Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson's disease and in comorbidity with psychiatric disorders.

Studies have demonstrated the neuroprotective effect of cannabidiol (CBD) and other Cannabis sativa L. derivatives on diseases of the central nervous system caused by their direct or indirect interaction with endocannabinoid system-related receptors and other molecular targets, such as the 5-HT1A receptor, which is a potential pharmacological target of CBD. Interestingly, CBD binding with the 5-HT1A receptor may be suitable for the treatment of epilepsies, parkinsonian syndromes and amyotrophic lateral sclerosis, in which the 5-HT1A serotonergic receptor plays a key role. The aim of this review was to provide an overview of cannabinoid effects on neurological disorders, such as epilepsy, multiple sclerosis and Parkinson's diseases, and discuss their possible mechanism of action, highlighting interactions with molecular targets and the potential neuroprotective effects of phytocannabinoids. CBD has been shown to have significant therapeutic effects on epilepsy and Parkinson's disease, while nabiximols contribute to a reduction in spasticity and are a frequent option for the treatment of multiple sclerosis. Although there are multiple theories on the therapeutic potential of cannabinoids for neurological disorders, substantially greater progress in the search for strong scientific evidence of their pharmacological effectiveness is needed.

Anxiolytic-like Effects and Quantitative EEG Profile of Palmitone Induces Responses Like Buspirone Rather Than Diazepam as Clinical Drugs.

Anxiety is a mental disorder with a growing worldwide incidence due to the SARS-CoV-2 virus pandemic. Pharmacological therapy includes drugs such as benzodiazepines (BDZs) or azapirones like buspirone (BUSP) or analogs, which unfortunately produce severe adverse effects or no immediate response, respectively. Medicinal plants or their bioactive metabolites are a shared global alternative to treat anxiety. Palmitone is one active compound isolated from Annona species due to its tranquilizing activity. However, its influence on neural activity and possible mechanism of action are unknown. In this study, an electroencephalographic (EEG) spectral power analysis was used to corroborate its depressant activity in comparison with the anxiolytic-like effects of reference drugs such as diazepam (DZP, 1 mg/kg) and BUSP (4 mg/kg) or 8-OH-DPAT (1 mg/kg), alone or in the presence of the GABAA (picrotoxin, PTX, 1 mg/kg) or serotonin 5-HT1A receptor antagonists (WAY100634, WAY, 1 mg/kg). The anxiolytic-like activity was assayed using the behavioral response of mice employing open-field, hole-board, and plus-maze tests. EEG activity was registered in both the frontal and parietal cortex, performing a 10 min baseline and 30 min recording after the treatments. As a result, anxiety-like behavior was significantly decreased in mice administered with palmitone, DZP, BUSP, or 8-OH-DPAT. The effect of palmitone was equivalent to that produced by 5-HT1A receptor agonists but 50% less effective than DZP. The presence of PTX and WAY prevented the anxiolytic-like response of DZP and 8-OH-DPAT, respectively. Whereas only the antagonist of the 5-HT1A receptor (WAY) inhibited the palmitone effects. Palmitone and BUSP exhibited similar changes in the relative power bands after the spectral power analysis. This response was different to the changes induced by DZP. In conclusion, brain electrical activity was associated with the anxiolytic-like effects of palmitone implying a serotoninergic rather than a GABAergic mechanism of action.

Anxiolytic-like effects of citral in the mouse elevated plus maze: involvement of GABAergic and serotonergic transmissions.

