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The Journal of Physiology Jul 2022Cholinergic neurones in the basal forebrain (BF) project into various brain regions and receive excitatory inputs from the cortex and brain stem. These cholinergic...
Cholinergic neurones in the basal forebrain (BF) project into various brain regions and receive excitatory inputs from the cortex and brain stem. These cholinergic neurones receive serotonergic fibres from the dorsal raphe nuclei. This study was aimed to elucidate serotonin (5-HT)-induced modulation of glutamatergic transmission onto rat BF cholinergic neurones identified with Cy3-192IgG. Excitatory postsynaptic currents (EPSCs) were evoked by focal stimulation. Bath application of either 5-HT, the 5-HT receptor agonist 8-OH-DPAT (DPAT), or the 5-HT receptor agonist CP93129 (CP), inhibited the amplitude of EPSCs. In the presence of both 5-HT and 5-HT receptor antagonists, the 5-HT-induced effect disappeared. The paired-pulse ratio (PPR) and coefficient of variation (CV) of the EPSCs were increased by CP, whereas DPAT had no effect on PPR or CV. DPAT inhibited the inward currents induced by puff application of l-glutamate, which were unaffected by CP. DPAT suppressed the amplitude of miniature EPSCs (mEPSCs) without affecting their frequency. CP decreased the frequency of mEPSCs in more than half of the neurones examined, whereas the amplitude was unaffected. DPAT or CP alone inhibited the NMDA receptor-mediated currents. 5-HT-induced inhibition of EPSCs was reduced in the presence of ω-agatoxin TK (Aga). Furthermore, CP-induced inhibition of EPSCs was eliminated in the presence of Aga. DPAT-induced inhibition of EPSCs was unchanged in the presence of Aga. These results suggest that activation of 5-HT receptors reduces the sensitivity of postsynaptic glutamate receptors to glutamate, whereas presynaptic activation of 5-HT receptors inhibits glutamate release by blocking P/Q-type calcium channels. KEY POINTS: We performed a patch-clamp study to investigate serotonin (5-HT)-induced modulation of glutamatergic transmission onto cholinergic neurones in the rat basal forebrain slices. Excitatory postsynaptic currents (EPSCs) were inhibited by 5-HT as well as agonists of 5-HT or 5-HT receptors. 5-HT-induced inhibition was antagonized by co-application of 5-HT and 5-HT receptor antagonists. The effects of 5-HT receptor agonists on the paired-pulse ratio, coefficient of variation of EPSCs, inward currents induced by puff application of l-glutamate as well as miniature EPSCs suggest that activation of 5-HT receptors decreases the sensitivity of postsynaptic glutamate receptors to glutamate, whereas 5-HT receptors presynaptically inhibit glutamate release. The 5-HT agonist-induced inhibition was eliminated in the presence of a P/Q-type calcium channel blocker, whereas the 5-HT agonist still inhibited the EPSCs even in the presence of the blocker. The present study reveals different pre- and postsynaptic mechanisms underlying 5-HT and 5-HT receptor-mediated modulation of excitatory transmission.
Topics: Animals; Basal Forebrain; Cholinergic Agents; Cholinergic Neurons; Glutamic Acid; Rats; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT1B; Serotonin; Serotonin Receptor Agonists; Synaptic Transmission
PubMed: 35598305
DOI: 10.1113/JP282509 -
Physiology & Behavior Jan 2012Autistic spectrum disorders (ASDs) are classified as pervasive developmental disorders characterized by abnormalities in various cognitive and behavioral functions....
