Serotonergic Mechanisms Research Articles

Hippocampal Serotonin and Responses to Immobilization Stress in Rats Treated with Metformin

Background: Stress-related illnesses and depression are rising in modern society. Selective serotonin reuptake inhibitors as well as other antidepressants, are also not very effective and commonly exhibit partial remission, suggesting the need for novel therapeutic agents for treating anxiety and depression. Objective: The present study was designed to investigate serotonergic mechanisms in the potential anxiolytic and stress-reducing effects of metformin. Method: In the first experiment, rats were given two doses (50 and 100mg/kg) of metformin to monitor the effects of repeated administration on motor activity, anxiety, and 5-HT-1A receptor expression in the hippocampus and raphe nuclei. The second experiment was conducted in 2 parts, in 2a. experiment, control, and metformin (50 mg/kg) treated rats were immobilized for 2 hours for 5 consecutive days. Food intake and body weight were monitored daily and anxiety-like behavior was monitored on days 2 and 6. On day 6, rats were again immobilized for 2 hours, and after termination of stress rats were sacrificed to collect the hippocampus for HPLC-EC analysis of serotonin (5-hydroxytryptamine; 5-HT) and 5-hydroxy indole acetic acid (5-HIAA). In 2b. experiment, control, and metformin (50 mg/kg) treated rats were immobilized for 2 hours, and after 2 hours rats were sacrificed to collect the hippocampus for HPLC-EC analysis of 5-HT and 5-HIAA. Results: We found that metformin treatment exhibited anxiety reduction associated with greater expression of 5-HT-1A receptor in the hippocampus and reduced expression in the raphe nuclei. Immobilization stress-induced food intake and body weight deficits were comparable in control and metformin-treated rats, but the anxiogenic effects of stress were smaller in the metformintreated group. Stress-induced decreases of hippocampal 5-HT were smaller in metformin-treated than in control rats. result: We found that metformin treatment exhibited anxiety reduction associated with greater expression of 5-HT-1A receptor in the hippocampus and reduced expression in the raphe. Immobilization stress-induced food intake and body weight deficits were comparable in control and metformin-treated rats, but the anxiogenic effects of stress were smaller in the metformin-treated group. Stress-induced decreases of hippocampal 5-HT were smaller in metformin-treated than in control rats. Conclusion: Metformin can reduce stress-induced anxiety mediated via an increase in hippocampal 5-HT levels and 5-HT-1A heteroreceptor expression.

Antagonism of 5-HT2 receptors attenuates self-sustained firing of human motor units.

5-HT2 receptors on motoneurones play a critical role in facilitating persistent inward currents (PICs). Although facilitation of PICs can enhance self-sustained firing after periods of excitation, the relationship between 5-HT2 receptor activity and self-sustained firing in human motor units (MUs) has not been resolved. MU activity was assessed from the tibialis anterior of 10 healthy adults (24.9 ± 2.8 years) during two contraction protocols. Both protocols featured steady-state isometric contractions with constant descending drive to the motoneurone pool. However, one protocol also included an additional phase of superimposed descending drive. Adding and then removing descending drive in the middle of steady-state contractions altered MU firing behaviour across the motor pool, where newly recruited units in the superimposed phase were unable to switch off (P=0.0002), and units recruited prior to additional descending drive reduced their discharge rates (P<0.0001, difference in estimated marginal means (∆)=2.24 pulses/s). The 5-HT2 receptor antagonist, cyproheptadine, was then administered to determine whether changes in MU firing were mediated by serotonergic mechanisms. 5-HT2 receptor antagonism caused reductions in MU discharge rate (P<0.001, ∆=1.65 pulses/s), recruitment threshold (P=0.00112, ∆=1.09% maximal voluntary contraction) and self-sustained firing duration (P<0.0001, ∆=1.77s) after the additional descending drive was removed in the middle of the steady-state contraction. These findings indicate that serotonergic neuromodulation plays a key role in facilitating discharge and self-sustained firing of human motoneurones, where adaptive changes in MU recruitment must occur to meet the demands of the contraction. KEY POINTS: Animal and cellular preparations indicate that somato-dendritic 5-HT2 receptors regulate the intrinsic excitability of motoneurones. 5-HT2 receptor antagonism reduces estimates of persistent inward currents in motoneurones, which contribute to self-sustained firing when synaptic inputs are reduced or removed. This human study employed a contraction task that slowly increased (and then removed) the additional descending drive in the middle of a steady-state contraction where marked self-sustained firing occurred when the descending drive was removed. 5-HT2 receptor antagonism caused widespread reductions in motor unit (MU) discharge rates during contractions, which was accompanied by reduced recruitment threshold and attenuation of self-sustained firing duration after the removal of the additional descending drive to motoneurones. These findings support the role that serotonergic neuromodulation is a key facilitator of MU discharge and self-sustained firing of human motoneurones, where adaptative changes in MU recruitment must occur to meet the demands of the contraction.

