Authors: Munazzah Tasleem, Abdulwahed Alrehaily, Tahani M Almeleebia...

The use of pharmaceuticals to treat Major Depressive Disorder (MDD) has several drawbacks, including severe side effects. Natural compounds with great efficacy and few side effects are in high demand due to the global rise in MDD and ineffective treatment. Yohimbine, a natural compound, has been used to treat various ailments, including neurological conditions, since ancient times. Serotonergic neurotransmission plays a crucial role in the pathogenesis of depression; thus, serotonergic receptor agonist/antagonistic drugs are promising anti-depressants. Yohimbine was investigated in this study to determine its antidepressant activity using molecular docking and pharmacokinetic analyses. Additionally, the in silico mutational study was carried out to understand the increase in therapeutic efficiency using site-directed mutagenesis. Conformational changes and fluctuations occurring during wild type and mutant serotonergic receptor, 5-hydroxytryptamine receptors 1A (5HT1A) and yohimbine were assessed by molecular dynamics MD simulation studies. Yohimbine was found to satisfy all the parameters for drug-likeness and pharmacokinetics analysis. It was found to possess a good dock score and hydrogen-bond interactions with wild type 5HT1A structure. Our findings elaborate the substantial efficacy of yohimbine against MDD; however, further bench work studies may be carried out to prove the same.

Topics: Amino Acid Sequence; Antidepressive Agents; Binding Sites; Blood-Brain Barrier; Humans; Models, Molecular; Molecular Conformation; Molecular Structure; Mutation; Permeability; Protein Binding; Protein Conformation; Receptor, Serotonin, 5-HT1A; Structure-Activity Relationship; Yohimbine

PubMed: 34889886
DOI: 10.3390/cimb43030127

Authors: Chloé Laurencin, Sophie Lancelot, Florent Gobert...

Previous work introduced the [C]yohimbine as a suitable ligand of central α2-adrenoreceptors (α2-ARs) for PET imaging. However, reproducibility of [C]yohimbine PET measurements in healthy humans estimated with a simplified modeling method with reference region, as well as sensitivity of [C]yohimbine to noradrenergic competition were not evaluated. The objectives of the present study were therefore to fill this gap.

METHODS

Thirteen healthy humans underwent two [C]yohimbine 90-minute dynamic scans performed on a PET-MRI scanner. Seven had arterial blood sampling with metabolite assessment and plasmatic yohimbine free fraction evaluation at the first scan to have arterial input function and test appropriate kinetic modeling. The second scan was a simple retest for 6 subjects to evaluate the test-retest reproducibility. For the remaining 7 subjects the second scan was a challenge study with the administration of a single oral dose of 150 µg of clonidine 90 min before the PET scan. Parametric images of α2-ARs distribution volume ratios (DVR) were generated with two non-invasive models: Logan graphical analysis with Reference (LREF) and Simplified Reference Tissue Method (SRTM). Three reference regions (cerebellum white matter (CERWM), frontal white matter (FLWM), and corpus callosum (CC)) were tested.

RESULTS

We showed high test-retest reproducibility of DVR estimation with LREF and SRTM regardless of reference region (CC, CERWM, FLWM). The best fit was obtained with SRTM (r=0.94). Test-retest showed that the SRTM is highly reproducible (mean ICC>0.7), with a slight bias (-1.8%), whereas SRTM had lower bias (-0.1%), and excellent ICC (mean>0.8). Using SRTM, regional changes have been observed after clonidine administration with a significant increase reported in the amygdala and striatum as well as in several posterior cortical areas as revealed with the voxel-based analysis.

CONCLUSION

The results add experimental support for the suitability of [C]yohimbine PET in the quantitative assessment of α2-ARs occupancy in vivo in the human brain. Trial registration EudraCT 2018-000380-82.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adult; Brain; Carbon Radioisotopes; Humans; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Reference Standards; Reproducibility of Results; Yohimbine; Young Adult

PubMed: 34224852
DOI: 10.1016/j.neuroimage.2021.118328

Authors: Anna Mueller-Schoell, Robin Michelet, Ferdinand Weinelt...

