An update on migraine: Current and new treatment options.

ABSTRACT: Migraine headache is a common and potentially debilitating disorder often treated by physician associates/assistants (PAs) and other providers. With the recent advances in new drugs and device technology for the treatment of migraine, the American Headache Society has released a consensus statement on both preventive and acute strategies for clinical practice. The US FDA has recently approved various types of medications and devices for the treatment and prevention of migraine attacks including several calcitonin gene-related peptide (CGRP) receptor inhibitors, a selective serotonin receptor agonist (SSRA), noninvasive vagus nerve stimulation (nVNS), external trigeminal nerve stimulation (e-TNS), and external concurrent occipital and trigeminal neurostimulation (eCOT-NS), among other pharmacologic and nonpharmacologic options. This article provides a review of migraine prevention and acute treatment protocol, highlighting new approaches to both.

Photoactivatable Agonist-Antagonist Pair as a Tool for Precise Spatiotemporal Control of Serotonin Receptor 2C Signaling.

Orthogonal recreation of the signaling profile of a chemical synapse is a current challenge in neuroscience. This is due in part to the kinetics of synaptic signaling, where neurotransmitters are rapidly released and quickly cleared by active reuptake machinery. One strategy to produce a rapid rise in an orthogonally controlled signal is via photocaged compounds. In this work, photocaged compounds are employed to recreate both the rapid rise and equally rapid fall in activation at a chemical synapse. Specifically, a complementary pair of photocages based on BODIPY were conjugated to a 5-HT2C subtype-selective agonist, WAY-161503, and antagonist, N-desmethylclozapine, to generate "caged" versions of these drugs. These conjugates release the bioactive drug upon illumination with green light (agonist) or red light (antagonist). We report on the synthesis, characterization, and bioactivity testing of the conjugates against the 5-HT2C receptor. We then characterize the kinetics of photolysis quantitatively using HPLC and qualitatively in cell culture conditions stimulating live cells. The compounds are shown to be stable in the dark for 48 h at room temperature, yet photolyze rapidly when irradiated with visible light. In live cells expressing the 5-HT2C receptor, precise spatiotemporal control of the degree and length of calcium signaling is demonstrated. By loading both compounds in tandem and leveraging spectral multiplexing as a noninvasive method to control local small-molecule drug availability, we can reproducibly initiate and suppress intracellular calcium flux on a timescale not possible by traditional methods of drug dosing. These tools enable a greater spatiotemporal control of 5-HT2C modulation and will allow for more detailed studies of the receptors' signaling, interactions with other proteins, and native physiology.

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.

Ginsenoside Re Protects against Serotonergic Behaviors Evoked by 2,5-Dimethoxy-4-iodo-amphetamine in Mice via Inhibition of PKCδ-Mediated Mitochondrial Dysfunction.

It has been recognized that serotonin 2A receptor (5-HT2A) agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI) impairs serotonergic homeostasis. However, the mechanism of DOI-induced serotonergic behaviors remains to be explored. Moreover, little is known about therapeutic interventions against serotonin syndrome, although evidence suggests that ginseng might possess modulating effects on the serotonin system. As ginsenoside Re (GRe) is well-known as a novel antioxidant in the nervous system, we investigated whether GRe modulates 5-HT2A receptor agonist DOI-induced serotonin impairments. We proposed that protein kinase Cδ (PKCδ) mediates serotonergic impairments. Treatment with GRe or 5-HT2A receptor antagonist MDL11939 significantly attenuated DOI-induced serotonergic behaviors (i.e., overall serotonergic syndrome behaviors, head twitch response, hyperthermia) by inhibiting mitochondrial translocation of PKCδ, reducing mitochondrial glutathione peroxidase activity, mitochondrial dysfunction, and mitochondrial oxidative stress in wild-type mice. These attenuations were in line with those observed upon PKCδ inhibition (i.e., pharmacologic inhibitor rottlerin or PKCδ knockout mice). Furthermore, GRe was not further implicated in attenuation mediated by PKCδ knockout in mice. Our results suggest that PKCδ is a therapeutic target for GRe against serotonergic behaviors induced by DOI.

Acute Treatments for Episodic Migraine in Adults: A Systematic Review and Meta-analysis.