The role of brain serotonin signaling in excessive alcohol consumption and withdrawal: A call for more research in females

Alcohol Use Disorder (AUD) is a leading cause of death and disability worldwide, but current treatments are insufficient in fully addressing the symptoms that often lead to relapses in alcohol consumption. The brain's serotonin system has been implicated in AUD for decades and is a major regulator of stress-related behaviors associated with increased alcohol consumption. This review will discuss the current literature on the association between neurobiological adaptations in serotonin systems and AUD in humans as well as the effectiveness of serotonin receptor manipulations on alcohol-related behaviors like consumption and withdrawal. We will further discuss how these findings in humans relate to findings in animal models, including a comparison of systemic pharmacological manipulations modulating alcohol consumption. We next provide a detailed overview of brain region-specific roles for serotonin and serotonin receptor signaling in alcohol-related behaviors in preclinical animal models, highlighting the complexity of forming a cohesive model of serotonin function in AUD and providing possible avenues for more effective therapeutic intervention. Throughout the review, we discuss what is known about sex differences in the sequelae of AUD and the role of serotonin in these sequelae. We stress a critical need for additional studies in women and female animals so that we may build a clearer path to elucidating sex-specific serotonergic mechanisms and develop better treatments.

Antidepressant-Like Effect of the Polymethoxylated Flavone Tangeretin from Citrus Peels: The Role of Serotonergic Mechanisms

Objective: Depression is a mood disorder characterized by a set of emotional, cognitive, physical and behavioral symptoms. Low response rate to antidepressant treatment in patients with depression, late onset of action, side effects due to long-term drug use, and pharmacogenetic variations limit the effectiveness and tolerability of these drugs and lead to compliance problems in patients. Therefore, studies on the discovery and development of new antidepressant drugs continue, and molecules of natural origin are becoming the focus of attention of researchers. Tangeretin, which is commonly found in citrus peels and has a pentamethoxyflavone structure, is an important member of flavonoids. Since it lacks a glycoside structure, it is easily absorbed from the intestines and can easily pass through the blood-brain barrier due to its lipophilic structure. Previous studies indicating that tangeretin may be effective on the central nervous system suggest that it may be possible for this phytochemical to have an effect on mood. Based on this idea, this study aimed to investigate the possible antidepressant-like effects of tangeretin and to elucidate the pharmacological mechanisms mediating this effect. Methods: Male Balb/c mice of the same age, weighing 30-35 g, were used for the experiments. The antidepressant-like effect of tangeretin (10, 20 ve 40 mg/kg, p.o.) was examined by tail suspension and modified forced swimming tests, while its effect on the motor coordination of experimental animals was evaluated using the Rota-rod method. Results: The data obtained revealed that doses of 10 and 20 mg/kg tangeretin decreased the immobility time of mice in tail suspension test and immobility number of mice in modified forced swimming tests compared to control animals not receiving tangeretin. These findings indicated that tangeretin showed an antidepressant-like activity comparable to the reference drug fluoxetine (30 mg/kg) when administered at doses of 10 and 20 mg/kg. Tangeretin, at the same doses, did not alter the climbing number of mice in modified forced swimming tests, but significantly increased their swimming number. The 40 mg/kg dose of this flavonoid did not cause a statistically significant effect in either test. While α-methyl-para-tyrosine methyl ester (an inhibitor of catecholamine synthesis; 100 mg/kg i.p.) and ondansetron (a 5-HT3 receptor antagonist; 0.3 mg/kg i.p.) pretreatments did not change the antidepressant-like activity induced by 20 mg/kg dose of this flavonoid in the tail suspension tests; pretreatment of p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis; 100 mg/kg i.p., administered for 4-consecutive days), NAN-190 (a 5-HT1A receptor antagonist; 0.5 mg/kg i.p.) and ketanserin (a 5-HT2A/2C receptor antagonist; 1 mg/kg i.p.), reversed this activity. These findings indicated that tangeretin has antidepressant-like activity mediated by the serotonergic system and that 5-HT1A and 5-HT2A/5-HT2C serotonergic receptor subtypes participate in this effect. Conclusion: The findings of this study suggest that tangeretin may be a useful drug candidate in the treatment of depression. However, it is clear that for tangeretin to be considered an antidepressant agent, the antidepressant-like activity presented in this preclinical study must be confirmed by well-designed clinical studies conducted on various groups of patients with depressive disorders.

