shaped and dose-dependent manner, with a maximum frequency (0.85 ± 0.22) at 1 mg/kg, which was accompanied by a key central contribution as indicated by increased expression of c-fos, serotonin and substance P release in the shrew brainstem emetic nuclei. Our comparative study in shrews demonstrates that clonidine (0, 0.1, 1, 5, and 10 mg/kg, i.p.) and dexmedetomidine (0, 0.01, 0.05, and 0.1 mg/kg, i.p.) not only suppress yohimbine (1 mg/kg, i.p.)-evoked vomiting in a dose-dependent manner, but also display broad-spectrum antiemetic effects against diverse well-known emetogens, including 2-Methyl-5-HT, GR73632, McN-A-343, quinpirole, FPL64176, SR141716A, thapsigargin, rolipram, and ZD7288. The antiemetic inhibitory ID50 values of dexmedetomidine against the evoked emetogens are much lower than those of clonidine. At its antiemetic doses, clonidine decreased shrews' locomotor activity parameters (distance moved and rearing), whereas dexmedetomidine did not do so. The results suggest that dexmedetomidine represents a better candidate for antiemetic potential with advantages over clonidine. [ABSTRACT FROM AUTHOR]

Background: We investigated the effect of a 5-day low-dose ritonavir therapy, as it is used in the treatment of COVID-19 with nirmatrelvir/ritonavir, on the pharmacokinetics of three factor Xa inhibitors (FXaI). Concurrently, the time course of the activities of the cytochromes P450 (CYP) 3A4, 2C19, and 2D6 was assessed. Methods: In an open-label, fixed sequence clinical trial, the effect and duration of a 5-day oral ritonavir (100 mg twice daily) treatment on the pharmacokinetics of three oral microdosed FXaI (rivaroxaban 25 µg, apixaban 25 µg, and edoxaban 50 µg) and microdosed probe drugs (midazolam 25 µg, yohimbine 50 µg, and omeprazole 100 µg) was evaluated in eight healthy volunteers. The plasma concentrations of all drugs were quantified using validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) methods and pharmacokinetics were analysed using non-compartmental analyses. Results: Ritonavir increased the exposure of apixaban, edoxaban, and rivaroxaban, but to a different extent the observed area under the plasma concentration–time curve (geometric mean ratio 1.29, 1.46, and 1.87, respectively). A strong CYP3A4 inhibition (geometric mean ratio > 10), a moderate CYP2C19 induction 2 days after ritonavir (0.64), and no alteration of CYP2D6 were observed. A CYP3A4 recovery half-life of 2.3 days was determined. Conclusion: This trial with three microdosed FXaI suggests that at most the rivaroxaban dose should be reduced during short-term ritonavir, and only in patients receiving high maintenance doses. Thorough time series analyses demonstrated differential effects on three different drug-metabolising enzymes over time with immediate profound inhibition of CYP3A4 and only slow recovery after discontinuation. Clinical Trial Registration: EudraCT number: 2021-006643-39. [ABSTRACT FROM AUTHOR]

Quercetin, a plant-derived flavonoid, is an antioxidant and has demonstrated antidepressant and anti-inflammatory activities in several animal models. However, there is scanty information on the underlying mechanisms of its antidepressant property. This present study aimed at assessing the involvement of monoaminergic systems in the antidepressant-like activity of quercetin in experimental animals. Mice received varying doses of quercetin (25, 50 &100 mg/kg daily) and were then subjected to open field test (OPF), despair tests, the reserpine test, and the yohimbine lethality test (YLT). In addition, monoaminergic involvement was investigated by combining quercetin (100 mg/kg) with dopaminergic antagonists (haloperidol and sulpiride), adrenergic blockers (prazosin, propranolol and yohimbine), and serotonergic blockers/inhibitors (metergoline). The results showed that quercetin produced significant anti-immobility effects in the forced swim test (FST) and tail suspension test (TST), suggesting antidepressant activity. In addition, the potentiation of yohimbine lethality by quercetin further indicates its antidepressant-like property. This antidepressant action demonstrated was, however, blocked when quercetin was co-administered with dopaminergic, adrenergic and serotonergic antagonists, suggesting involvement of the monoaminergic system in the antidepressant action of quercetin. Nevertheless, quercetin did not significantly alter the locomotor activity of mice, which implies lack of stimulant effect. Taken together, these outcomes suggest that monoaminergic systems are likely involved in the anti-depressant effect of quercetin in mice. [ABSTRACT FROM AUTHOR]

Introduction: The adrenergic and opioidergic systems play a crucial role in regulating cognitive and non-cognitive behaviors. The aim of this study was to evaluate the effects of CA1 α2-adrenoceptors on the exploratory behaviors induced by morphine. Methods: This assessment was conducted in rats using the elevated plus-maze test based on a test-retest paradigm. Bilateral guide cannulas were stereotaxically implanted in the CA1 regions of rats to allow intra-CA1 α2-adrenoceptors agonist (clonidine) or antagonist (yohimbine) microinjections. Results: Pre-test administration of morphine (6 mg/kg) showed an anxiolytic-like response. The extension of this effect during the retest session, 24h later, indicated impairment of aversive memory. Pre-test microinjection of clonidine (4 µg/rat) induced anxiolytic-like behavior on the test day in the absence or presence of a subthreshold dose of morphine (4 mg/kg) and increased avoidance to the open-arms during the retest session, but it was not significant compared with control group. Pre-test microinjection of yohimbine (4 µg/rat) induced an anxiogenic-like behavior on test day in the absence or presence of an effective dose of morphine (6mg/kg) and increased avoidance to the open-arms during the retest session. Concurrent microinjection of a subthreshold dose of yohimbine (1 μg/rat) with an effective dose of clonidine or with an effective dose of clonidine plus a subthreshold dose of morphine blocked anxiolytic-like behaviors, but did not change avoidance to the open-arms. Conclusion: According to our findings, it appears that CA1 α2-adrenoceptors affect anxiolytic-like effects of morphine, but they do not appear to play a significant role in the morphine-induced memory impairment. [ABSTRACT FROM AUTHOR]