Importance: Migraine is common and can be associated with significant morbidity, and several treatment options exist for acute therapy. Objective: To evaluate the benefits and harms associated with acute treatments for episodic migraine in adults. Data Sources: Multiple databases from database inception to February 24, 2021. Study Selection: Randomized clinical trials and systematic reviews that assessed effectiveness or harms of acute therapy for migraine attacks. Data Extraction and Synthesis: Independent reviewers selected studies and extracted data. Meta-analysis was performed with the DerSimonian-Laird random-effects model with Hartung-Knapp-Sidik-Jonkman variance correction or by using a fixed-effect model based on the Mantel-Haenszel method if the number of studies was small. Main Outcomes and Measures: The main outcomes included pain freedom, pain relief, sustained pain freedom, sustained pain relief, and adverse events. The strength of evidence (SOE) was graded with the Agency for Healthcare Research and Quality Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Findings: Evidence on triptans and nonsteroidal anti-inflammatory drugs was summarized from 15 systematic reviews. For other interventions, 115 randomized clinical trials with 28 803 patients were included. Compared with placebo, triptans and nonsteroidal anti-inflammatory drugs used individually were significantly associated with reduced pain at 2 hours and 1 day (moderate to high SOE) and increased risk of mild and transient adverse events. Compared with placebo, calcitonin gene-related peptide receptor antagonists (low to high SOE), lasmiditan (5-HT1F receptor agonist; high SOE), dihydroergotamine (moderate to high SOE), ergotamine plus caffeine (moderate SOE), acetaminophen (moderate SOE), antiemetics (low SOE), butorphanol (low SOE), and tramadol in combination with acetaminophen (low SOE) were significantly associated with pain reduction and increase in mild adverse events. The findings for opioids were based on low or insufficient SOE. Several nonpharmacologic treatments were significantly associated with improved pain, including remote electrical neuromodulation (moderate SOE), transcranial magnetic stimulation (low SOE), external trigeminal nerve stimulation (low SOE), and noninvasive vagus nerve stimulation (moderate SOE). No significant difference in adverse events was found between nonpharmacologic treatments and sham. Conclusions and Relevance: There are several acute treatments for migraine, with varying strength of supporting evidence. Use of triptans, nonsteroidal anti-inflammatory drugs, acetaminophen, dihydroergotamine, calcitonin gene-related peptide antagonists, lasmiditan, and some nonpharmacologic treatments was associated with improved pain and function. The evidence for many other interventions, including opioids, was limited.

The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice.

OBJECTIVE: To incorporate recent research findings, expert consensus, and patient perspectives into updated guidance on the use of new acute and preventive treatments for migraine in adults. BACKGROUND: The American Headache Society previously published a Consensus Statement on the use of newly introduced treatments for adults with migraine. This update, which is based on the expanded evidence base and emerging expert consensus concerning postapproval usage, provides practical recommendations in the absence of a formal guideline. METHODS: This update involved four steps: (1) review of data about the efficacy, safety, and clinical use of migraine treatments introduced since the previous Statement was published; (2) incorporation of these data into a proposed update; (3) review and commentary by the Board of Directors of the American Headache Society and patients and advocates associated with the American Migraine Foundation; (4) consideration of these collective insights and integration into an updated Consensus Statement. RESULTS: Since the last Consensus Statement, no evidence has emerged to alter the established principles of either acute or preventive treatment. Newly introduced acute treatments include two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (ubrogepant, rimegepant); a serotonin (5-HT1F ) agonist (lasmiditan); a nonsteroidal anti-inflammatory drug (celecoxib oral solution); and a neuromodulatory device (remote electrical neuromodulation). New preventive treatments include an intravenous anti-CGRP ligand monoclonal antibody (eptinezumab). Several modalities, including neuromodulation (electrical trigeminal nerve stimulation, noninvasive vagus nerve stimulation, single-pulse transcranial magnetic stimulation) and biobehavioral therapy (cognitive behavioral therapy, biofeedback, relaxation therapies, mindfulness-based therapies, acceptance and commitment therapy) may be appropriate for either acute and/or preventive treatment; a neuromodulation device may be appropriate for acute migraine treatment only (remote electrical neuromodulation). CONCLUSIONS: The integration of new treatments into clinical practice should be informed by the potential for benefit relative to established therapies, as well as by the characteristics and preferences of individual patients.

Receptor-mediated biological effects of extracts obtained from three Asplenium species.