The indole alkaloid yohimbine is an alpha-2 receptor antagonist used for its sympathomimetic effects. Several cases of yohimbine intoxication have been reported and the most recent one involved four individuals taking a yohimbine-containing drug powder. All individuals developed severe intoxication symptoms and were admitted to the hospital. Even though all individuals were assumed to have taken the same dose of the drug powder, toxicology analyses revealed yohimbine blood concentrations of 249-5631 ng/mL, amounting to a 22-fold difference. The reason for this high variability remained to be elucidated. We used recently reported knowledge on the metabolism of yohimbine together with state-of-the art nonlinear mixed-effects modelling and simulation and show that a patient's cytochrome P450 2D6 (CYP2D6) phenotype can explain the large differences observed in the measured concentration after intake of the same yohimbine dose. Our findings can be used both for the identification of safe doses in therapeutic use of yohimbine and for an explanation of individual cases of overdosing.

Topics: Adrenergic alpha-2 Receptor Antagonists; Computer Simulation; Cytochrome P-450 CYP2D6; Humans; Models, Biological; Nonlinear Dynamics; Phenotype; Yohimbine

PubMed: 34027562
DOI: 10.1007/s00204-021-03082-4

Randomized Controlled Trial

Authors: Sophie Metz, Woo R Chae, Christian E Deuter...

INTRODUCTION

Facial expressions contain important affective information, and selective attention to facial expression provides an advantage in the face of loss, stress and danger. In addition, the sympathetic nervous system and hypothalamus-pituitary-adrenal axis mediate the organism's response to loss and danger. Here, we aimed at investigating the influence of sympathetic nervous system and hypothalamus-pituitary-adrenal axis activation on selective attention to affective facial stimuli.

METHODS AND MATERIALS

One hundred-and-four healthy men between 18-35 years old (mean (standard deviation) age: 24.1 (3.5) years) participated in the study. We used a randomised, double-blind, placebo-controlled design. Participants received either: (a) yohimbine, (b) hydrocortisone, (c) yohimbine and hydrocortisone or (d) placebo only and participated in a dot-probe task with sad, happy and neutral faces. We collected salivary samples to measure cortisol and alpha amylase activity in addition to measurements of blood pressure and heart rate. Salivary cortisol served as correlate of hypothalamus-pituitary-adrenal axis activation and salivary alpha amylase activity, blood pressure and heart rate as correlates of sympathetic nervous system activation. Measurements were carried out before and after drug administration.

RESULTS

We did not find a main effect or interaction effect of hydrocortisone or yohimbine administration on selective attention to happy faces. However, we found an interaction of yohimbine and hydrocortisone on selective attention to sad faces. Post-hoc -test revealed an attentional bias away from sad stimuli and towards neutral faces in the hydrocortisone-only group.

DISCUSSION

Only hydrocortisone administration led to an attentional bias away from sad faces. Future studies should investigate these effects in major depression disorder, as this disorder is characterised by glucocorticoid resistance and increased processing of sad stimuli.

Topics: Adolescent; Adrenergic alpha-2 Receptor Antagonists; Adult; Attentional Bias; Cues; Double-Blind Method; Emotions; Facial Recognition; Glucocorticoids; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Pituitary-Adrenal System; Salivary alpha-Amylases; Yohimbine; Young Adult

PubMed: 33779376
DOI: 10.1177/0269881121997100

Authors: Manuela Vay, Marleen Julia Meyer, Antje Blank...

OBJECTIVE

Yohimbine pharmacokinetics were determined after oral administration of a single oral dose of yohimbine 5 mg and a microdose of yohimbine 50 µg in relation to different cytochrome P450 (CYP) 2D6 genotypes. The CYP2D6 inhibitor paroxetine was used to investigate the influence on yohimbine pharmacokinetics. Microdosed midazolam was applied to evaluate a possible impact of yohimbine on CYP3A activity and the possibility of combining microdosed yohimbine and midazolam to simultaneously determine CYP2D6 and CYP3A activity.

METHODS

In a fixed-sequence clinical trial, 16 healthy volunteers with a known CYP2D6 genotype [extensive (10), intermediate (2) and poor (4) metaboliser] received an oral dose of yohimbine 50 µg, yohimbine 5 mg at baseline and during paroxetine as a CYP2D6 inhibitor. Midazolam (30 µg) was co-administered to determine CYP3A activity at each occasion. Plasma concentrations of yohimbine, its main metabolite 11-OH-yohimbine, midazolam and paroxetine were quantified using validated liquid chromatography-tandem mass spectrometry assays.