Thymoquinone (TQ) is the main biologically active substance of Nigella sativa (black seeds). It has anti-cancer, anti-inflammatory, anti-diabetic, anti-oxidative and anti-nociceptive properties. This study was aimed to explore the effect of TQ on acetic acid-induced visceral nociception. The central mechanisms of the effect of TQ were investigated using cannabinergic (AM251) and a2-adrenergic (yohimbine [Yoh]) antagonists. The lateral ventricle of the brain was cannulated for intracerebroventricular (ICV) injections. Visceral nociception was induced by intra-peritoneal (IP) injection of acetic acid (1.00% in a volume of 1.00 mL). Measuring the latency time to the first writhing appearance and counting the number of writhing in 5-min intervals for a period of 60 min were performed. Locomotor activity was determined using an open-field test. Oral administration (PO) of 2.50 and 10.00 mg kg-1 TQ increased the latency time to the first writhing appearance and decreased the number of writhing. The AM251 (5.00 µg per rat; ICV) and Yoh (5.00 µg per rat; ICV) partially prevented TQ (10.00 mg kg-1; PO)-induced anti-nociception. Locomotor activity was not altered by these treatments. The results of the present study showed that TQ had the ability to reduce visceral nociception caused by IP injection of acetic acid. The central mechanisms of this action of TQ might be partially mediated by cannabinergic and a2-adrenegic receptors. [ABSTRACT FROM AUTHOR]

Exercise performance tends to suffer during the morning compared to the evening, which may decrease potential training adaptations. Currently, it is unclear how nutritional interventions may affect this phenomenon and whether supplementation may allow for the attainment of optimal performance regardless of the time of day. The purpose of this study was to investigate the effects of acute yohimbine ingestion on morning-associated decrements in performance and psychophysiological responses to exercise. Physically active females (n = 16) were recruited to participate in three total visits, each with a different treatment: (1) placebo-morning (PL-AM), (2) yohimbine-morning (YHM-AM; oral 2.5 mg), and (3) placebo-afternoon (PM). The morning and afternoon visits occurred between 7:00–8:00 h and 16:00–17:00 h, respectively. The experimental treatments in the morning were ingested 20 min prior to capillary blood collection, which was completed pre- and post-exercise. Following a warm-up, participants completed a 2000 m time trial on a rowing ergometer. Power output, heart rate (HR), and rating of perceived exertion (RPE) were recorded every minute. Time to competition (TTC) and subjective energy, focus, and alertness were documented post-exercise. Pre- and post-exercise blood lactate (La) and plasma hypoxanthine (HX) levels were also assessed. The trials were separated by a 48 h washout period. The results showed that power output (p = 0.010) was lower and TTC (p = 0.003) was significantly slower with PL-AM compared to PM. Furthermore, YHM-AM resulted in higher power output (p = 0.035) and faster TTC (p = 0.007) compared to PL-AM, with no differences compared to PM (p > 0.05). Post-exercise La was significantly lower with YHM-AM compared to PL-AM (p = 0.046) and PM (p = 0.001). Pre-exercise plasma HX, as measured via conversion to xanthine, was significantly higher with PM (p = 0.039), while the levels trended higher with YHM-AM (p = 0.060) compared to PL-AM. Subjective energy was higher with YHM-AM (p = 0.045) and PM (p = 0.009) compared to PL-AM, while alertness was only higher for YHM-AM compared to PL-AM (p = 0.045). No statistical differences between the treatments were found for RPE or HR (p > 0.05). These findings indicate that YHM ingestion attenuates performance decrements in the morning. Improvements in performance may be underpinned by improved feelings of energy and alterations in metabolism. Practically, YHM may represent an effective ergogenic aid to combat a lack of energy and low performance during the morning. [ABSTRACT FROM AUTHOR]

Simple Summary: Surgical anesthetic management during short-term procedures such as sterilization is highly relevant due to the hemodynamic, cardiorespiratory, and autonomic alterations that could be present. In the case of sterilization aimed at free-roaming cats, a drug combination to provide hypnosis, analgesia, and autonomic balance can reduce these anesthetic risks. Cat neutering through trap-neuter-return (TNR) programs is a non-lethal alternative for free-roaming cat population control. This study is an evaluation of anesthesia used in the high-quality, high-volume spay and neuter (HQHVSN) model of a TNR program for free-roaming cats in Seoul, Korea. A combination of tiletamine-zolazepam, ketamine, and xylazine (ZKX) was intramuscularly administered to obtain anesthesia. The evaluation was based on the records of 1261 cats with complete records of the injected volume of anesthetics and times, out of a total of 1361 cats. The study confirmed the safety and efficacy of the ZKX combination administered IM in a TNR program in the HQHVSN model and provided a range of appropriate doses. This will enable TNR programs to be more effective and contribute to a stable free-roaming cat population that can be successfully controlled for welfare. This study was performed to evaluate the anesthetic protocol used in the high-quality, high-volume spay and neuter (HQHVSN) of free-roaming cats in Seoul, Korea from 2017 to 2022. The evaluation was performed on a total of 1261 free-roaming cats, with an average weight of 3.48 ± 1.04 kg. The anesthetic combination tiletamine-zolazepam, ketamine, and xylazine (ZKX) was injected intramuscularly. The actual drug doses administered were tiletamine-zolazepam 5.52 ± 1.70 mg/kg, ketamine 8.94 ± 3.60 mg/kg, and xylazine 1.11 ± 0.34 mg/kg. Additional doses were required in 275 cats out of a total of 1261 (21.8%). Following anesthesia and surgery, 1257 cats (99.7%) were returned to their original locations. Four cats (0.3%) died postoperatively. The mean duration of anesthesia (from ZKX combination to yohimbine administration) was 26 ± 22 min for males and 55 ± 36 min for females, while the time from yohimbine administration to the recovery was 31 ± 22 min for males and 20 ± 17 min for females. The use of ZKX for HQHVSN of free-roaming cats is inexpensive, provides predictable results, can be administered quickly and easily in a small volume, and is associated with a low mortality rate during the first 72 h post-surgery. [ABSTRACT FROM AUTHOR]