This study reports the effects of aqueous extracts obtained from three fern species of Bulgarian origin: Asplenium ceterach L., Asplenium scolopendrium L., and Asplenium trichomanes L. on the contractility and bioelectrogenesis of rat gastric smooth muscle tissues. In the concentration range 0.015-0.150 mg/mL the three extracts contracted smooth muscle tissues in a concentration-dependent manner. The contractions caused by A. ceterach L. and A. scolopendrium L. extracts (0.150 mg/mL) were reduced by ketanserin (5 × 10-7 and 5 × 10-6 mol/L), an antagonist of serotonin 5-HT2 receptor. The contraction evoked by A. trichomanes L. (0.150 mg/mL) was significantly reduced by 1 × 10-6 mol/L atropine, an antagonist of muscarinic receptors, and turned into relaxation against the background of 3 × 10-7 mol/L galantamine. After combined pretreatment with galantamine and l-arginine (5 × 10-4 mol/L), this relaxation become more pronounced. The study demonstrates that constituents of A. ceterach L. and A. scolopendrium L. extracts act as agonists of 5-HT2 receptors and cause contraction by activating serotonergic signaling system. A. trichomanes L.-induced reaction is an additive result of two opposite-in-character effects. The dominant contraction is initiated by inhibition of acetylcholinesterase activity. The relaxation develops with pre-inhibited acetylcholinesterase, it is significantly potentiated by l-arginine, and therefore associated with nitrergic signaling pathway.

Serotonin 1A agonist and cardiopulmonary improvements with whole-body exercise in acute, high-level spinal cord injury: a retrospective analysis.

PURPOSE: High-level spinal cord injury (SCI) can result in spinal and supraspinal respiratory control deficits leading to insufficient ventilatory responses to exercise and training-related adaptations. We hypothesized a serotonin agonist, known to improve respiratory function in animal models, would improve adaptations to whole-body functional electrical stimulation (FES) exercise training in patients with acute high-level SCI. METHODS: We identified 10 patients (< 2 years of injury with SCI from C4 to T3) in our program who had performed 6 months of FES-row training while on Buspirone (29 ± 17 mg/day) between 2012 and 2018. We also identified well-matched individuals who trained for six months but not on Buspirone (n = 11). A peak incremental FES-rowing exercise test and resting pulmonary function test had been performed before and after training. RESULTS: Those on Buspirone demonstrated greater increases in peak oxygen consumption (VO2peak: + 0.24 ± 0.23 vs. + 0.10 ± 0.13 L/min, p = 0.08) and peak ventilation (VEpeak: + 6.5 ± 8.1 vs. - 0.7 ± 6.9 L/min, p < 0.05) compared to control. In addition, changes in VO2peak and VEpeak were correlated across all patients (r = 0.63, p < 0.01), but most strongly in those on Buspirone (r = 0.85, p < 0.01). Furthermore, changes in respiratory function correlated with increased peak tidal volume in the Buspirone group (r > 0.66, p < 0.05). CONCLUSION: These results suggest Buspirone improves cardiorespiratory adaptations to FES-exercise training in individuals with acute, high-level SCI. The strong association between increases in ventilatory and aerobic capacities suggests improved respiratory function is a mechanism; however, controlled studies are needed to determine if this preliminary finding is reproducible.

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.

Effect of serotonin modulation on dystrophin-deficient zebrafish.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by mutation of the dystrophin gene. Pharmacological therapies that function independently of dystrophin and complement strategies aimed at dystrophin restoration could significantly improve patient outcomes. Previous observations have suggested that serotonin pathway modulation ameliorates dystrophic pathology, and re-application of serotonin modulators already used clinically would potentially hasten availability to DMD patients. In our study, we used dystrophin-deficient sapje and sapje-like zebrafish models of DMD for rapid and easy screening of several classes of serotonin pathway modulators as potential therapeutics. None of the candidate drugs tested significantly decreased the percentage of zebrafish exhibiting the dystrophic muscle phenotype in the short-term birefringence assay or lengthened the lifespan in the long-term survival assay. Although we did not identify an effective drug, we believe our data is of value to the DMD research community for future studies, and there is evidence that suggests serotonin modulation may still be a viable treatment strategy with further investigation. Given the widespread clinical use of selective serotonin reuptake inhibitors, tricyclic antidepressants and reversible inhibitors of monoamine oxidase, their reapplication to DMD is an attractive strategy in the field's pursuit to identify pharmacological therapies to complement dystrophin restoration strategies.

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.

Shuangxia decoction alleviates p-chlorophenylalanine induced insomnia through the modification of serotonergic and immune system.