Phytochemical Properties and Antidepressant Potential of Satureja khuzestanica Jamzad Essential Oil in Mouse Models of Depression

Oxidative stress may play a pivotal role in the pathogenesis of depression. Furthermore, antioxidants are also believed to have antidepressant properties. Previous studies have reported the antioxidant effects of Satureja khuzestanica Jamzad. Therefore, this study examined the antidepressant potential of Satureja khuzestanica essential oil (SKEO) in male mice based on a forced swim test (FST) and tail suspension test (TST). The GC-MS was used to evaluate the phytochemistry of SKEO. In behavioral studies, 72 male mice were allocated to twelve groups of six and intraperitoneally received the vehicle (10 mL/kg), fluoxetine (20 mg/kg), imipramine (30 mg/kg), or SKEO (25, 50, and 100 mg/kg). Immobility time in TST and immobility, swimming, and climbing times in FST were measured. In the open-field test (OFT), the number of crossings and rearings was recorded. According to GC-MS results, carvacrol, γ-terpinene, cymene, and 2-pinene were the most abundant compounds in SKEO. In FST and TST, all doses of SKEO (except for 25 mg/kg in FST), fluoxetine, and imipramine reduced the immobility time compared to the control group. Moreover, 50 and 100 mg/kg doses of SKEO and fluoxetine increased the swimming time without significantly changing the climbing time. However, imipramine increased the climbing time without significantly changing the swimming time. None of SKEO doses caused a significant change in the number of crossings or rearings in OFT. According to our findings, the antidepressant-like effects of SKEO are similar to those of fluoxetine. While the compounds in SKEO seem to induce their effects through the serotonergic mechanism, further studies are warranted to clarify their exact mechanism of action.

Evaluation of the anti-nociceptive profile of essential oil from Melissa officinalis L. (lemon balm) in acute and chronic pain models

Ethnopharmacological relevanceMelissa officinalis L. (Lamiaceae) is a medicinal plant native to Mediterranean regions and found in other parts of the world. Extracts and essential oil from this widely cultivated culinary medicinal herb are used in traditional medicine to manage a variety of disorders that include epilepsy and pain. Aim of the studyTo assess the anti-nociceptive potentials of Melissa officinalis essential oil (MO) and probe the involvement of adrenergic, opioidergic, serotonergic and potassium adenosine triphosphate (KATP) mechanisms in its anti-nociceptive effects. Material and methodsWe employed formalin-, acetic acid and hot plate-induced nociception to study the acute anti-nociceptive effects of MO. The sciatic nerve injury (CCI) model of neuropathic pain was utilized to study the anti-nociceptive effects of MO on chronic pain. Effects of MO on anxiety, cognitive deficits, oxidative stress and inflammation in the CCI rats were evaluated on elevated plus maze, open field test, novel object recognition, oxidative stress parameters and pro-inflammatory cytokines, respectively. The possible mechanism(s) of MO's anti-nociceptive effects were elucidated using prazosin, yohimbine, propranolol, glibenclimide, naloxone and metergoline, which are acknowledged antagonists for α1–, α2– and β–adrenergic, potassium adenosine triphosphate (KATP), opioidergic and serotonergic systems, respectively. ResultsMO significantly attenuated acetic acid- and formalin-induced nociception; prolonged the mean reaction time of rats on hot plate before and following sciatic nerve chronic injury (CCI). MO ameliorated anxiety, cognitive deficits and oxidative stress, reduced pro-inflammatory cytokine levels and produced a near total restoration of injured sciatic nerves in CCI rats. Naloxone, metergoline and glibenclimide significantly blocked, while prazosin, yohimbine and popranolol failed to block the anti-nociceptive effects of MO in formalin-induced nociception. ConclusionsMO contains biologically active compounds with potential anti-nociceptive properties that modulate KATP, opioidergic and serotonergic pathways. These support the development of bioactive compounds from MO as anti-nociceptive agents.