Citral, a monoterpene which is a part of the essential oil of several medicinal plants, is generally regarded as safe for human and animal consumption. Studies have introduced citral as a functional component of some essential oils in anxiolytic and antidepressant therapies; however, the neuropharmacological characteristics of citral have not yet been reported. In the present study, we evaluated the anxiolytic activities of citral in comparison to two standard anxiolytics, diazepam and buspirone, in Swiss albino mice by intraperitoneal administration of 1, 2, 5, 10, and 20 mg/kg using elevated plus maze (EPM) and open-field test (OFT). Moreover, we also examined whether the GABAA-benzodiazepine and 5-HT1A receptor are involved in the anxiolytic-like effects of citral by pretreatment with flumazenil and WAY-100635, respectively. Citral dose-dependently decreased the number of border crossings and time spent in borders, and also the number of grooming and rearing in OFT without altering the exploratory behavior of mice. In the EPM, this monoterpene led to a significant increase in number of entries in open arms and time spent in open arms, as well as a decrease in time spent in closed arms. Pretreatment with flumazenil and WAY-100635 both could reverse the anxiolytic effects of the citral in the EPM. These results suggest that anxiolytic activity of citral occurs via the GABAA and 5-HT1A receptor modulation.

Preparation and characterization of immobilized 5-HT1A receptor stationary phase for high throughput screening of the receptor-binding ligands from complex systems like Curcuma wenyujin Y. H. Chen et C. Ling extract.

The incidence of depression has increased significantly during the COVID-19 pandemic. This disease is closely associated with serotonin 1A (5-HT1A) receptor and often treated by complex prescription containing Curcuma wenyujin Y. H. Chen et C. Ling. Therefore, we hypothesized that this herb contains bioactive compounds specially binding to the receptor. However, the rapid discovery of new ligands of 5-HT1A receptor is still challenging due to the lack of efficient screening methods. To address this problem, we developed and characterized a novel approach for the rapid screening of ligands by using immobilized 5-HT1A receptor as the chromatographic stationary phase. Briefly, haloalkane dehalogenase was fused at the C-terminal of 5-HT1A receptor, and the modified 5-HT1A receptor was immobilized on amino-microspheres by the reaction between haloalkane dehalogenase and 6-chlorohexanoic acid linker. Scanning electron microscope and X-ray photo-electron were used to characterize the morphology and element of the immobilized receptor. The binding of three specific ligands to 5-HT1A receptor was investigated by two different methods. Moreover, we examined the feasibility of 5-HT1A receptor colume in high throughput screening of new ligands from complex systems as exemplified by Curcuma wenyujin Y. H. Chen et C. Ling. Gweicurculactone, 2-hydroxy-1-(3,4-dihydroxybenzene)-7-(4'-hydroxybezene)-heptane and curcuminol F were identified as the ligands of 5-HT1A receptor with the binding energies of -7.06 kcal/mol, -7.77 kcal/mol and -5.26 kcal/mol, respectively. Collectively, these results indicated that the immobilized 5-HT1A receptor was capable of screening bioactive compound from complex system, providing an effective methodology for high throughput screening.

Improvement Effects of Myelophil on Symptoms of Chronic Fatigue Syndrome in a Reserpine-Induced Mouse Model.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is associated with various symptoms, such as depression, pain, and fatigue. To date, the pathological mechanisms and therapeutics remain uncertain. The purpose of this study was to investigate the effect of myelophil (MYP), composed of Astragali Radix and Salviaemiltiorrhizae Radix, on depression, pain, and fatigue behaviors and its underlying mechanisms. Reserpine (2 mg/kg for 10 days, intraperitoneally) induced depression, pain, and fatigue behaviors in mice. MYP treatment (100 mg/kg for 10 days, intragastrically) significantly improved depression behaviors, mechanical and thermal hypersensitivity, and fatigue behavior. MYP treatment regulated the expression of c-Fos, 5-HT1A/B receptors, and transforming growth factor ß (TGF-ß) in the brain, especially in the motor cortex, hippocampus, and nucleus of the solitary tract. MYP treatment decreased ionized calcium binding adapter molecule 1 (Iba1) expression in the hippocampus and increased tyrosine hydroxylase (TH) expression and the levels of dopamine and serotonin in the striatum. MYP treatment altered inflammatory and anti-oxidative-related mRNA expression in the spleen and liver. In conclusion, MYP was effective in recovering major symptoms of ME/CFS and was associated with the regulation of dopaminergic and serotonergic pathways and TGF-ß expression in the brain, as well as anti-inflammatory and anti-oxidant mechanisms in internal organs.