Background Acute stress alters risk-based decision-making; however, the underlying neural and neurochemical substrates are underexplored. Given their well-documented stress-inducing effects in humans and laboratory animals, glucocorticoids such as cortisol and corticosterone and the α2-adrenoceptor antagonist yohimbine represent potent pharmacological tools to mimic some characteristics of acute stress. Methods Here, we analyzed the effects of the pharmacological stressors corticosterone and yohimbine given systemically on risk-based decision-making in male rats. Moreover, we investigated whether pharmacological stressor effects on risk-based decision-making involve dopamine D1 receptor stimulation in the dorsal prelimbic cortex (PL). We used a risk discounting task that requires choosing between a certain/small reward lever that always delivered 1 pellet and a risky/large reward lever that delivered 4 pellets with a decreasing probability across subsequent trials. Results Systemic administration of yohimbine increased the preference for the risky/large reward lever. By contrast, systemic single administration of corticosterone did not significantly promote risky choice. Moreover, co-administration of corticosterone did not enhance the effects of yohimbine on risky choice. The data further show that the increased preference for the risky/large reward lever under systemic yohimbine was lowered by a concurrent pharmacological blockade of dopamine D1 receptors in the PL. Conclusions Our rodent data provide causal evidence that stimulation of PL D1 receptors may represent a neurochemical mechanism by which the acute pharmacological stressor yohimbine, and possibly nonpharmacological stressors as well, promote risky choice. [ABSTRACT FROM AUTHOR]

Introduction. Alzheimer's disease (AD) is a neurodegenerative disorder with no conclusive remedy. Yohimbine, found in Rauwolfia vomitoria, may reduce brain inflammation by targeting tumour necrosis factor-alpha (TNFα), implicated in AD pathogenesis. Metoserpate, a synthetic compound, may inhibit TNFα. The study is aimed at assessing the potential utility of repurposing metoserpate for TNFα inhibition to reduce neuronal damage and inflammation in AD. The development of safe and effective treatments for AD is crucial to address the growing burden of the disease, which is projected to double over the next two decades. Methods. Our study repurposed an FDA-approved drug as TNFα inhibitor for AD management using structural similarity studies, molecular docking, and molecular dynamics simulations. Yohimbine was used as a reference compound. Molecular docking used SeeSAR, and molecular dynamics simulation used GROMACS. Results. Metoserpate was selected from 10 compounds similar to yohimbine based on pharmacokinetic properties and FDA approval status. Molecular docking and simulation studies showed a stable interaction between metoserpate and TNFα over 100 ns (100000 ps). This suggests a reliable and robust interaction between the protein and ligand, supporting the potential utility of repurposing metoserpate for TNFα inhibition in AD treatment. Conclusion. Our study has identified metoserpate, a previously FDA-approved antihypertensive agent, as a promising candidate for inhibiting TNFα in the management of AD. [ABSTRACT FROM AUTHOR]

The crucial function of bioactive ligands in the interaction with diverse proteins has garnered significant attention in the fields of pharmacokinetics and pharmacodynamics, hence generating considerable interest in the discipline of medicinal chemistry. To better comprehend its molecular mechanism, we implored a detailed biophysical analyses (using multi-spectroscopic, calorimetric, and computational tools) of the carrier protein Lysozyme, Lyz (also known as "Muramidase") with Yohimbine (Yoh). The binding constant (K) of the Lyz-Yoh complex was estimated to be 105 M−1, exhibiting a progressive decline as temperature increased. The thermodynamic-profiling indicated the binding to be associated with an exothermic interaction driven by entropy. The confirmation of spontaneous binding is evidenced by the observed decrease in free energy. The variation in ionic strength indicated that non-polyelectrolytic forces were involved in the association. In addition, it was investigated how different metal ions affected the Lyz-Yoh binding. Calorimetric studies revealed the binding to be exothermic in nature, which also aligns with spectroscopic data. Results from circular dichroism (CD) experiments, demonstrated the structural alterations brought about in Lyz by Yoh. The likely binding sites and protein residuals to the ligand (Yoh) were illustrated using theoretical techniques, viz., molecular docking and molecular dynamic (MD) simulation. In clinical and pharmaceutical assessments, these metrics are especially relevant for rational drug development. [Display omitted] • Spontaneous and thermodynamically favorable association. • Competition between the metal ions and Yoh binding to Lyz at the same binding site. • A crucial role was played by the hydrophobic forces and hydrogen bonding. • Lyz microenvironmental changes after ligation with Yoh. [ABSTRACT FROM AUTHOR]