Autistic spectrum disorders (ASDs) are classified as pervasive developmental disorders characterized by abnormalities in various cognitive and behavioral functions. Although exact underlying causes are still unknown, nearly 30% of autistic patients show elevated blood levels of serotonin (5-HT) and, therefore, various genetic and environmental factors that are known to elevate 5-HT levels may play a role in the development of ASDs. In the present study, we used the socially monogamous male prairie vole (Microtus ochrogaster) as an animal model to examine the effects of perinatal exposure to 5-methoxytryptamine (5-MT), a non-selective serotonin agonist, on subsequent behavioral and neurochemical changes in the brain. 5-MT treated males showed a decrease in affiliation and an increase in anxiety-related behavior, as well as a decrease in the density of 5-HT immunoreactive (ir) fibers in the amygdala and oxytocin-ir and vasopressin-ir cells in the paraventricular nucleus of the hypothalamus, compared to saline treated controls. These data indicate that exposure to 5-HT during early development can induce abnormalities in various neurochemical systems which, in turn, may underlie deficits in social and anxiety-related behaviors. In addition, these data will help to establish the prairie vole model to study the neurobiological underpinnings of complex neuropsychiatric disorders such as ASDs.
Topics: 5-Methoxytryptamine; Animals; Arginine Vasopressin; Arvicolinae; Behavior, Animal; Brain; Exploratory Behavior; Female; Male; Maze Learning; Neurochemistry; Pregnancy; Prenatal Exposure Delayed Effects; Serotonin; Serotonin Receptor Agonists; Social Behavior
PubMed: 21958679
DOI: 10.1016/j.physbeh.2011.09.015 -
Bioorganic Chemistry Dec 2023The serotonin 1A (5-HT) receptors and serotonin transporter (SERT) are important biological targets in the treatment of diseases of the central nervous system,...
The serotonin 1A (5-HT) receptors and serotonin transporter (SERT) are important biological targets in the treatment of diseases of the central nervous system, especially for depression. In this study, new 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives linked with the 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole moiety were synthesised and evaluated for their affinity for 5-HT receptor and serotonin reuptake inhibition. Selected compounds were then tested for their affinity for D, 5-HT, 5-HT and 5-HT receptors, and also in in vitro metabolic stability assays in human microsomes. Finally, in vivo assays allowed us to evaluate the agonist-antagonist properties of pre- and postsynaptic 5-HT receptors. 3-(1-(4-(3-(5-methoxy-1H-indol-3-yl)-2,5-dioxopyrrolidin-1-yl)butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile (4f) emerged as the most promising compound from the series, due to its favourable receptor binding profile (K = 10.0 nM; K = 2.8 nM), good microsomal stability and 5-HT receptor agonistic activity.
Topics: Humans; Serotonin Plasma Membrane Transport Proteins; Serotonin; Receptor, Serotonin, 5-HT1A; Indoles; Serotonin Receptor Agonists; Structure-Activity Relationship
PubMed: 37827015
DOI: 10.1016/j.bioorg.2023.106903 -
Clinical and Translational Science Mar 2021Gastrointestinal (GI) motility disorders are common, decreases quality of life, and imposes a substantial economic burden. YH12852 is a novel agonist of... (Randomized Controlled Trial)
Randomized Controlled Trial
YH12852, a Potent and Selective Receptor Agonist of 5-hydroxytryptamine, Increased Gastrointestinal Motility in Healthy Volunteers and Patients With Functional Constipation.
Gastrointestinal (GI) motility disorders are common, decreases quality of life, and imposes a substantial economic burden. YH12852 is a novel agonist of 5-hydroxytryptamine for the treatment of GI motility disorders. This phase I/IIa study assessed the tolerability, pharmacodynamic (PD) and pharmacokinetic (PK) profiles of YH12852. In the multiple dose (MD) cohort, healthy subjects and patients with functional constipation were randomized and received orally YH12852 at 0.3, 0.5, 1, 2, or 3 mg or prucalopride 2 mg or their matching placebo, once daily for 14 days after breakfast. In the multiple low-dose cohort (MLD), healthy subjects randomly received once-daily oral doses of YH12852 at 0.05 or 0.1 mg for 14 days after breakfast. Questionnaires, gastric emptying breath test for PDs, and plasma samples for PKs were collected. In the MD cohort, a total of 56 subjects (29 healthy volunteers and 27 patients with functional constipation) were randomized, of whom 48 completed the study. In the MLD cohort, a total of 16 healthy subjects were randomized, and 15 subjects completed the study. YH12852 increased the average weekly frequency of spontaneous bowel movements and loosened the stool. In addition, YH12852 increased quality of life satisfaction, and decreased severity of constipation symptom and GI symptoms. YH12852 was safe and well-tolerated up to 3 mg and showed nearly dose proportional PKs. In conclusion, YH12852 was safe and enhanced GI motility. YH12852 can be developed as an effective treatment option for GI motility disorders, including functional constipation. Further studies are warranted to confirm this possibility.