Elevated Serotonin in Mouse Spinal Dorsal Horn Is Pronociceptive.

Serotonergic neurons in the rostral ventral medulla (RVM) contribute to bidirectional control of pain through modulation of spinal and trigeminal nociceptive networks. Deficits in this pathway are believed to contribute to pathologic pain states, but whether changes in serotonergic mechanisms are pro- or antinociceptive is debated. We used a combination of optogenetics and fiber photometry to examine these mechanisms more closely. We find that optogenetic activation of RVM serotonergic afferents in the spinal cord of naive mice produces mechanical hypersensitivity and conditioned place aversion (CPA). Neuropathic pain, produced by chronic constriction injury of the infraorbital nerve (CCI-ION), evoked a tonic increase in serotonin (5HT) concentrations within the spinal trigeminal nucleus caudalis (SpVc), measured with liquid chromatography-tandem mass spectroscopy (LC-MS/MS). By contract, CCI-ION had no effect on the phasic serotonin transients in SpVc, evoked by noxious pinch, and measured with fiber photometry of a serotonin sensor. These findings suggest that serotonin release in the spinal cord is pronociceptive and that an increase in sustained serotonin signaling, rather than phasic or event driven increases, potentiate nociception in models of chronic pain.

Chemical Space of Small Molecule Exploration for the Elucidation of Cough Suppressant Pharmacology of Ying Su Ke/Zi

IntroductionChronic cough, a prevalent condition, lacks effective medical solutions. Traditionally, Ying Su Ke/Zi (derived from Papaver somniferum L.) has been used in certain ethnic herbal formulas to address cough. However, there is a notable absence of molecular-level exploration regarding their mechanism for treating cough. MethodsStarting with the chemical ingredients of Ying Su Ke/Zi, this study used principal component analysis to explore the chemical space of these compounds and set four rounds of screening criteria based on the chemical space distribution to quickly identify active compounds. Following that, their targets were predicted using the weighted ensemble system model, and target enrichment analysis was executed. ResultsIn total, 247 compounds in Ying Su Ke/Zi were data-mined from literature reports, based on which four rounds of screening yielded 88 potential active chemicals, mostly alkaloids. Besides, 168 target proteins, mostly G-protein-coupled receptors, were identified, and meanwhile the results of the enrichment analysis revealed that these target proteins are, mostly, localised at cell membranes, cell junctions, and cell projections, and they were primarily involved in biological processes ranging from stimulus response, signalling, and bioregulation, possessing molecular functions concerning altering molecular transduction activity and binding. Moreover, the key biological pathways covered by these target proteins are neuroactive receptor-ligand interaction pathway, serotonergic synapse pathway, etc. ConclusionsIntegrating the foregoing findings with the pathophysiological characteristics of cough, the current study reveals that Ying Su Ke/Zi exert their antitussive pharmacological effects primarily via opioidergic and serotonergic mechanisms.

A Water Nymph's Curse and the Serotonergic Mechanism of Postictal Breathing Dysfunction.

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Anti-angiogenic mechanisms and serotonergic dysfunction in the Rgs2 knockout model for the study of psycho-obstetric risk.