Conditioned place preference (CPP) paradigm in zebrafish has been used to measure drug reward, but there is limited research on CPP reinstatement to determine relapse vulnerability. The present study aimed to investigate extinction and reinstatement of methamphetamine (MA)‐induced CPP in zebrafish and evaluate the model's predictive validity. Zebrafish received different doses of MA (0–60 mg/kg) during CPP training. The preferred dose of MA at 40 mg/kg was used for extinction via either confined or nonconfined procedures. The extinguished CPP was reinstated by administering a priming dose of MA (20 mg/kg) or various stressors. To assess persistent susceptibility to reinstatement, MA CPP and reinstatement were retested following 14 days of abstinence. In addition, the effects of SCH23390, naltrexone, and clonidine on MA CPP during acquisition, expression, or reinstatement phases were monitored. MA induced CPP in a dose‐dependent manner. Both nonconfined and confined extinction procedures time‐dependently reduced the time spent on the MA‐paired side. A priming dose of MA, chasing stress, or yohimbine reinstated the extinguished CPP. After 14 days of abstinence, the MA CPP remained extinguished and was significantly reinstated by MA priming or chasing stress. Similar to the observations in rodents, SCH23390 suppressed the acquisition of MA CPP, naltrexone reduced the expression and MA priming‐induced reinstatement, while clonidine prevented stress‐induced reinstatement of MA CPP. This work expanded the zebrafish CPP paradigm to include extinction and reinstatement phases, demonstrating predictive validity and highlighting its potential as a valuable tool for exploring drug relapse. [ABSTRACT FROM AUTHOR]

The communication between the nervous and immune systems plays a crucial role in regulating immune cell function and inflammatory responses. Sympathetic neurons, which innervate the spleen, have been implicated in modulating immune cell activity. The neurotransmitter norepinephrine (NE), released by sympathetic neurons, influences immune cell responses by binding to adrenergic receptors on their surface. The alpha-2 adrenergic receptor (α2AR), expressed predominantly on sympathetic neurons, has received attention due to its autoreceptor function and ability to modulate NE release. In this study, we used fast-scan cyclic voltammetry (FSCV) to provide the first subsecond measurements of NE released in the white pulp region of the spleen and validated it with yohimbine, a known antagonist of α2AR. For further application of FSCV in neuroimmunology, we investigated the extent to which subsecond NE from sympathetic neurons is important for immune cell physiology and cytokine production, focusing on tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), and interleukin-6 (IL-6). Our findings provide insights into the regulatory mechanisms underlying sympathetic-immune interactions and show the significance of using FSCV, a traditional neurochemistry technique, to study these neuroimmune mechanisms. [ABSTRACT FROM AUTHOR]

Cleomin, a 1,3-oxazolidine-2-thione, was recently isolated from Neocalyptrocalyx longifolium, a species traditionally used for treating painful conditions. Reports about the pharmacological activities of cleomin are lacking. Here, the antinociceptive effects of cleomin were investigated using mice models of pain, namely the formalin, the cold plate, and the tail flick tests. Motor integrity was assessed in the rota-rod test. Antagonism assays and in silico docking analyses were performed to investigate the putative mechanisms of action. Cleomin (12.5–25 mg/kg), at doses that did not induce motor impairment, induced dose-dependent antinociception in both early and late phases of the formalin test and reduced nociceptive behaviors in both the cold plate and tail flick tests. Pretreatments with phaclofen and atropine attenuated the antinociceptive effects of cleomin, implicating the involvement of GABAB and muscarinic receptors. In silico docking studies suggested satisfactory coupling between cleomin and GABAB and M2 receptors, hence corroborating their role in cleomin's activity. Pretreatments with naloxone, yohimbine, bicuculline, and methysergide did not affect the antinociception of cleomin. In silico pharmacokinetics prediction showed a good drug ability profile of cleomin. In conclusion, cleomin promoted antinociception mediated by GABAB and muscarinic receptors. These findings support further investigation of the analgesic potential of cleomin. [ABSTRACT FROM AUTHOR]

Aim. To characterize a new hormone-independent strain 1-27 of R. serpentina tissue culture. Methods. Plant tissue culture, biochemical and cytological analysis, statistical methods. Results. The strain is maintained on the specially designed simple-composition hormone-free 10C medium. The maximum biomass yield was at day 69 of subculture (693.5 g/l of live biomass, 43.0 g/l of dry biomass), the weight of cell biomass increased 15-18 times over a subculture period. The maximum content of indole alkaloids was observed from 88 to 108 days of subculture. The dry biomass contained 4.0% of total indole alkaloids, 1.64% of ajmaline-like alkaloids, 0.789% of ajmaline, 0.337% of vomilenine, and 0.006% of each yohimbine and reserpine. The strain is a heterogeneous mixoploid cell population with a modal class of 22 to 33 chromosomes (2n = 22), which characterized by significant cell and nuclear polymorphism. Conclusions. The K-27M strain of R. serpentina cultured tissue is a prospective producer of indole alkaloids. [ABSTRACT FROM AUTHOR]

Yohimbine (YHB) has been reported to possess anti-inflammatory, anticancer, and cardiac function-enhancing properties. Additionally, it has been reported to inhibit the proliferation, migration, and neointimal formation of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor (PDGF) stimulation by suppressing the phospholipase C-gamma 1 pathway. However, the transcriptional regulatory mechanism of YHB controlling the behavior of VSMCs is not fully understood. In this study, YHB downregulated the expression of cell cycle regulatory proteins, such as proliferating cell nuclear antigen (PCNA), cyclin D1, cyclin-dependent kinase 4 (CDK4), and cyclin E, by modulating the transcription factor FOXO3a in VSMCs induced by PDGF. Furthermore, YHB decreased p-38 and mTOR phosphorylation in a dose-dependent manner. Notably, YHB significantly reduced the phosphorylation at Y397 and Y925 sites of focal adhesion kinase (FAK), and this effect was greater at the Y925 site than Y397. In addition, the expression of paxillin, a FAK-associated protein known to bind to the Y925 site of FAK, was significantly reduced by YHB treatment in a dose-dependent manner. A pronounced reduction in the migration and proliferation of VSMCs was observed following co-treatment of YHB with mTOR or p38 inhibitors. In conclusion, this study shows that YHB inhibits the PDGF-induced proliferation and migration of VSMCs by regulating the transcription factor FOXO3a and the mTOR/p38/FAK signaling pathway. Therefore, YHB may be a potential therapeutic candidate for preventing and treating cardiovascular diseases such as atherosclerosis and vascular restenosis.