RESULTS

Pharmacokinetics of yohimbine were highly variable and a CYP2D6 genotype dependent clearance was observed. After yohimbine 5 mg, the clearance ranged from 25.3 to 15,864 mL/min and after yohimbine 50 µg, the clearance ranged from 39.6 to 38,822 mL/min. A more than fivefold reduction in clearance was caused by paroxetine in CYP2D6 extensive metabolisers, while the clearance in poor metabolisers was not affected. Yohimbine did not alter CYP3A activity as measured by microdosed midazolam.

CONCLUSIONS

The pharmacokinetics of yohimbine were highly correlated with CYP2D6, which was further supported by the clearance inhibition caused by the CYP2D6 inhibitor paroxetine. With these data, yohimbine is proposed to be a suitable probe drug to predict CYP2D6 activity. In addition, the microdose can be used in combination with microdosed midazolam to simultaneously evaluate CYP2D6 and CYP3A activity without any interaction between the probe drugs and because the microdoses exert no pharmacological effects.

CLINICAL TRIAL REGISTRATION

EudraCT2017-001801-34.

Topics: Cytochrome P-450 CYP2D6; Genotype; Humans; Paroxetine; Yohimbine

PubMed: 32060866
DOI: 10.1007/s40262-020-00862-6

Authors: D Funk, S Tamadon, K Coen...

Dynorphin (DYN), and its receptor, the kappa opioid receptor (KOR) are involved in drug seeking and relapse but the mechanisms are poorly understood. One hypothesis is that DYN/KOR activation promotes drug seeking through increased impulsivity, because many stimuli that induce DYN release increase impulsivity. Here, we systematically compare the effects of drugs that activate DYN/KOR on performance on the 5-choice serial reaction time task (5-CSRTT), a test of sustained attention and impulsivity. In Experiment 1, we determined the effects of U50,488 (0, 2.5, 5 mg/kg), yohimbine (0, 1.25, 2.5 mg/kg), and nicotine (0, 0.15, 0.3 mg/kg) on 5-CSRTT performance. In Experiment 2, we determined the effects of alcohol (0, 0.5, 1.0, 1.5 g/kg) on 5-CSRTT performance before and after voluntary, intermittent alcohol exposure. In Experiment 3, we determined the potential role of KOR in the pro-impulsive effects of yohimbine (1.25 mg/kg) and nicotine (0.3 mg/kg) by the prior administration of the KOR antagonist nor-BNI (10 mg/kg). Premature responding, the primary measure of impulsivity, was reduced by U50,488 and alcohol, but these drugs had a general suppressive effect. Yohimbine and nicotine increased premature responding. Yohimbine-, but not nicotine-induced increases in premature responding were blocked by nor-BNI, suggesting that impulsivity induced by yohimbine is KOR dependent. This may suggests a potential role for KOR-mediated increases in impulsivity in yohimbine-induced reinstatement.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Attention; Choice Behavior; Dose-Response Relationship, Drug; Ethanol; Impulsive Behavior; Male; Neurotransmitter Agents; Nicotine; Rats, Long-Evans; Receptors, Opioid, kappa; Yohimbine

PubMed: 30414973
DOI: 10.1016/j.bbr.2018.11.006

Escalated Alcohol Self-Administration and Sensitivity to Yohimbine-Induced Reinstatement in Alcohol Preferring Rats: Potential Role of Neurokinin-1 Receptors in the Amygdala.

Authors: Britta S Nelson, Hannah D Fulenwider, Sadie E Nennig...

Genetic factors significantly contribute to the risk for developing alcoholism. To study these factors and other associated phenotypes, rodent lines have been developed using selective breeding for high alcohol preference. One of these models, the alcohol preferring (P) rat, has been used in hundreds of preclinical studies over the last few decades. However, very few studies have examined relapse-like behavior in this rat strain. In this study, we used operant self-administration and yohimbine-induced reinstatement models to examine relapse-like behavior in P rats. Our previous work has demonstrated that P rats show increased expression of the neurokinin-1 receptor (NK1R) in the central nucleus of the amygdala (CeA), and this functionally contributes to escalated alcohol consumption in this strain. We hypothesized that P rats would show increased sensitivity to yohimbine-induced reinstatement that is also mediated by NK1R in the CeA. Using Fos staining, site-specific infusion of NK1R antagonist, and viral vector overexpression, we examined the influence of NK1R on the sensitivity to yohimbine-induced reinstatement of alcohol seeking. We found that P rats displayed increased sensitivity to yohimbine-induced reinstatement as well as increased neuronal activation in the CeA after yohimbine injection compared to the control Wistar strain. Intra-CeA infusion of NK1R antagonist attenuates yohimbine-induced reinstatement in P rats. Conversely, upregulation of NK1R within the CeA of Wistar rats increases alcohol consumption and sensitivity to yohimbine-induced reinstatement. These findings suggest that NK1R upregulation in the CeA contributes to multiple alcohol-related phenotypes in the P rat, including alcohol consumption and sensitivity to relapse.