Topics: Adult; Constipation; Double-Blind Method; Female; Gastrointestinal Motility; Healthy Volunteers; Humans; Male; Middle Aged; Patient Satisfaction; Pyrimidines; Quality of Life; Serotonin Receptor Agonists; Treatment Outcome; Young Adult
PubMed: 33202093
DOI: 10.1111/cts.12924 -
Current Drug Metabolism Oct 20105-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) belongs to a group of naturally-occurring psychoactive indolealkylamine drugs. It acts as a nonselective serotonin (5-HT)... (Review)
Review
5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) belongs to a group of naturally-occurring psychoactive indolealkylamine drugs. It acts as a nonselective serotonin (5-HT) agonist and causes many physiological and behavioral changes. 5-MeO-DMT is O-demethylated by polymorphic cytochrome P450 2D6 (CYP2D6) to an active metabolite, bufotenine, while it is mainly inactivated through the deamination pathway mediated by monoamine oxidase A (MAO-A). 5-MeO-DMT is often used with MAO-A inhibitors such as harmaline. Concurrent use of harmaline reduces 5-MeO-DMT deamination metabolism and leads to a prolonged and increased exposure to the parent drug 5-MeO-DMT, as well as the active metabolite bufotenine. Harmaline, 5-MeO-DMT and bufotenine act agonistically on serotonergic systems and may result in hyperserotonergic effects or serotonin toxicity. Interestingly, CYP2D6 also has important contribution to harmaline metabolism, and CYP2D6 genetic polymorphism may cause considerable variability in the metabolism, pharmacokinetics and dynamics of harmaline and its interaction with 5-MeO-DMT. Therefore, this review summarizes recent findings on biotransformation, pharmacokinetics, and pharmacological actions of 5-MeO-DMT. In addition, the pharmacokinetic and pharmacodynamic drug-drug interactions between harmaline and 5-MeO-DMT, potential involvement of CYP2D6 pharmacogenetics, and risks of 5-MeO-DMT intoxication are discussed.
Topics: Animals; Bufotenin; Cytochrome P-450 CYP2D6; Drug Interactions; Hallucinogens; Harmaline; Humans; Methoxydimethyltryptamines; Pharmacogenetics; Serotonin Receptor Agonists
PubMed: 20942780
DOI: 10.2174/138920010794233495 -
The American Journal of Managed Care Feb 2002The safety and tolerability of medications used to treat acute migraine attacks are summarized, the classification of headaches and the causes of and diagnostic criteria... (Review)
Review
OBJECTIVE
The safety and tolerability of medications used to treat acute migraine attacks are summarized, the classification of headaches and the causes of and diagnostic criteria for migraine are reviewed, and the clinical tolerability profiles and therapeutic benefits of second-generation triptans are presented.
BACKGROUND
Migraine is a paroxysmal disorder characterized by attacks of headache, nausea, vomiting, photophobia, and phonophobia. Drugs used to prevent migraine and those that effectively treat acute migraine attacks are readily available.
METHODS
Mild or moderate migraines are often treated with aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs, antiemetic drugs, or isometheptene. Triptans (5-HT1 receptor agonists) are used to treat moderate or severe migraine and when nonspecific medications have been ineffective. Because sumatriptan, the first triptan used, is effective but can induce adverse events, second-generation triptans (zolmitriptan, naratriptan, rizatriptan, and almotriptan) were developed to increase the benefit-to-risk ratio in migraine management.