As a Traditional Chinese Medicine (TCM), Shuangxia Decoction (SXD) has been used to treat insomnia in oriental countries for more than thousands of years and it presents remarkable clinical effects. However, its active pharmacological fraction and the mechanism of sedative-hypnotic effects have not been explored. In this paper, we investigated active pharmacological fraction and revealed the detailed mechanisms underlying the sedative-hypnotic effects of SXD. It showed that SXD water extract compared to ethanol extract possessed better sedative effects on locomotion activity in normal mice and increased sleep duration in subhypnotic dose of sodium pentobarbital-treated mice. SXD alleviated p-chlorophenylalanine (PCPA) -induced insomnia by increasing the content of 5-HT in cortex [F (4, 55) = 12.67], decreasing the content of dopamine (DA) and norepinephrine (NE). Furthermore, SXD enhanced the expression of 5-HT1A and 5-HT2A receptors in hypothalamic and reduced serum levels of IL-1,TNF-α [F (5, 36) = 15.58]. In conclusion, these results indicated that SXD produced beneficial sedative and hypnotic bioactivities mediated by regulating the serotonergic and immune system.

Systemic serotonin inhibits brown adipose tissue sympathetic nerve activity via a GABA input to the dorsomedial hypothalamus, not via 5HT1A receptor activation in raphe pallidus.

AIM: Serotonin (5-hydroxytryptamine, 5-HT), an important neurotransmitter and hormone, modulates many physiological functions including body temperature. We investigated neural mechanisms involved in the inhibition of brown adipose tissue (BAT) sympathetic nerve activity (SNA) and BAT thermogenesis evoked by 5-HT. METHODS: Electrophysiological recordings, intravenous (iv) injections and nanoinjections in the brains of anaesthetized rats. RESULTS: Cooling-evoked increases in BAT SNA were inhibited by the intra-rostral raphé pallidus (rRPa) and the iv administration of the 5-HT1A receptor agonist, 8-OH-DPAT or 5-HT. The intra-rRPa 5-HT, the intra-rRPa and the iv 8-OH-DPAT, but not the iv 5-HT-induced inhibition of BAT SNA were prevented by nanoinjection of a 5-HT1A receptor antagonist in the rRPa. The increase in BAT SNA evoked by nanoinjection of NMDA in the rRPa was not inhibited by iv 5-HT, indicating that iv 5-HT does not inhibit BAT SNA by acting in the rRPa or in the sympathetic pathway distal to the rRPa. In contrast, under a warm condition, blockade of 5HT1A receptors in the rRPa increased BAT SNA and BAT thermogenesis, suggesting that endogenous 5-HT in the rRPa contributes to the suppression of BAT SNA and BAT thermogenesis. The increases in BAT SNA and BAT thermogenesis evoked by nanoinjection of NMDA in the dorsomedial hypothalamus (DMH) were inhibited by iv 5-HT, but those following bicuculline nanoinjection in the DMH were not inhibited. CONCLUSIONS: The systemic 5-HT-induced inhibition of BAT SNA requires a GABAergic inhibition of BAT sympathoexcitatory neurones in the DMH. In addition, during warming, 5-HT released endogenously in rRPa inhibits BAT SNA.

Effects of 5-HT1 and 5-HT 2 Receptor Agonists on Electromagnetic Field-Induced Analgesia in Rats.

Much evidence demonstrates the antinociceptive effect of magnetic fields (MFs). However, the analgesic action mechanism of the electromagnetic field (EMF) is not exactly understood. The aim of the present study was to investigate the effects of 5-HT1 and 5-HT2 receptor agonists (serotonin HCl and 2,5-dimethoxy-4-iodoamphetamine [DOI] hydrochloride) on EMF-induced analgesia. In total, 66 adult male Wistar albino rats with an average body mass of 225 ± 13 g were used in this study. The animals were subjected to repeated exposures of alternating 50 Hz and 5 mT EMF for 2 h a day for 15 days. Prior to analgesia tests, serotonin HCl (5-HT1 agonist) 4 mg/kg, WAY 100635 (5-HT1 antagonist) 0.04 mg/kg, DOI hydrochloride (5-HT2 receptor agonist) 4 mg/kg, and SB 204741 (5-HT2 antagonist) 0.5 mg/kg doses were injected into rats. For statistical analysis of the data, analysis of variance was used and multiple comparisons were determined by Tukey's test. Administration of serotonin HCl MF (5 mT)-exposed rats produced a significant increase in percent maximal possible effect (% MPE) as compared with EMF group (P < 0.05). On the contrary, injection of WAY 100635 to MF-exposed rats produced a significant decrease in analgesic activity (P < 0.05). Similarly, the administration of DOI hydrochloride significantly increased % MPE values as compared with the EMF group while SB 204741 reduced it (P < 0.05). In conclusion, our results suggested that serotonin 5-HT1 and 5-HT2 receptors play an important role in EMF-induced analgesia; however, further research studies are necessary to understand the mechanism. Bioelectromagnetics. 2019;40:319-330. © 2019 Bioelectromagnetics Society.