In contrast to cats and dogs, here we report that the α2-adrenergic receptor antagonist yohimbine is emetic and corresponding agonists clonidine and dexmedetomidine behave as antiemetics in the least shrew model of vomiting. Yohimbine (0, 0.5, 0.75, 1, 1.5, 2, and 3 mg/kg, i.p.) caused vomiting in shrews in a bell-shaped and dose-dependent manner, with a maximum frequency (0.85 ± 0.22) at 1 mg/kg, which was accompanied by a key central contribution as indicated by increased expression of c-fos, serotonin and substance P release in the shrew brainstem emetic nuclei. Our comparative study in shrews demonstrates that clonidine (0, 0.1, 1, 5, and 10 mg/kg, i.p.) and dexmedetomidine (0, 0.01, 0.05, and 0.1 mg/kg, i.p.) not only suppress yohimbine (1 mg/kg, i.p.)-evoked vomiting in a dose-dependent manner, but also display broad-spectrum antiemetic effects against diverse well-known emetogens, including 2-Methyl-5-HT, GR73632, McN-A-343, quinpirole, FPL64176, SR141716A, thapsigargin, rolipram, and ZD7288. The antiemetic inhibitory ID50 values of dexmedetomidine against the evoked emetogens are much lower than those of clonidine. At its antiemetic doses, clonidine decreased shrews’ locomotor activity parameters (distance moved and rearing), whereas dexmedetomidine did not do so. The results suggest that dexmedetomidine represents a better candidate for antiemetic potential with advantages over clonidine.

DNA interactions with multivalent ligand(s) have increasingly become the subject of substantial research. For several small molecules with therapeutic potential, nucleic acids serve as their primary molecular target. Such interaction has been shown to affect transcription or replication, ultimately leading to apoptotic cell death. As a result, researchers are becoming increasingly interested in understanding how small molecules interact with DNA making it possible to develop new, DNA-specific drugs. The bioactive indole alkaloid, Yohimbe (Yohimbine; Yh) has been broadly studied in pharmacological properties while its binding mode to DNA has not been explicated so far. This study adopted molecular modelling and multi-spectroscopic methods to investigate the interaction between Yohimbine and herring testes (HT DNA) in physiological conditions. Minor hypochromic and bathochromic shifts of fluorescence intensity were observed, suggesting the binding of Yh to HT DNA. The Scatchard plot analyses using the McGhee-von Hipple method revealed non-cooperative binding and affinities in the range of 105 M−1. The thermodynamic parameters suggested exothermic binding, which was favoured by negative enthalpy and positive entropy changes from temperature-dependent fluorescence experiments. Salt-dependent fluorescence suggested that the interaction between the ligand and DNA was governed by non-polyelectrolytic forces. The results of iodide quenching, urea denaturation assay, dye displacement, and in silico molecular docking, suggested groove binding of Yh to HT DNA. Thus, the groove binding mechanism of interaction was validated by both biophysical and computational techniques. The structural elucidation and energetic profiling of Yh's interaction with naturally occurring polymeric DNA can be useful to the development of DNA-targeted therapeutics. [ABSTRACT FROM AUTHOR]

Rationale: Balancing approach of positive and avoidance of negative stimuli is essential when faced with approach-avoidance conflicts, e.g., situations with both positive and negative outcomes. This balance is disturbed in several mental disorders, e.g., excessive avoidance in anxiety disorders, and heightened approach in substance use disorders. Since stress is assumed to impact these disorders' etiology and maintenance, it seems crucial to understand how stress influences behavior in approach-avoidance conflicts. Indeed, some studies suggested altered approach-avoidance behavior under acute stress, but the mechanism underlying these effects is unknown. Objectives: Investigate how the pharmacological manipulation of major stress mediators (cortisol and noradrenaline) influences task-based approach-avoidance conflict behavior in healthy individuals. Methods: Ninety-six participants (48 women, 48 men) received either 20mg hydrocortisone, 20mg yohimbine, both, or placebo before performing a task targeting foraging under predation in a fully crossed double-blind between-subject design. Moreover, we investigated effects of gender and endogenous testosterone and estradiol levels on approach-avoidance behavior. Results: While biological stress markers (cortisol concentration, alpha amylase activity) indicated successful pharmacological manipulation, behavior in approach-avoidance conflicts was not affected as expected. Although yohimbine administration affected risky foraging latency under predation, we found no main effect of hydrocortisone or their interaction on behavior. In contrast, we found gender differences for almost all behavioral outcome measures, which might be explained by differences in endogenous testosterone levels. Conclusions: The investigated major stress mediators were not sufficient to imitate previously shown stress effects on approach-avoidance conflict behavior. We discuss potential reasons for our findings and implications for future research. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy is the loss of sensory function beginning distally in the lower extremities, which is also characterized by pain and substantial morbidity. Furthermore, the locus coeruleus (LC) nucleus has been proposed to play an important role in descending pain control through the activation of a2-noradrenergic (NA) receptors in the spinal dorsal horn. We studied, on control and diabetic mice, the effect of electrical stimulation of the LC nucleus on the tactile responses in the caudalis division of the spinal trigeminal nucleus (Sp5C), which is involved in the relay of orofacial nociceptive information. Diabetes was induced in young adult C57BL/6J mice with one intraperitoneal injection of streptozotocin (50 mg/kg) daily for 5 days. The diabetic animals showed pain in the orofacial area because they had a decrease in the withdrawal threshold to the mechanical stimulation in the vibrissal pad. LC electrical stimulation induced the inhibition of vibrissal responses in the Sp5C neurons when applied at 50 and 100ms before vibrissal stimulation in the control mice; however, the inhibition was reduced in the diabetic mice. These effects may be due to a reduction in the tyrosine hydroxylase positive (TH+) fibers in the Sp5C, as was observed in diabetic mice. LC-evoked inhibition was decreased by an intraperitoneal injection of the antagonist of the a2-NA receptors, yohimbine, indicating that it was due to the activation of a2-NA receptors. The decrease in the LC-evoked inhibition in the diabetic mice was partially recovered when clonidine, a non-selective a2-agonist, was injected intraperitoneally. These findings suggest that in diabetes, there is a reduction in theNA inputs fromthe LC in the Sp5C thatmay favor the development of chronic pain. [ABSTRACT FROM AUTHOR]

