Potential Anxiolytic Properties Research Articles

Network pharmacology combined with molecular docking and experimental verification to elucidate the effect of flavan-3-ols and aromatic resin on anxiety

This study investigated the potential anxiolytic properties of flavan-3-ols and aromatic resins through a combined computational and experimental approach. Network pharmacology techniques were utilized to identify potential anxiolytic targets and compounds by analyzing protein–protein interactions and KEGG pathway data. Molecular docking and simulation studies were conducted to evaluate the binding interactions and stability of the identified targets. Behavioral tests, including the elevated plus maze test, open field test, light–dark test, actophotometer, and holeboard test, were used to assess anxiolytic activity. The compound-target network analysis revealed complex interactions involving 306 nodes and 526 edges, with significant interactions observed and an average node degree of 1.94. KEGG pathway analysis highlighted pathways such as neuroactive ligand-receptor interactions, dopaminergic synapses, and serotonergic synapses as being involved in anxiety modulation. Docking studies on EGCG (Epigallocatechin gallate) showed binding energies of −9.5 kcal/mol for MAOA, −9.2 kcal/mol for SLC6A4, and −7.4 kcal/mol for COMT. Molecular dynamic simulations indicated minimal fluctuations, suggesting the formation of stable complexes between small molecules and proteins. Behavioral tests demonstrated a significant reduction in anxiety-like behavior, as evidenced by an increased number of entries into and time spent in the open arm of the elevated plus maze test, light–dark test, open field center activity, hole board head dips, and actophotometer beam interruptions (p < 0.05 or p < 0.01). This research provides a comprehensive understanding of the multi-component, multi-target, and multi-pathway intervention mechanisms of flavan-3-ols and aromatic resins in anxiety treatment. Integrated network and behavioral analyses collectively support the anxiolytic potential of these compounds and offer valuable insights for future research in this area.

Experimental study of neuropsychotropic activity

Objective. To study the neuropsychotropic activity of 2,4-dioxobutanoic acid derivatives containing a fragment of benzimidazole as well as to determine the relationship between the structure of substances and their biological effects. Materials and methods. The spectrum of neuropsychotropic activity of 2,4-dioxobutanoic acid derivatives with benzimidazole was studied on experimental animals using the open field, black-and-white camera, and extrapolation deliverance tests. Results. A compound with potential anxiolytic properties has been identified. The dependence of the manifestation of anxiogenic or anxiolytic properties in the presence of mono- or bicyclic arenes in the structure, respectively, is shown. Conclusions. 2,4-Dioxobutane acids containing a fragment of benzimidazole are of interest for the search for substances with neuropsychotropic activity. The results of the structure-activity analysis should be used in further targeted synthesis.

Effects of ethylenediamine in rodent models of seizure, motor coordination and anxiety

Ethylenediamine (EDA) activates GABAA receptors via both direct and indirect mechanisms. EDA has been shown to reduce seizures caused by systemic injection of proconvulsants in an animal model of generalized tonic–clonic seizures. However, there does not appear to have been any report on the effects of EDA in other seizure models. Hence, we used male Sprague-Dawley rats to test the effects of EDA on topically applied bicuculline (a model of simple partial seizures) and on maximal electroshock (MES, a model of generalized tonic–clonic seizures). We also examined the effects of EDA on motor coordination using a rotarod treadmill, and its potential anxiolytic properties using an elevated plus maze (EPM). EDA at concentrations of 50μM and above reduced the frequency of epileptiform spikes on an electrocorticogram in a concentration-dependent manner. EDA at 100 and 1000mg/kg i.p. increased the threshold for inducing limb extension on the MES. EDA did not affect the time spent by rats on the rotarod at 10 or 100mg/kg, but significantly reduced the time spent at doses of 1000mg/kg. In the EPM, EDA at 10 or 100mg/kg significantly increased the frequency of entries and time spent in the open arms. We conclude that EDA has antiepileptic and anxiolytic activity at doses that do not affect motor coordination.

Anti-Aversive Effects of Cannabidiol on Innate Fear-Induced Behaviors Evoked by an Ethological Model of Panic Attacks Based on a Prey vs the Wild Snake Epicrates cenchria crassus Confrontation Paradigm

Several pharmacological targets have been proposed as modulators of panic-like reactions. However, interest should be given to other potential therapeutic neurochemical agents. Recent attention has been given to the potential anxiolytic properties of cannabidiol, because of its complex actions on the endocannabinoid system together with its effects on other neurotransmitter systems. The aim of this study was to investigate the effects of cannabidiol on innate fear-related behaviors evoked by a prey vs predator paradigm. Male Swiss mice were submitted to habituation in an arena containing a burrow and subsequently pre-treated with intraperitoneal administrations of vehicle or cannabidiol. A constrictor snake was placed inside the arena, and defensive and non-defensive behaviors were recorded. Cannabidiol caused a clear anti-aversive effect, decreasing explosive escape and defensive immobility behaviors outside and inside the burrow. These results show that cannabidiol modulates defensive behaviors evoked by the presence of threatening stimuli, even in a potentially safe environment following a fear response, suggesting a panicolytic effect.