Dimethyltryptamine: Endogenous Role and Therapeutic Potential.

N, N-dimethyltryptamine (DMT) is an indole alkaloid produced by a number of plants and animals, including humans. Its psychoactive effects were first described in 1956 by Stephen Szára, but have been exploited for centuries by South American indigenous populations in the form of ayahuasca. In the present review, we assess the state of the art regarding a putative role for endogenous DMT and potential clinical applications of ayahuasca and DMT. A review assessing the pharmacological profile of DMT and its clinical effects in humans was performed using the PubMed data base until 5 August 2018 with the words: ayahuasca and N,N-dimethyltryptamine. While the role of endogenous DMT remains unclear, ayahuasca has promising results in anxiety, depression and substance dependence. Since ayahuasca has a good safety profile, it is crucial to conduct further research aimed at developing new treatments for psychiatric disorders.

Fluoxetine oral treatment discloses 5-HT1D receptor as vagoinhibitor of the cardiac cholinergic neurotransmission in rat.

Although depression and cardiovascular diseases are related, the role of antidepressants such as fluoxetine (increasing serotonin levels) within cardiac regulation remains unclear. We aimed to determine whether fluoxetine modifies the pharmacological profile of serotonergic influence on vagal cardiac outflow. Rats were treated with fluoxetine (10 mg/kg per day; p.o.) for 14 days or equivalent volumes of drinking water (control group); then, they were pithed and prepared for vagal stimulation. Bradycardic responses were obtained by electrical stimulation of the vagal fibers (3, 6, and 9 Hz) or i.v. acetylcholine (ACh; 1, 5, and 10 µg/kg). The i.v. administration of 5-hydroxytryptamine (5-HT; 10 and 50 µg/kg) inhibited the vagally induced bradycardia. 5-CT (5-HT1/7 agonist) and L-694,247 (5-HT1D agonist) mimicked the serotonin inhibitory effect while α-methyl-5-HT (5-HT2 agonist) was devoid of any action. SB269970 (5-HT7 antagonist) did not abolish 5-CT inhibitory action on the electrically induced bradycardia. Pretreatment with LY310762 (5-HT1D antagonist) blocked the effects induced by L-694,247 and 5-CT. 5-HT and 5-CT failed to modify the bradycardia induced by exogenous ACh. Our outcomes suggest that fluoxetine treatment modifies 5-HT modulation on heart parasympathetic neurotransmission in rats, evoking inhibition of the bradycardia via prejunctional 5-HT1D in pithed rats.

Engaging cervical spinal circuitry with non-invasive spinal stimulation and buspirone to restore hand function in chronic motor complete patients.

The combined effects of cervical electrical stimulation alone or in combination with the monoaminergic agonist buspirone on upper limb motor function were determined in six subjects with motor complete (AIS B) injury at C5 or above and more than one year from time of injury. Voluntary upper limb function was evaluated through measures of controlled hand contraction, handgrip force production, dexterity measures, and validated clinical assessment batteries. Repeated measure analysis of variance was used to evaluate functional metrics, EMG amplitude, and changes in mean grip strength. In aggregate, mean hand strength increased by greater than 300% with transcutaneous electrical stimulation and buspirone while a corresponding clinically significant improvement was observed in upper extremity motor scores and the action research arm test. Some functional improvements persisted for an extended period after the study interventions were discontinued. We demonstrate that, with these novel interventions, cervical spinal circuitry can be neuromodulated to improve volitional control of hand function in tetraplegic subjects. The potential impact of these findings on individuals with upper limb paralysis could be dramatic functionally, psychologically, and economically.

Emerging Treatments in Episodic Migraine.

PURPOSE OF REVIEW: The purpose of this review is to evaluate and describe recent and emerging treatment options for episodic migraine. RECENT FINDINGS: Recent advances have been made in better understanding the pathophysiology of migraine, which has led to further investigation of potential new pharmacologic and non-pharmacologic treatment options. A number of new medications are emerging for the acute and preventive treatment of migraine, including CGRP monoclonal antibodies, CGRP receptor antagonists, serotonin 5-HT1F agonists, and PACAP receptor monoclonal antibodies. Additionally, newer studies on existing non-invasive neuromodulation devices including transcranial magnetic stimulation, supraorbital transcutaneous nerve stimulation, and transcutaneous vagus nerve stimulation have recently received FDA approval for use in migraine. Neuromodulation devices including percutaneous mastoid electrical stimulation, non-painful remote electrical stimulation, and caloric vestibular stimulation are undergoing further investigation and have shown promising results thus far. These new developments are expected to contribute to better treatment and decreased disability in migraine.