Anti-depressant effects of ethanol extract from Cannabis sativa (hemp) seed in chlorpromazine-induced Drosophila melanogaster depression model.

CONTEXT: Depression is a severe mental illness caused by a deficiency of dopamine and serotonin. Cannabis sativa L. (Cannabaceae) has long been used to treat pain, nausea, and depression. OBJECTIVE: This study investigates the anti-depressant effects of C. sativa (hemp) seed ethanol extract (HE) in chlorpromazine (CPZ)-induced Drosophila melanogaster depression model. MATERIALS AND METHODS: The normal group was untreated, and the control group was treated with CPZ (0.1% of media) for 7 days. The experimental groups were treated with a single HE treatment (0.5, 1.0, and 1.5% of media) and a mixture of 0.1% CPZ and HE for 7 days. The locomotor activity, behavioural patterns, depression-related gene expression, and neurotransmitters level of flies were investigated. RESULTS: The behavioural patterns of individual flies were significantly reduced with 0.1% CPZ treatment. In contrast, combination treatment of 1.5% HE and 0.1% CPZ significantly increased subjective daytime activity (p < 0.001) and behavioural factors (p < 0.001). These results correlate with increased transcript levels of dopamine (p < 0.001) and serotonin (p < 0.05) receptors and concentration of dopamine (p < 0.05), levodopa (p < 0.001), 5-HTP (p < 0.05), and serotonin (p < 0.001) compared to those in the control group. DISCUSSION AND CONCLUSIONS: Collectively, HE administration alleviates depression-like symptoms by modulating the circadian rhythm-related behaviours, transcript levels of neurotransmitter receptors, and neurotransmitter levels in the CPZ-induced Drosophila model. However, additional research is needed to investigate the role of HE administration in behavioural patterns, reduction of the neurotransmitter, and signalling pathways of depression in a vertebrate model system.

Therapeutic Potential for Cannabinoids in Sports Medicine: Current Literature Review.

ABSTRACT: Cannabidiol and other cannabinoids are being used more frequently for sports medicine-related conditions. This review will help sports medicine clinicians answer questions that their athletes and active patients have about the potential effectiveness of cannabinoids on common sports medicine conditions. In the article, the authors compare cannabidiol and delta-9-tetrahydrocannabinol effects, noting the difference on the endocannabinoid and nonendocannabinoid receptors. The theoretical benefits of these two compounds and the current legality in the United States surrounding cannabidiol and delta-9-tetrahydrocannabinol use also are addressed.

Cannabidiol as a Potential Treatment for Anxiety and Mood Disorders: Molecular Targets and Epigenetic Insights from Preclinical Research.

Cannabidiol (CBD) is the most abundant non-psychoactive component of cannabis; it displays a very low affinity for cannabinoid receptors, facilitates endocannabinoid signaling by inhibiting the hydrolysis of anandamide, and stimulates both transient receptor potential vanilloid 1 and 2 and serotonin type 1A receptors. Since CBD interacts with a wide variety of molecular targets in the brain, its therapeutic potential has been investigated in a number of neuropsychiatric diseases, including anxiety and mood disorders. Specifically, CBD has received growing attention due to its anxiolytic and antidepressant properties. As a consequence, and given its safety profile, CBD is considered a promising new agent in the treatment of anxiety and mood disorders. However, the exact molecular mechanism of action of CBD still remains unknown. In the present preclinical review, we provide a summary of animal-based studies that support the use of CBD as an anxiolytic- and antidepressant-like compound. Next, we describe neuropharmacological evidence that links the molecular pharmacology of CBD to its behavioral effects. Finally, by taking into consideration the effects of CBD on DNA methylation, histone modifications, and microRNAs, we elaborate on the putative role of epigenetic mechanisms in mediating CBD's therapeutic outcomes.

Enzymolysis peptides from Mauremys mutica plastron improve the disorder of neurotransmitter system and facilitate sleep-promoting in the PCPA-induced insomnia mice.