Alcohol use disorder is a significant public health concern, further exacerbated by an increased risk of relapse due to stress. In addition, factors such as biological sex may contribute to the progression of addiction, as females are especially susceptible to stress-induced relapse. While there have been many studies surrounding potential pharmacological interventions for male stress-induced ethanol reinstatement, research regarding females is scarce. Recently, the neuropeptide oxytocin has gained interest as a possible pharmacological intervention for relapse. The present study examines how oxytocin affects yohimbine-induced reinstatement of ethanol-seeking in female rats using a self-administration paradigm. Adult female rats were trained to press a lever to access ethanol in daily self-administration sessions. Rats then underwent extinction training before a yohimbine-induced reinstatement test. Rats administered with yohimbine demonstrated significantly higher lever response indicating a reinstatement of ethanol-seeking behavior. Oxytocin administration, both systemically and directly into the central amygdala, attenuated the effect of yohimbine-induced reinstatement of ethanol-seeking behavior. The findings from this study establish that oxytocin is effective at attenuating alcohol-relapse behavior mediated by the pharmacological stressor yohimbine and that this effect is modulated by the central amygdala in females. This provides valuable insight regarding oxytocin's potential therapeutic effect in female stress-induced alcohol relapse. [ABSTRACT FROM AUTHOR]

Background: Yohimbine has been suggested as a possible therapy for type 2 diabetes mellitus. Thus, we evaluated antidiabetic activity of yohimbine in Streptozocin (STZ)-induced rats. Materials and Methods: Yohimbine's anti-diabetic effects were investigated by giving male Wistar rats an injection of Streptozotocin (STZ) to cause diabetes and then analyzing their blood samples. Blood Glucose Levels (BGLs) and glucose tolerance was recorded using an FBG and an OGTT, respectively. Triglyceride, Low-Density Lipoprotein (LDL-c), and High-Density Lipoprotein (HDL-c) levels were determined to examine the impact of yohimbine administration on the lipid profile of diabetic rats. Finally, yohimbine's impact on pancreatic histological damage due to diabetes was investigated. Results: Overall, our findings imply that yohimbine, an alpha-2 adrenoceptor antagonist, helped diabetic group have better glucose tolerance. Yohimbine-treated mice had lower BGLs and enhanced lipid profiles, with lessened triglyceride and LDL-c levels and improved HDL-c levels. Histopathological analyses showed that the size and density of pancreatic cells had increased and that they had regenerated remarkably. Conclusion: As a result, we can conclude that yohimbine may have therapeutic value for restoring lipid-carbohydrate equilibrium and in repairing diabetes-related pancreatic damage. [ABSTRACT FROM AUTHOR]

Preclinical and clinical work suggests that mifepristone may be a viable treatment for alcohol use disorder (AUD). This was a Phase 1/2, outpatient, cross‐over, randomized, double‐blind, placebo‐controlled trial with non‐treatment‐seeking individuals with AUD (N = 32). We assessed safety, alcohol craving and consumption, after 1‐week mifepristone 600 mg/day administration, in a human laboratory study comprised of a single oral yohimbine administration (32.4 mg), a cue‐reactivity procedure and alcohol self‐administration. Safety was monitored by adverse events and hemodynamic parameters, alcohol craving by alcohol craving questionnaire and cue‐induced saliva output. During the alcohol self‐administration, we assessed alcohol pharmacokinetics, subjective effects and consumption. Outcomes were assessed using Generalized Estimating Equations and mediation analysis. Mild‐moderate adverse events were reported in both conditions. There was no statistically significant difference between mifepristone and placebo in alcohol pharmacokinetics and subjective effects. Furthermore, blood pressure increased only in the placebo condition after the stress‐induced laboratory procedures. Mifepristone, compared to placebo, significantly reduced alcohol craving and increased cortisol levels. Mifepristone‐induced cortisol increase was not a mediator of alcohol craving. Mifepristone, compared to placebo, did not reduce alcohol consumption in the laboratory or in a naturalistic setting. This study successfully translated a developed preclinical procedure to a human laboratory study, confirming the safety of mifepristone in people with AUD and providing evidence to its role in reducing alcohol craving under stress procedures. The lack of effects on alcohol drinking may be related to the selection of non‐treatment seekers and suggests future treatment‐oriented trials should investigate mifepristone in people with AUD. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy is the loss of sensory function beginning distally in the lower extremities, which is also characterized by pain and substantial morbidity. Furthermore, the locus coeruleus (LC) nucleus has been proposed to play an important role in descending pain control through the activation of α2-noradrenergic (NA) receptors in the spinal dorsal horn. We studied, on control and diabetic mice, the effect of electrical stimulation of the LC nucleus on the tactile responses in the caudalis division of the spinal trigeminal nucleus (Sp5C), which is involved in the relay of orofacial nociceptive information. Diabetes was induced in young adult C57BL/6J mice with one intraperitoneal injection of streptozotocin (50 mg/kg) daily for 5 days. The diabetic animals showed pain in the orofacial area because they had a decrease in the withdrawal threshold to the mechanical stimulation in the vibrissal pad. LC electrical stimulation induced the inhibition of vibrissal responses in the Sp5C neurons when applied at 50 and 100 ms before vibrissal stimulation in the control mice; however, the inhibition was reduced in the diabetic mice. These effects may be due to a reduction in the tyrosine hydroxylase positive (TH+) fibers in the Sp5C, as was observed in diabetic mice. LC-evoked inhibition was decreased by an intraperitoneal injection of the antagonist of the α2-NA receptors, yohimbine, indicating that it was due to the activation of α2-NA receptors. The decrease in the LC-evoked inhibition in the diabetic mice was partially recovered when clonidine, a non-selective α2-agonist, was injected intraperitoneally. These findings suggest that in diabetes, there is a reduction in the NA inputs from the LC in the Sp5C that may favor the development of chronic pain.