RESULTS
Important pharmacologic, pharmacokinetic, and clinical differences exist among those drugs, but the tolerability profile of the newer triptans is very good, and they provide rapid relief from headache and sustained duration of effect.
CONCLUSION
Primary care physicians must manage migraine patients with treatments that demonstrate a balance between efficacy and tolerability.
Topics: Analgesics; Humans; Migraine Disorders; Serotonin Receptor Agonists; United States
PubMed: 11859906
DOI: No ID Found -
Bioorganic & Medicinal Chemistry Letters Oct 2021Despite the better understanding of the mechanisms underlying Alzheimer's Disease (AD) and launched clinical trials, no AD-modifying treatment based on a synthetic drug... (Review)
Review
Despite the better understanding of the mechanisms underlying Alzheimer's Disease (AD) and launched clinical trials, no AD-modifying treatment based on a synthetic drug has been introduced for almost twenty years. The serotonin 5-HT and 5-HT receptors turned out to be promising biological targets for modulation of central nervous system dysfunctions including cognitive impairment. Within this paper, we evaluate the pharmacological potency of both, 5-HTR and 5-HTR, agents in search for novel AD treatment. An overview of chemical structures of the 5-HTRs ligands with simultaneous procognitive action which have undergone preclinical and clinical studies within the last 10 years has been performed.
Topics: Alzheimer Disease; Animals; Humans; Nootropic Agents; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists
PubMed: 34311086
DOI: 10.1016/j.bmcl.2021.128275 -
Neurotherapeutics : the Journal of the... Sep 2023Migraine constitutes the world's second-leading cause of disability. Triptans, as serotonin 5-HT receptor agonists, remain the first-line treatment, despite discouraged...
Migraine constitutes the world's second-leading cause of disability. Triptans, as serotonin 5-HT receptor agonists, remain the first-line treatment, despite discouraged use in individuals at high cardiovascular risk. Lasmiditan, a selective lipophilic 5-HT agonist without vasoconstrictive effects, is an emerging option. We aimed to investigate the safety profile of lasmiditan in the WHO pharmacovigilance database (VigiBase) using a comparative disproportionality analysis with triptans. VigiBase was queried for all reports involving lasmiditan and triptans. Disproportionality analyses relied on the calculation of the information component (IC), for which 95% confidence interval (CI) lower bound positivity was required for signal detection. We obtained 826 reports involving lasmiditan. Overall, 10 adverse drug reaction classes were disproportionately reported with triptans, while only neurological (IC 1.6; 95% CI 1.5-1.7) and psychiatric (IC 1.5; 95% CI 1.3-1.7) disorders were disproportionately reported with lasmiditan. Sedation, serotonin syndrome, euphoric mood, and autoscopy had the strongest signals. When compared with triptans, 19 out of 22 neuropsychiatric signals persisted. The results of our analysis provide a more precise semiology of the neuropsychiatric effects of lasmiditan, with symptoms such as autoscopy and panic attacks. The cardiovascular adverse drug reaction risk with triptans was confirmed. In contrast, caution is warranted with lasmiditan use in patients with neurological or psychiatric comorbidities or serotonin syndrome risk. Our study was hindered by pharmacovigilance flaws, and further studies should help in validating these results. Our findings suggest that lasmiditan is a safe alternative for migraine treatment, especially when the neuropsychiatric risk is outweighed by the cardiovascular burden.
Topics: Humans; Tryptamines; Serotonin; Serotonin Syndrome; Receptors, Serotonin; Serotonin Receptor Agonists; Migraine Disorders; Drug-Related Side Effects and Adverse Reactions
PubMed: 37436579
DOI: 10.1007/s13311-023-01404-1 -
British Journal of Pharmacology Jan 20011. The interaction of serotonergic ligands at human (h) 5-HT(1A) receptors expressed in Chinese hamster ovary cells was examined with the selective 'neutral' 5-HT(1A)...