ETHNOPHARMACOLOGY RELEVANCY: For many centuries, Mauremys mutica is highly valued as a food homologous Chinese herbal medicine. It has been considered useful to sedate, nourish brain and promote sleep. However, the animal experimental evidence of its sleep-promoting activity is missing in literature. AIM OF THE STUDY: In this study, PCPA-induced insomnia model was used to explore the sleep-promoting mechanism of enzymolysis peptides from PMM, and its main composition and chemical structure were analyzed. MATERIALS AND METHODS: Experiments were performed using PCPA-induced insomnia model, all animals were intraperitoneally injected with PCPA (350 mg/kg·d) for two days. The sleep-promoting effect evaluated using measuring content of 5-HT, GABA, DA, IL-1, BDNF and expression of 5-HT1A receptor and GABAA receptor α1-subunit in mice brain. Primary structure of peptides was identified by HPLC-ESI-QqTOF-MS/MS. RESULTS: Compared with the model group, the content of 5-HT, GABA, IL-1, BDNF in mice brain of PMM peptide groups was increased to varying degrees, the content of DA was decreased, and the gene transcription and protein expression of 5-HT1A receptor and GABAA receptor α1-subunit were almost all returned to normal levels. In addition, the primary structures of most abundant nine typical peptides in PMM peptides were identified. CONCLUSIONS: The results showed that PMM peptides could improve the disorder of neurotransmitter system, restore compensatory over-expression 5-HT1A receptor and GABAA receptor α1-subunit, and have a good sleep-promoting effect. The specific amino acid composition, sequence and glycosylation modification of PMM peptides may be the key reason for their activity, which lays a foundation for the subsequent development of sleep-promoting peptide products.

Zingiber officinale Roscoe Rhizomes Attenuate Oxaliplatin-Induced Neuropathic Pain in Mice.

Oxaliplatin is a platinum derivative chemotherapeutic drug widely used against cancers, but even a single treatment can induce a severe allodynia that requires treatment interruption and dose diminution. The rhizome of Zingiber officinale roscoe (Z. officinale, ginger), has been widely used in traditional medicine to treat various diseases causing pain; however, its effect against oxaliplatin-induced neuropathic pain has never been assessed. In mice, a single oxaliplatin (6 mg/kg, i.p.) treatment induced significant cold and mechanical allodynia. Cold and mechanical allodynia were assessed by acetone drop and von Frey filament tests, respectively. Water extracts of Z. officinale (100, 300, and 500 mg/kg, p.o.) significantly attenuated both cold and mechanical allodynia induced by oxaliplatin. Intrathecal pre-treatment with the antagonist 5-HT1A (NAN-190, i.t., 1 µg), but not with the antagonist 5-HT2A (ketanserin, i.t., 1 µg), significantly blocked the analgesic effect of Z. officinale against both cold and mechanical allodynia. However, 5-HT3 antagonist (MDL-72222, i.t., 15 µg) administration only blocked the anti-allodynic effect of Z. officinale against cold allodynia. Real-time PCR analysis demonstrated that Z. officinale significantly increased the mRNA expression of the spinal 5-HT1A receptor that was downregulated after oxaliplatin injection. These results suggest that Z. officinale may be a viable treatment option for oxaliplatin-induced neuropathic pain.