The neurofunctional basis of the noradrenergic (NA) system and its associated disorders is still very incomplete because in vivo imaging tools in humans have been missing up to now. Here, for the first time, we use [11C]yohimbine in a large sample of subjects (46 healthy volunteers, 23 females, 23 males; aged 20–50) to perform direct quantification of regional alpha 2 adrenergic receptors' (α2-ARs) availability in the living human brain. The global map shows the highest [11C]yohimbine binding in the hippocampus, the occipital lobe, the cingulate gyrus, and the frontal lobe. Moderate binding was found in the parietal lobe, thalamus, parahippocampus, insula, and temporal lobe. Low levels of binding were found in the basal ganglia, the amygdala, the cerebellum, and the raphe nucleus. Parcellation of the brain into anatomical subregions revealed important variations in [11C]yohimbine binding within most structures. Strong heterogeneity was found in the occipital lobe, the frontal lobe, and the basal ganglia, with substantial gender effects. Mapping the distribution of α2-ARs in the living human brain may prove useful not only for understanding the role of the NA system in many brain functions, but also for understanding neurodegenerative diseases in which altered NA transmission with specific loss of α2-ARs is suspected. [ABSTRACT FROM AUTHOR]

The noradrenaline system attracts attention for its role in mood disorders and neurodegenerative diseases but the lack of well-validated methods impairs our understanding when assessing its function and release in vivo. This study combines simultaneous positron emission tomography (PET) and microdialysis to explore if [11C]yohimbine, a selective antagonist radioligand of the α2 adrenoceptors, may be used to assess in vivo changes in synaptic noradrenaline during acute pharmacological challenges. Anesthetised Göttingen minipigs were positioned in a head holder in a PET/CT device. Microdialysis probes were placed in the thalamus, striatum and cortex and dialysis samples were collected every 10 min. Three 90 min [11C]yohimbine scans were acquired: at baseline and at two timepoints after the administration of amphetamine (1–10 mg/kg), a non-specific releaser of dopamine and noradrenaline, or nisoxetine (1 mg/kg), a specific noradrenaline transporter inhibitor. [11C]yohimbine volumes of distribution (VT) were obtained using the Logan kinetic model. Both challenges induced a significant decrease in yohimbine VT, with time courses reflecting their different mechanisms of action. Dialysis samples revealed a significant increase in noradrenaline extracellular concentrations after challenge and an inverse correlation with changes in yohimbine VT. These data suggest that [11C]yohimbine can be used to evaluate acute variations in synaptic noradrenaline concentrations after pharmacological challenges. [ABSTRACT FROM AUTHOR]

Temporal discounting is a phenomenon where a reward loses its value as a function of time (e.g., a reward is more valuable immediately than when it delays in time). This is a type of intertemporal decision-making that has an association with impulsivity and self-control. Many pathologies exhibit higher discounting rates, meaning they discount more the values of rewards, such as addictive behaviors, bipolar disorder, attention-deficit/hyperactivity disorders, social anxiety disorders, and major depressive disorder, among others; thus, many studies look for the mechanism and neuromodulators of these decisions. This systematic review aims to investigate the association between pharmacological administration and changes in temporal discounting. A search was conducted in PubMed, Scopus, Web of Science, Science Direct and Cochrane. We used the PICO strategy: healthy humans (P-Participants) that received a pharmacological administration (I-Intervention) and the absence of a pharmacological administration or placebo (C-Comparison) to analyze the relationship between the pharmacological administration and the temporal discounting (O-outcome). Nineteen studies fulfilled the inclusion criteria. The most important findings were the involvement of dopamine modulation in a U-shape for choosing the delayed outcome (metoclopradime, haloperidol, and amisulpride). Furthermore, administration of tolcapone and high doses of d-amphetamine produced a preference for the delayed option. There was a time-dependent hydrocortisone effect in the preference for the immediate reward. Thus, it can be concluded that dopamine is a crucial modulator for temporal discounting, especially the D2 receptor, and cortisol also has an important time-dependent role in this type of decision. One of the limitations of this systematic review is the heterogeneity of the drugs used to assess the effect of temporal discounting. [ABSTRACT FROM AUTHOR]

Introduction: Phytochemicals have garnered much attention because they are useful in managing several human diseases. Yohimbine is one such phytochemical with significant pharmacological potential and could be exploited for research by medicinal chemists. It is an indole alkaloid obtained from various natural/synthetic sources.Aims and Results: The research on yohimbine started early, and its use as a stimulant and aphrodisiac by humans has been reported for a long time. The pharmacological activity of yohimbine is mediated by the combined action of the central and peripheral nervous systems. It selectively blocks the pre and postsynaptic α2-adrenergic receptors and has a moderate affinity for α1 and α2 subtypes. Yohimbine also binds to other behaviourally relevant monoaminergic receptors in the following order: α-2 NE > 5HT-1A>, 5HT-1B > 1-D > D3 > D2 receptors.Conclusion: The current review highlights some significant findings that contribute to developing yohimbine-based drugs. It also highlights the therapeutic potential of yohimbine against selected human diseases. However, further research is recommended on the pharmacokinetics, molecular mechanisms, and drug safety requirements using well-designed randomized clinical trials to produce yohimbine as a pharmaceutical agent for human use.Key MessagesYohimbine is a natural indole alkaloid with significant pharmacological potential.Humans have used it as a stimulant and aphrodisiac from a relatively early time.It blocks the pre- and postsynaptic α2-adrenergic receptors that could be exploited for managing erectile dysfunction, myocardial dysfunction, inflammatory disorders, and cancer.