SS05-04 - Overcoming the challenges of the anxiety spectrum

Anxiety disorders are considered to be the most prevalent of the psychiatric disorders, with generalized anxiety disorder (GAD) being one of the most common in primary care practice. GAD is a chronic and disabling disorder, which is frequently underdiagnosed and undertreated. It is characterized by both psychic symptoms (particularly worry) and somatic symptoms, and often complicated by comorbid conditions such as depression.Agomelatine, the first melatonergic antidepressant, has been shown to be effective and well tolerated, not only in treating major depressive disorder, but also in treating the anxiety symptoms of depression. These findings give impetus to investigation of its potential anxiolytic properties in GAD.Two randomized, double-blind, placebo-controlled studies assessed the efficacy of agomelatine in GAD. The first, a 12-week study, used the HAM-A total score as the primary outcome measure. In the second, a relapse prevention study, the responders to a 16-week open treatment period with agomelatine were randomized to maintenance treatment with either agomelatine or placebo for a 26-week period.In the short-term treatment of GAD,1 agomelatine was superior to placebo with a HAM-A total score difference of 3.28 (P = 0.04). In the maintenance treatment of GAD, the incidence of relapse was significantly lower with agomelatine than with placebo. Agomelatine was well tolerated in both trials.In summary, these studies showed that the novel antidepressant agomelatine is also efficacious in the treatment of GAD.

Acute effects of bergamot oil on anxiety‐related behaviour and corticosterone level in rats

Bergamot essential oil (BEO), Citrus aurantium subsp. bergamia (Risso) Wright & Arn. (Rutaceae), is used widely in aromatherapy to reduce stress and anxiety despite limited scientific evidence. A previous study showed that BEO significantly increased gamma-aminobutyric acid levels in rat hippocampus, suggesting potential anxiolytic properties. The aim of this study was to investigate the effect of BEO (1.0%, 2.5% and 5.0% w/w) administered to rats on both anxiety-related behaviours (the elevated plus-maze (EPM) and hole-board tests) and stress-induced levels of plasma corticosterone in comparison with the effects of diazepam. Inhalation of BEO (1% and 2.5%) and injection of diazepam (1 mg/kg, i.p.) significantly increased the percentage of open arm entries on the EPM. The percentage time spent in the open arms was also significantly enhanced following administration of either BEO (2.5% and 5%) or diazepam. Total arm entries were significantly increased with the highest dose (5%), suggesting an increase in locomotor activity. In the hole-board test, 2.5% BEO and diazepam significantly increased the number of head dips. 2.5% BEO and diazepam attenuated the corticosterone response to acute stress caused by exposure to the EPM. In conclusion, both BEO and diazepam exhibited anxiolytic-like behaviours and attenuated HPA axis activity by reducing the corticosterone response to stress.

2‐(Dimethylaminomethyl)‐tetrahydroisoxazolopyridobenzazepine Derivatives. Synthesis of a New 5‐HT2C Antagonist with Potential Anxiolytic Properties.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Defensive burying in rodents: ethology, neurobiology and psychopharmacology

Defensive burying refers to the typical rodent behavior of displacing bedding material with vigorous treading-like movements of their forepaws and shoveling movements of their heads directed towards a variety of noxious stimuli that pose a near and immediate threat, such as a wall-mounted electrified shock-prod. Since its introduction 25 years ago by Pinel and Treit [J. Comp. Physiol. Psychol. 92 (1978) 708], defensive (shock-prod) burying has been the focus of a considerable amount of research effort delineating the methodology/ethology, psychopharmacology and neurobiology of this robust and species-specific active avoidance or coping response. The present review gives a summary of this research with special reference to the behavioral (face and construct) and pharmacological (predictive) validity of the shock-prod burying test as an animal model for human anxiety. Emphasis is also placed on some recent modifications of the paradigm that may increase its utility and reliability as to individual differences in expressed emotional coping responses and sensitivity to pharmacological treatments. Overall, the behavioral and physiological responses displayed in the shock-prod paradigm are expressions of normal and functionally adaptive coping patterns and the extremes of either active (i.e., burying) or passive (i.e., freezing) forms of responding in this test cannot simply be regarded as inappropriate, maladaptive or pathological. For this reason, the shock-prod paradigm is not an animal model for anxiety disorder or for any other psychiatric disease, but instead possesses a high degree of face and construct validity for normal and functionally adaptive human fear and anxious apprehension. However, the apparent good pharmacological validation (predictive validity) of this test reinforces the view that normal and pathological anxiety involves, at least partly, common neurobiological substrates. Therefore, this paradigm is not only suitable for screening potential anxiolytic properties of new drugs, but seems to be especially valuable for unraveling the neural circuitry and neurochemical mechanisms underlying the generation of active and passive coping responses as different expressions of anxiety.