A mixture of quercetin 4'-O-rhamnoside and isoquercitrin from Tilia americana var. mexicana and its biotransformation products with antidepressant activity in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The aerial parts of Tilia americana var. mexicana (Malvaceae, formerly Tiliaceae) or "sirimo" are used in Mexican traditional medicine for the relief of mild symptoms of mental stress, commonly referred to as "nerve diseases". Individuals use this plant to fall asleep, to calm states of nervous excitement, headaches, mood disorders, and general discomfort. Recent studies indicated that fractions standardized in their flavonoid content possess antidepressant activity in behavioral assays in mice. The present study aims to focus on the evaluation of the antidepressant effect of the mixture of two flavonoids (FMix), and its interaction with serotonergic drugs. Also, the pharmacological effect of the products of the metabolism of aglycone, quercetin, was evaluated in mice subjected to forced swimming test (FST) and open field test (OFT). MATERIALS AND METHODS: A methanol-soluble extract obtained from leaves of Tilia americana was fractionated in an open column chromatographic separation. One of the fractions contained FMix wich is constituted of the mixture of quercetin 4'-O-rhamnoside (1, 47%) y isoquercitrin (2, 53%). The mice were divided into the several following groups: FMix (0.01, 0.1, 0.5, 1.0, and 2 mg/kg); FMix (1.0 mg/kg) and agonist DOI (2.0 mg/kg); FMix (1.0 mg/kg) and antagonist ketanserin (KET, 0.03 mg/kg) of 5-HT2A receptors; FMix (1.0 mg/kg) and selective agonist 8-OH-DPAT (8-OH, 0.01 mg/kg); FMix (1.0 mg/kg) and antagonist WAY100635 (WAY, 0.5 mg/kg) of 5HT1 receptors; Phloroglucinol (PHL); 3,4-dihydroxy-phenyl acid (DOPAC); p-hydroxyphenyl acetic acid (p-HPAA); and m-hydroxyphenyl acetic acid (m-HPAA) were tested in FST or OFT. RESULTS: FMix induced dependent-dose antidepressant activity and, at the highest dose administered, a sedative effect was also observed. The 8-OH-DPAT, or the DOI, or the KET combination with FMix (1.0 mg/kg) induced a higher antidepressant effect than compounds alone; there was no effect exerted with WAY. The activity on OFT increased only with the FMix and KET combination. At the same time, the products of the aglycone metabolism of quercetin, that is, DOPAC and p-HPAA, decreased the immobility time of the mice in FST at 1.0 mg/kg, and a dose-curve was formed for these. CONCLUSION: The antidepressant effect of FMix could depend, at least in part, on the degradation products of quercetin and with a possible action mode through interaction with the serotoninergic system.

Uncaria rhynchophylla ameliorates unpredictable chronic mild stress-induced depression in mice via activating 5-HT1A receptor: Insights from transcriptomics.

BACKGROUND: Depression is a pervasive or persistent mental disorder that causes mood, cognitive and memory deficits. Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history, although its efficacy and potential mechanism are still uncertain. PURPOSE: The present study aimed to investigate anti-depression effect and potential mechanism of U. rhynchophylla extract (URE). STUDY DESIGN AND METHODS: A mouse depression model was established using unpredictable chronic mild stress (UCMS). Effects of URE on depression-like behaviours, neurotransmitters, and neuroendocrine hormones were investigated in UCMS-induced mice. The potential target of URE was analyzed by transcriptomics and bioinformatics methods and validated by RT-PCR and Western blot. The agonistic effect on 5-HT1A receptor was assayed by dual-luciferase reporter system. RESULTS: URE ameliorated depression-like behaviours, and modulated levels of neurotransmitters and neuroendocrine hormones, including 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), corticosterone (CORT), corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH), in UCMS-induced mice. Transcriptomics and bioinformatics results indicated that URE could regulate glutamatergic, cholinergic, serotonergic, and GABAergic systems, especially neuroactive ligand-receptor and cAMP signaling pathways, revealing that Htr1a encoding 5-HT1A receptor was a potential target of URE. The expression levels of downstream proteins of 5-HT1A signaling pathway 5-HT1A, CREB, BDNF, and PKA were increased in UCMS-induced mice after URE administration, and URE also displayed an agonistic effect against 5-HT1A receptor with an EC50 value of 17.42 µg/ml. CONCLUSION: U. rhynchophylla ameliorated depression-like behaviours in UCMS-induced mice through activating 5-HT1A receptor.

Contribution of serotonin receptor subtypes to hallucinogenic activity of 25I-NBOMe and to its effect on neurotransmission.