Yohimbine is a small indole alkaloid derived from the bark of the yohimbe tree with documented biological activity, including anti-inflammatory, erectile dysfunction relieving, and fat-burning properties. Hydrogen sulfide (H2S) and sulfane sulfur-containing compounds are regarded as important molecules in redox regulation and are involved in many physiological processes. Recently, their role in the pathophysiology of obesity and obesity-induced liver injury was also reported. The aim of the present study was to verify whether the mechanism of biological activity of yohimbine is related to reactive sulfur species formed during cysteine catabolism. We tested the effect of yohimbine at doses of 2 and 5 mg/kg/day administered for 30 days on aerobic and anaerobic catabolism of cysteine and oxidative processes in the liver of high-fat diet (HFD)-induced obese rats. Our study revealed that HFD resulted in a decrease in cysteine and sulfane sulfur levels in the liver, while sulfates were elevated. In the liver of obese rats, rhodanese expression was diminished while lipid peroxidation increased. Yohimbine did not influence sulfane sulfur and thiol levels in the liver of obese rats, however, this alkaloid at a dose of 5 mg decreased sulfates to the control level and induced expression of rhodanese. Moreover, it diminished hepatic lipid peroxidation. It can be concluded that HFD attenuates anaerobic and enhances aerobic cysteine catabolism and induces lipid peroxidation in the rat liver. Yohimbine at a dose of 5 mg/kg can alleviate oxidative stress and reduce elevated concentrations of sulfate probably by the induction of TST expression. [ABSTRACT FROM AUTHOR]

Rationale: Stress may contribute to relapse to alcohol use in part by enhancing reactivity to cues previously paired with alcohol. Yet, standard models of stress-induced reinstatement generally use contingent presentations of alcohol-paired cues to reinforce instrumental behaviors, making it difficult to isolate the ability of cues to invigorate alcohol-seeking. Objective: Here we sought to test the impact of stress on behavioral responses to alcohol-paired cues, using a model of stress-induced reinstatement of Pavlovian conditioned approach, inspired by Nadia Chaudhri's work on context-induced reinstatement. Methods: Long Evans rats were trained to associate one auditory cue with delivery of alcohol or sucrose and an alternative auditory cue with no reward. Following extinction training, rats were exposed to a stressor prior to being re-exposed to the cues under extinction conditions. We assessed the effects of yohimbine, intermittent footshock and olfactory cues paired with social defeat on responses to alcohol-paired cues and the effects of yohimbine on responses to sucrose-paired cues. Results: The pharmacological stressor, yohimbine, enhanced alcohol seeking in a Pavlovian setting, but not in a cue-selective manner. Intermittent footshock and social defeat cues did not enhance alcohol seeking in this paradigm. Conclusions: While yohimbine elicited reinstatement of reward-seeking in a Pavlovian setting, these effects may be unrelated to activation of stress systems or to interactions with specific cues. [ABSTRACT FROM AUTHOR]

Photoremovable protecting groups (PPGs) releasable by two‐photon excitation (2PE) provide spatio‐temporal control over the photoactivation of biological effectors to study biological systems. We synthesized four derivatives of the (8‐cyano‐7‐hydroxyquinolin‐2‐yl)methyl (CyHQ) chromophore by functionalization of position C4 to generate four different derivatives (MeO‐CyHQ, Mor‐CyHQ, pTol‐CyHQ, and TMP‐CyHQ) for studying the release of tertiary amines via 2PE. Sulpiride, an anti‐dopaminergic drug, was selected as a model substrate. All probes had excellent properties for use in biological settings, including high quantum yield (Φu), hydrolytic stability, and good aqueous solubility in simulated physiological buffer. The TMP‐CyHQ probe enhanced the two‐photon uncaging action cross‐section (δu) 8‐fold (2.64 GM) compared to the parent CyHQ‐sulpiride. The optimized PPG was used to mediate the photoactivation of various biological effectors containing the tertiary amine functionality (tamoxifen, 4‐hydroxytamoxifen, yohimbine) using 2PE. All constructs showed excellent efficiency with δu ranging from 1.21 to 2.42 GM and moderate to excellent yields of tertiary amines released. [ABSTRACT FROM AUTHOR]

Background: Rauwolscine (RW), also known as a-Yohimbine, is an α-2-adrenergic receptor antagonist which possesses sympathomimetic properties. RW is commercially sold in pre-workout and energy supplements. However, the ergogenic potential of RW has not been determined. The purpose of this study was to investigate the effects of acute RW supplementation on repeated sprint performance. Methods: Healthy male participants (n=12) completed 3 × 15-second Wingate anaerobic tests (WAnT) separated by 2 minutes of active recovery. Blood lactate (La) was collected before exercise (Pre) and immediately following exercise (Post). Mean power, peak power, fatigue index, heart rate (HR), and rate of perceived exertion (RPE) were taken immediately after each WAnT. Point of application #1: Acute RW supplementation does not result in the enhancement of repeated anaerobic sprint performance. Point of application #2: HR and RPE are not altered during repeated sprints with RW ingestion. Point of application #3: RW ingestion results in higher La levels post-exercise despite no changes in fatigue index. [ABSTRACT FROM AUTHOR]