1. The interaction of serotonergic ligands at human (h) 5-HT(1A) receptors expressed in Chinese hamster ovary cells was examined with the selective 'neutral' 5-HT(1A) antagonist [(3)H]-WAY100,635. Its binding was saturable (K(D)=0.056 nM) with a B(max) (3.65 pmol mg(-1)) significantly higher than that of two other selective 5-HT(1A) radioligands: the partial agonist, [(3)H]-S15535 (2.77 pmol mg(-1)) and the agonist, [(3)H]-8-OH-DPAT (2.02 pmol mg(-1)). 2. The influence of GTPgammaS (100 microM) on the binding affinity of 15 serotonergic agonists, partial agonists, antagonists and inverse agonists was investigated in competition binding experiments with [(3)H]-WAY100,635. 3. Agonists, including 5-HT, 8-OH-DPAT and buspirone, displayed biphasic isotherms which shifted to the right in the presence of GTPgammaS. In contrast, isotherms of the inverse agonists, methiothepin, (+)butaclamol and spiperone, were shifted to the left in the presence of GTPgammaS. Unlabelled WAY100,635 was the only ligand that was unaffected by GTPgammaS, consistent with 'neutral' antagonist properties. 4. The magnitude of affinity changes induced by GTPgammaS for 13 ligands was highly correlated (r = 0.98) with their efficacy (positive and negative) previously determined by [(35)S]GTPgammaS binding. 5. In contrast, the napthylpiperazine derivative and high efficacy agonist, S14506, displayed only a modest GTPgammaS shift, in accordance with previous indications of 'atypical' binding properties of this ligand. A further full agonist, S14671, which is chemically closely-related to S14506, also displayed a minimal GTPgammaS shift, underpinning this observation. 6. In conclusion, [(3)H]-WAY100,635 constitutes a useful neutral antagonist radioligand for the characterization of drug actions at h5-HT(1A) receptors. GTPgammaS-induced affinity changes of agonist and inverse agonist competition isotherms generally correlate well with ligand efficacy, with the notable exception of two chemically-similar agents, S14506 and S14671, which are efficacious agonists, yet relatively insensitive to h5-HT(1A) receptor/G-protein coupling changes.
Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; CHO Cells; Cricetinae; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Kinetics; Ligands; Piperazines; Pyridines; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Antagonists; Serotonin Receptor Agonists
PubMed: 11159702
DOI: 10.1038/sj.bjp.0703832 -
Arquivos de Neuro-psiquiatria Jun 2003The migraine-specific triptans have revolutionized the treatment of migraine and are usually the drugs of choice to treat a migraine attack in progress. Different... (Review)
Review
The migraine-specific triptans have revolutionized the treatment of migraine and are usually the drugs of choice to treat a migraine attack in progress. Different triptans are available in different strengths and formulations including oral tablets, orally disintegrating tablets, nasal sprays and subcutaneous injections. In Europe, sumatriptan is also available as a suppository. Specific differences among the triptans exist as evidenced by different pharmacological profiles including T1/2, Tmax, Cmax, AUC, metabolism, drug-drug interaction profiles, amongst other parameters. How or whether these differences translate to clinical efficacy and tolerability differences is not well differentiated. Clinical distinctions among these agents are subtle and proper choice of triptan requires attention to the specific characteristics of each individual patient, knowledge of patient preference, accurate history of the efficacy of previous acute care medications as well as individual features of the drug being considered. Delivery systems may play an important role in the onset of action of triptans. The selection of an acute antimigraine drug for a patient depends upon the stratification of the patient's migraine attack by peak intensity, time to peak intensity, level of associated symptoms such as nausea and vomiting, time to associated symptoms, comorbid diseases, and concomitant treatments that might cause drug-drug interactions. The clinician has in his armamentarium an ever-expanding variety of medications, available in multiple formulations and dosages, with good safety and tolerability profiles. Continued clinical use will yield familiarity with the various triptans, and it should become possible for the interested physician to match individual patient needs with the specific characteristics of a triptan to optimize therapeutic benefit.
Topics: Analgesics; Humans; Migraine Disorders; Serotonin Receptor Agonists
PubMed: 12806521
DOI: 10.1590/s0004-282x2003000200032