BACKGROUND: 4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a potent serotonin (5-HT) receptor agonist with hallucinogenic properties. The aim of our research was to examine the role of the 5-HT2A, 5-HT2C and 5-HT1A serotonin receptor subtypes in 25I-NBOMe hallucinogenic activity and its effect on dopamine (DA), 5-HT and glutamate release in the rat frontal cortex. METHODS: Hallucinogenic activity was investigated using the wet dog shake (WDS) test. The release of DA, 5-HT and glutamate in the rat frontal cortex was studied using a microdialysis in freely moving rats. Neurotransmitter levels were analyzed by HPLC with electrochemical detection. The selective antagonists of the 5-HT2A, 5-HT2C and 5-HT1A serotonin receptor subtypes: M100907, SB242084 and WAY100635, respectively were applied through a microdialysis probe. RESULTS: The WDS response to 25I-NBOMe (1 and 3 mg/kg) was significantly reduced by local administration of M100907 and SB242084 (100 nM). The 25I-NBOMe-induced increase in glutamate, DA and 5-HT release was inhibited by M100907 and SB242084. WAY100635 had no effect on 25I-NBOMe-induced WDS and glutamate release, while it decreased DA and 5-HT release from cortical neuronal terminals. CONCLUSION: The obtained results suggest that 5-HT2A and 5-HT2C receptors play a role in 25I-NBOMe-induced hallucinogenic activity and in glutamate, DA and 5-HT release in the rat frontal cortex as their respective antagonists attenuated the effect of this hallucinogen. The disinhibition of GABA cells by the 5-HT1A receptor antagonist seems to underlie the mechanism of decreased DA and 5-HT release from neuronal terminals in the frontal cortex.

Neferine, a bisbenzylisoquinoline alkaloid of Nelumbo nucifera, inhibits glutamate release in rat cerebrocortical nerve terminals through 5-HT1A receptors.

Neferine, a bisbenzylisoquinoline alkaloid present in Nelumbo nucifera, has been reported to exhibit neuroprotective effects. Because reduced glutamatergic transmission through inhibition of glutamate release has been proposed as a mechanism of neuroprotection, we investigated whether and how neferine inhibits glutamate release in the nerve terminals of the cerebral cortex of rats. The results demonstrated that neferine inhibits the glutamate release that is evoked by the potassium channel blocker 4-aminopyridine, doing so in a dose-dependent manner. This effect was prevented by removing extracellular calcium and blocking vesicular transporters or N- and P/Q-type calcium channels but not by blocking glutamate transporters. Neferine decreased the 4-aminopyridine-stimulated elevation in intrasynaptosomal calcium concentration; however, it had no effect on the synaptosomal membrane potential. The inhibition of glutamate release by neferine was also eliminated by the selective 5-hydroxytryptamine 1A (5HT1A) receptor antagonist WAY100635, Gi/o protein inhibitor pertussis toxin, adenylyl cyclase inhibitor MDL12330A, and protein kinase A inhibitor H89. Moreover, immunocytochemical analysis revealed the presence of 5-HT1A receptor proteins in the vesicular transporter of glutamate type 1 positive synaptosomes. The molecular docking study also demonstrated that neferine exhibited the highest binding affinity with 5-HT1A receptors (Autodock scores for 5-HA1A = -11.4 kcal/mol). Collectively, these results suggested that neferine activates 5-HT1A receptors in cortical synaptosomes, which decreases calcium influx and glutamate release through the activation of Gi/o protein and the inhibition of adenylyl cyclase/cAMP/protein kinase A cascade.

Expression of serotonin 1A and 2A receptors in molecular- and projection-defined neurons of the mouse insular cortex.