2-(Dimethylaminomethyl)-tetrahydroisoxazolopyridobenzazepine derivatives. Synthesis of a new 5-HT 2C antagonist with potential anxiolytic properties

Following the program started at Johnson & Johnson Pharmaceutical Research & Development searching for 5-HT 2A/2C antagonists, we now report on the synthesis of 2-(dimethylaminomethyl)-2,3,3a,8-tetrahydroisoxazolo[3,2- a]pyrido[3,4- c]-[2]benzazepine and 2-(dimethylaminomethyl)-2,3,3a,8-tetrahydroisoxazolo[3,2- a]pyrido[3,2- c]-[2]benzazepine. A new method for the synthesis of pyridobenzazepines is described as well. The affinities for several receptors as well as the mCPP antagonistic activity of the compounds synthesised are described.

Central action of 5-HT 3 receptor ligands in the regulation of sleep-wakefulness and raphe neuronal activity in the rat

Anxiolytic drugs, such as the benzodiazepines and the azapirones (ipsapirone, gepirone, buspirone), are well known to affect states of vigilance and to decrease the firing rate of serotoninergic neurones within the dorsal raphe nucleus in rats. In order to examine whether the newly developed 5-HT 3 antagonists with potential anxiolytic properties act through similar mechanisms, the effects of several of such antagonists: MDL 72222, ICS 205-930, ondansetron and/or zacopride on both sleep-wakefulness and the discharge of serotoninergic neurones within the dorsal raphe nucleus were investigated in rats. When tested in a wide range of doses (0.05–10 mg/kg, i.p.), none of these drugs significantly affected the states of vigilance, except ondansetron, at 0. 1 mg/kg, which increased paradoxical sleep for the first 2 hr after administration and MDL 72222, at 10 mg/kg, which reduced both paradoxical and slow wave sleep and increased wakefulness for the same initial period after treatment. In vivo, in chloral hydrate anaesthetized rats, as well as in vitro, in slices of brain stem, none of the 5-HT 3 antagonists tested affected the firing rate of serotoninergic neurones. Similarly, no change in the electrical activity of serotoninergic neurones could be evoked in vitro by superfusion of the tissue with the 5-HT 3 agonists, phenylbiguanide (10μM) and 2-methyl-5-HT (l μM). At a larger concentration (10 μM), the latter compound reduced the neuronal discharge probably through the stimulation of somatodendritic 5-HT 1A autoreceptors since this effect, as that of ipsapirone, could be prevented by 10μM l-propranolol. Comparison of these data with those obtained with benzodiazepines and 5-HT 1A agonists of the azapirone series, supports the concept that different mechanisms are responsible for the anxiolytic-like properties of 5-HT 3 agonists, compared to those of other anxiolytic drugs.

NMDA receptor complex antagonists have potential anxiolytic effects as measured with separation-induced ultrasonic vocalizations

Pre-weaning rat pups emit ultrasonic vocalizations when removed from the litter. These ‘separation-induced vocalizations’ (SIV) are suppressed by classical benzodiazepine anxiolytics and by non-benzodiazepine anxiolytics which lack muscle relaxant and sedative propertes. The present study used the SIV model to assess potential anxiolytic properties of compounds which target different sites associated with the NMDA receptor complex. Comparison was made to drugs which affect benzodiazepine or serotonin (5-HT) receptors. Muscle relaxant potential was assessed using ‘TIP’ (time on an inclined plane), the amount of time a pup was able to retain its position on a steeply inclined surface. Mephenesin, a centrally acting muscle relaxant, significantly suppressed TIP but not SIV. The benzodiazepine agonist diazepam suppressed both SIV and TIP, whereas the 5-HT 1A partial agonists, buspirone and MDL 73,005EF, suppressed SIV without affecting TIP. The 5-HT 2 antagonist MDL 11,939 suppressed TIP but not SIV, whereas neither measure was affected by the 5-HT 3 antagonist MDL 73,147EF. SIV was suppressed by NMDA a antagonist including those acting at the glutamate recognition site (D,L-amino-phosphonovaleric acid (AP5) and MDL 100,453) or at the ion channel (MK-801), or by the strychnine-insensitive glycine antagonist 5,7-dichlorokynurenic acid (5,7-DCKA). TIP was suppressed even more potently by AP5, MDL 100,453 and MK-801, whereas 5,7-DCKA was inactive on this measure. Thus, antagonists acting at different sites present on the glutamate recognition site exhibit potential anxiolytic activity, but the glycine antagonist was unusual in its lack of prominent muscle relaxant side effects.

Absence of anxiolytic effects of calcium channel antagonists

AbstractThe potential anxiolytic effects of some calcium channel antagonists (nifedipine, nicardipine, and ±verapamil) were investigated in the elevated plus‐maze test in mice. The acute effects of the above‐mentioned drugs were compared with those of phenobarbitone and ±propanolol. Results showed that control mice spent less time in the open than in the closed arms, reflecting increased anxiety. Both phenobarbitone (20 mg/kg i.p.) and ±propanolol (5 mg/kg i.p.) increased the percentage of entries into open arms as well as the time spent on the open arms. Nifedipine (2 and 4 mg/kg i.p.), nicardipine (0.5 and 1.0 mg/kg i.p.), and ±verapamil (5 and 10 mg/kg i.p.) failed to alter significantly the behavior of mice. In summary, although there have been some reports based on other tests that calcium antagonists may have potential anxiolytic properties, this conclusion has not been supported by our results from the elevated plus‐maze test.