Topics: Adrenergic alpha-2 Receptor Antagonists; Alcohol-Related Disorders; Animals; Central Amygdaloid Nucleus; Central Nervous System Depressants; Conditioning, Operant; Disease Models, Animal; Ethanol; Male; Neurokinin-1 Receptor Antagonists; Neurons; Proto-Oncogene Proteins c-fos; Rats, Wistar; Receptors, Neurokinin-1; Recurrence; Self Administration; Yohimbine

PubMed: 31242442
DOI: 10.1016/j.neuroscience.2019.06.023

Authors: Nicholas G Paciaroni, Verrill M Norwood, Ranjala Ratnayake...

G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.

Topics: Antineoplastic Agents; Biological Products; Dose-Response Relationship, Drug; Humans; Molecular Structure; Molecular Targeted Therapy; Neoplasms; Receptors, G-Protein-Coupled; Structure-Activity Relationship; Yohimbine

PubMed: 32616180
DOI: 10.1016/j.bmc.2020.115546

Authors: R M Mwobobia, T I Kanui, K S P Abelson...

OBJECTIVE

The naked mole rat (NMR) (Heterocephalus glaber) is increasingly considered an important biomedical research model for various conditions like hypoxic brain injury, cancer and nociception. This study was designed to investigate the effects of clonidine and yohimbine, an alpha-2 (α) adrenoceptor agonist and antagonist respectively in the tail flick and hot plate tests.

RESULTS

A significant difference in tail flick latency was noted between saline control and 30 µg/kg clonidine, which was reduced after administration of 30 µg/kg yohimbine. A significant difference in hot plate latency was also noted between saline control and 30 µg/kg clodinine during the periods 30, 45, 60, 75 and 90 min after administration, and between saline control and 10 µg/kg clonidine during 30 min after administration. The hot plate latency by 30 µg/kg clonidine was also reduced by 30 µg/kg yohimbine during 30 min after administration. Since the tail-flick and hot plate tests mediate the effects at spinal and supraspinal levels respectively, the present study indicates the presence and involvement of noradrenergic receptors in thermal antinociception at spinal and supraspinal levels of the NMR, similar to what has been found in other mammals.

Topics: Analgesics; Animals; Clonidine; Mole Rats; Yohimbine

PubMed: 34001271
DOI: 10.1186/s13104-021-05607-7

Authors: Aleksandra M Herman, Hugo D Critchley, Theodora Duka...

RATIONALE

State-dependent changes in physiological arousal may influence impulsive behaviours.

OBJECTIVES

To examine the relationship between arousal and impulsivity, we assessed the effects of yohimbine (an α-adrenergic receptor antagonist, which increases physiological arousal via noradrenaline release) on performance on established laboratory-based impulsivity measures in healthy volunteers.

METHODS

Forty-three participants received a single dose of either yohimbine hydrochloride or placebo before completing a battery of impulsivity measures. Blood pressure and heart rate were monitored throughout the study.

RESULTS

Participants in the yohimbine group showed higher blood pressure and better response inhibition in the Stop Signal Task, relative to the placebo group. Additionally, individual changes in blood pressure were associated with performance on Delay Discounting and Information Sampling tasks: raised blood pressure following drug ingestion was associated with more far-sighted decisions in the Delay Discounting Task (lower temporal impulsivity) yet reduced information gathering in the Information Sampling Task (increased reflection impulsivity).

CONCLUSIONS

These results support the notion that impulsive behaviour is dependent upon state physiological arousal; however, distinct facets of impulsivity are differentially affected by physiological changes.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adult; Arousal; Decision Making; Delay Discounting; Female; Humans; Impulsive Behavior; Male; Psychomotor Performance; Yohimbine; Young Adult

PubMed: 30635680
DOI: 10.1007/s00213-018-5160-9