5-HT1A receptor-mediated activation of neuroendocrine responses and multiple protein kinase pathways in the peripubertal rat hypothalamus.

Increasing evidence suggests that multiple factors can produce effects on the immature brain that are distinct and more long-lasting than those produced in adults. The hypothalamic paraventricular nucleus (PVN) is a region integral to the hypothalamic-pituitary-adrenal axis and is affected by anxiety, depression, and drugs used to treat these disorders, yet receptor signaling mechanisms operative in hypothalamus prior to maturation remain to be elucidated. In peripubertal male rats, systemic injection of the selective serotonin 1A (5-HT1A) receptor agonist (+)8-OH-DPAT (0.2 mg/kg) markedly elevated plasma levels of oxytocin and adrenocorticotropic hormone (ACTH) at 5 and 15 min post-injection. The 5-HT1A receptor selectivity was demonstrated by the ability of the 5-HT1A receptor selective antagonist WAY100635 to completely block both oxytocin and ACTH responses at 5 min, with some recovery of the ACTH response at 15 min. At 15 min post-injection, (+)8-OH-DPAT also increased levels of phosphorylated extracellular signal-regulated kinase (pERK) and phosphorylated protein kinase B (pAkt) in the PVN. As previously observed in adults, (+)8-OH-DPAT reduced levels of pERK in hippocampus. WAY100635 also completely blocked (+)8-OH-DPAT-mediated elevations in hypothalamic pERK and pAkt and the reductions in hippocampal pERK, demonstrating 5-HT1A receptor selectivity of both kinase responses. This study provides the first demonstration of functional 5-HT1A receptor-mediated ERK and Akt signaling pathways in the immature hypothalamus, activated by a dose of (+)8-OH-DPAT that concomitantly stimulates neuroendocrine responses. This information is fundamental to identifying potential signaling pathways targeted by biased agonists in the development of safe and effective treatment strategies in children and adolescents.

Cananga odorata essential oil reverses the anxiety induced by 1-(3-chlorophenyl) piperazine through regulating the MAPK pathway and serotonin system in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Cananga odorata essential oil, known as ylang-ylang essential oil (YYO), was commonly used in the aromatherapy for relaxation and mood adjusting use. In our previous study, YYO played anxiolytic effects on the mice in several behavioral tests that based on the instinctive responses to novel environments. AIM OF THE STUDY: To investigate the effects and mechanisms of YYO reversing the anxiety induced by 5-HT2C receptor agonist 1-(3-chlorophenyl) piperazine (m-CPP). MATERIALS AND METHODS: m-CPP was administrated to the male ICR mice to develop an anxiety model. The anxiolytic effect of YYO (0.1%, 1% and 10%, v/v) was evaluated in the elevated plus maze (EPM) test after odor exposure. Western blot was used to detect the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2) and cAMP response element-binding protein (CREB) and the expression of c-Fos in the prefrontal cortex (PFC) and hippocampus after the EPM test. Serotonin and its metabolite change in the brain were detected by liquid chromatogram with an electrochemical detector. The effect of YYO on the plasma corticosterone level was evaluated using enzyme-linked immunosorbent assay (ELISA) after the odor exposure. RESULTS: The behavior analysis showed that m-CPP (2 mg/kg and 4 mg/kg) could induce anxiety behaviors in the mice while diazepam (2 mg/kg) reversed the anxiety behavior induced by m-CPP. YYO dose-dependently increased the time and number of entries in the open arms (p < 0.05) compared to the Tween 80 group. YYO reduced the phosphorylation levels of ERK1/2 (p < 0.05) in both PFC and hippocampus. Down-regulations of phosphor-CREB (p < 0.05) and c-Fos (p < 0.05) were only observed in the hippocampus. YYO also affected the brain serotonin metabolism and reduced the blood plasma corticosterone level of the m-CPP treated mice. CONCLUSION: YYO odor exposure could reverse the anxiety behaviors generated by m-CPP. The anxiolytic effect of YYO was associated with the ERK1/2/CREB pathway in the hippocampus and relevant to the serotonin system.