The serotonin (5-HT) system is the target of multiple anxiolytics, including Buspirone, which is a partial agonist of the serotonin 1A receptor (5-HT1A). Similarly, ligands of the serotonin 2A receptor (5-HT2A) were shown to alter anxiety level. The 5-HT1A and 2A receptors are widely expressed across the brain, but the target region(s) underlying the influence of those receptors on anxiety remain unknown. Interestingly, recent studies in human and non-human primates have shown that the 5-HT1A and 5-HT2A binding potentials within the insular cortex (insula) are correlated to anxiety. As an initial step to define the function of 5-HT transmission in the insula, we quantified the proportion of specific neuronal populations of the insula expressing 5-HT1A or 5-HT2A. We analyzed seven neural populations, including three defined by a molecular marker (putative glutamate, GABA or parvalbumin), and four defined by their projections to different downstream targets. First, we found that more than 70% of putative glutamatergic neurons, and only 30% of GABAergic neurons express the 5-HT1A. Second, within insular projection neurons, 5-HT1A is highly expressed (75-80%) in the populations targeting one sub-nuclei of the amygdala (central or basolateral), or targeting the rostral or caudal sections of the lateral hypothalamus (LH). Similarly, 70% of putative glutamatergic neurons and only 30% of insular GABAergic neurons contain 5-HT2A. Finally, the 5-HT2A is present in a majority of insula-amygdala and insula-LH projection neurons (73-82%). These observations suggest that most glutamatergic neurons can respond to 5-HT through 5-HT1A or 5-HT2A in the insula, and that 5-HT directly affects a limited number of GABAergic neurons. This study defines a molecular and neuroanatomical map of the 5-HT system within the insular cortex, providing ground knowledge to identify the potential role of serotonergic modulation of selective insular populations in anxiety.

Electroacupuncture improves synaptic plasticity by regulating the 5-HT1A receptor in hippocampus of rats with chronic unpredictable mild stress.

OBJECTIVES: To investigate the antidepressant effects of electroacupuncture (EA) on chronic unpredictable mild stress (CUMS) in rats, as well as the effects of EA on hippocampal neurons, synaptic morphology, and 5-hydroxytryptamine (HT) receptor expression. METHODS: Forty adult male Wistar rats were randomly divided into normal control, CUMS, EA, and paroxetine groups. CUMS modeling was performed for 21 days, followed by 14 days of intervention: rats in the EA group underwent stimulation of GV20 and GV29 acupuncture points for 30 minutes daily; rats in the paroxetine group were administered paroxetine daily. Behavioral tests, transmission electron microscopy, western blotting, and real-time quantitative polymerase chain reaction were used to evaluate the effects of the intervention. RESULTS: EA treatment reversed the behavioral changes observed in rats due to CUMS modeling; it also improved the pathological changes in organelles and synaptic structures of hippocampal neurons, and upregulated the protein and mRNA expression levels of 5-HT1A receptor. There were no significant differences in 5-HT1B receptor protein and mRNA expression levels among the groups. CONCLUSIONS: EA treatment can alleviate depression-like symptoms in CUMS rats. The underlying mechanism may include promoting the expression of 5-HT1A receptor mRNA and protein, thereby improving synaptic plasticity in the hippocampus.

Acute administration of levetiracetam in tonic pain model modulates gene expression of 5HT1A and 5HT7 receptors in the thalamus of rats (Rattus norvergicus).

The nociceptive effect of Levetiracetam (LEV) on the expression of 5-HT1A and 5-HT7 receptors found in the thalamus was evaluated. Thirty-six male rats (Wistar) were randomized into six groups: in the Control group without treatment; LEV50 group LEV was administered in a single dose of 50 mg/kg i.g.; in the LEV300 group LEV dose of 300 mg/kg i.g.; in the FORMALIN group the formalin test was performed; in the LEV50/FORMALIN group LEV dose of 50 mg/kg i.g and the formalin test was performed; in the LEV300/FORMALIN group LEV dose of 300 mg/kg i.g and the formalin test was performed, subsequently the thalamus was dissected in all groups. In the formalin tests LEV exhibited an antinociceptive effect in the LEV300/FORMALIN group (p < 0.05) and a pronociceptive effect in the LEV50/FORMALIN group (p < 0.001). The results obtained by Real-time PCR confirmed the expression of the 5-HT1A and 5-HT7 receptors in the thalamus, 5-HT1A receptors increased significantly in the FORMALIN group and the LEV300/FORMALIN group (p < 0.05). 5-HT7 receptors are only over expressed at a dose of 300 mg/Kg of LEV with formalin (p < 0.05). This suggests that LEV modulates the sensation of pain by controlling the expression of 5-HT1A and 5-HT7 in a tonic pain model, and that changes in the expression of 5-HT1A and 5-HT7 receptors are associated with the sensation of pain, furthermore its possibility to be used in clinical treatments for pain.

Role of 5-HT1A Receptor in the Anxiolytic-Relaxant Effects of Bergamot Essential Oil in Rodent.

The essential oil obtained by the fresh fruit of Citrus bergamia Risso et Poiteau is used worldwide in aromatherapy to reduce pain, facilitate sleep induction, and/or minimize the effects of stress-induced anxiety. Preclinical pharmacological data demonstrate that bergamot essential oil (BEO) modulates specific neurotransmissions and shows an anxiolytic-relaxant effect not superimposable to that of the benzodiazepine diazepam, suggesting that neurotransmissions, other than GABAergic, could be involved. Several studies on essential oils indicate a role for serotonergic (5-HT) neurotransmission in anxiety. Interestingly, among serotonergic receptors, the 5-HT1A subtype seems to play a key role in the control of anxiety. Here, we report that modulation of the 5-HT1A receptor by selective agonist ((±)8-OH-DPAT) or antagonist (WAY-100635) may influence some of the anxiolytic-relaxant effects of BEO in Open Field and Elevated Plus Maze tests.

Network Pharmacology-based Research of Active Components of Albiziae Flos and Mechanisms of Its Antidepressant Effect.

Albiziae Flos (AF) has been experimentally proven to have an antidepressant effect. However, due to the complexity of botanical ingredients, the exact pharmacological mechanism of action of AF in depression has not been completely deciphered. This study used the network pharmacology method to construct a component-target-pathway network to explore the active components and potential mechanisms of action of AF. The methods included collection and screening of chemical components, prediction of depression-associated targets of the active components, gene enrichment, and network construction and analysis. Quercetin and 4 other active components were found to exert antidepressant effects mainly via monoaminergic neurotransmitters and cAMP signaling and neuroactive ligand-receptor interaction pathways. DRD2, HTR1A, and SLC6A4 were identified as important targets of the studied bioactive components of AF. This network pharmacology analysis provides guidance for further study of the antidepressant mechanism of AF.

Role of ß-Caryophyllene in the Antinociceptive and Anti-Inflammatory Effects of Tagetes lucida Cav. Essential Oil.

Tagetes lucida Cav. (Asteraceae) is an ancient medicinal plant commonly used to alleviate pain. Nevertheless, scientific studies validating this property are lacking in the literature. Animal models of pain were used to evaluate the antinociceptive and anti-inflammatory activities of T. lucida essential oil (TLEO) and a bioactive metabolite. The chemical constitution and possible toxicity of the extract and the mechanism of action of ß-caryophyllene were also explored. Temporal course curves and dose-response graphics were generated using TLEO (0.1-10 mg/kg or 3.16-31.62 mg/kg) and ß-caryophyllene (3.16-10 mg/kg). Metamizole (80 mg/kg) and indomethacin (20 mg/kg) were used as reference drugs in the formalin assay and writhing test in rats and mice, respectively. The ß-caryophyllene mechanism of action was explored in the presence of naloxone (1 mg/kg), flumazenil (10 mg/kg), WAY100635 (0.16 mg/kg), or nitro-l-arginine methyl ester (L-NAME) (20 mg/kg) in the formalin test in rats. GC/MS analysis demonstrated the presence of geranyl acetate (49.89%), geraniol (7.92%), and ß-caryophyllene (6.27%). Significant and dose-dependent antinociceptive response was produced by TLEO and ß-caryophyllene without the presence of gastric damage. In conclusion, ß-caryophyllene was confirmed as a bioactive compound in the T. lucida analgesic properties by involving the participation of receptors like opioids, benzodiazepines, and Serotonin 1A receptor (5-HT1A), as well as nitric oxide.