Psychiatric and obstetric diseases are growing threats to public health and share high rates of co-morbidity. G protein-coupled receptor signaling (e.g., vasopressin, serotonin) may be a convergent psycho-obstetric risk mechanism. Regulator of G Protein Signaling 2 (RGS2) mutations increase risk for both the gestational disease preeclampsia and for depression. We previously found preeclampsia-like, anti-angiogenic obstetric phenotypes with reduced placental Rgs2 expressionin mice. Here,we extend this to test whether conserved cerebrovascular and serotonergic mechanisms are also associated with risk for neurobiological phenotypes in the Rgs2 KO mouse. Rgs2 KO exhibited anxiety-, depression-, and hedonic-like behaviors. Cortical vascular density and vessel length decreased in Rgs2 KO; cortical and white matter thickness and cell densities were unchanged. In Rgs2 KO, serotonergic gene expression was sex-specifically changed (e.g., cortical Htr2a, Maoa increased in females but all serotonin targets unchanged or decreased in males); redox-related expression increased in paraventricular nucleus and aorta; and angiogenic gene expression was changed in male but not female cortex. Whole-cell recordings from dorsal raphe serotonin neurons revealed altered 5-HT1A receptor-dependent inhibitory postsynaptic currents (5-HT1A-IPSCs) in female but not male KO neurons. Additionally, serotonin transporter blockade by the SSRI sertraline increased the amplitude and time-to-peak of 5-HT1A-IPSCs in KO neurons to a greater extent than in WT neurons in females only. These results demonstrate behavioral, cerebrovascular, and sertraline hypersensitivity phenotypes in Rgs2 KOs, some of which are sex-specific. Disruptions may be driven by vascular and cell stress mechanisms linking the shared pathogenesis of psychiatric and obstetric disease to reveal future targets.

Synthesis, molecular docking, ADMET, and evaluation of the anxiolytic effect in adult zebrafish of synthetic chalcone (E)-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one: An in vivo and in silico approach.

Anxiety disorders represent the complex interaction between biological, psychological, temperamental, and environmental factors; drugs available to treat anxiety such as benzodiazepines (BZDs) are associated with several unwanted side effects. Although there are useful treatments, there is still a need for more effective anxiolytics with better safety profiles than BZDs. Chalcones or 1,3-diphenyl-2-proper-1-ones can be an alternative since this class of compounds has shown therapeutic potential mainly due to interactions with GABAA receptors and serotonergic system. This study evaluated the anxiolytic potential of chalcone (E)-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (C2OHPDA) in adult zebrafish (Danio rerio) (ZFa). Each animal (n = 6/group) was treated intraperitoneally (i.p.; 20 μL) with the chalcone (4, 20, and 40 mg/kg) and with the vehicle (DMSO 3%; 20 μL), being submitted to the tests of locomotor activity and 96-h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5-HT) was evaluated through the antagonists of the 5-HTR1 , 5-HTR2A/2C , and 5-HTR3A/3B receptors. It was investigated the prediction of the chalcone's position and preferential orientation concerning its receptor, as well as the pharmacokinetic parameters (ADMET) involved in the process after administration. As a result, C2OHPDA was not toxic and reduced the locomotor activity of ZFa. Furthermore, chalcone demonstrated an anxiolytic effect on the central nervous system (CNS), mediated by the serotonergic system, with action on 5-HT2A and 5-HTR3A/3B receptors. The interaction of C2OHPDA with 5-HT2A R and 5-HT3A receptors was confirmed by molecular docking study, the affinity energy observed was -8.7 and -9.1kcal/mol, respectively. Thus, this study adds new evidence and highlights that chalcone can potentially be used to develop compounds with anxiolytic properties.

Anxiolytic-like action of 3-((4-methoxyphenyl)selanyl)-2-phenylbenzofuran (SeBZF3) in mice: A possible contribution of the serotonergic system

Anxiety disorders, characterized by high prevalence rates, cause psychiatric disabilities and are related to impairments in serotoninergic system function. Frequent anxiety recurrence, resistance, and drug adverse effects have driven searches for new therapies. We initially evaluated the anxiolytic-like activity of 3-selanyl-benzo[b]furan compounds (SeBZF1–5) (50 mg/kg, i.g.) in male Swiss mice using the light-dark test (LDT). The compound 3-((4-methoxyphenyl)selanyl)-2-phenylbenzofuran (SeBZF3) exhibited anxiolytic-like activity. SeBZF3 anxiolytic-like effects were also observed in the novelty-suppressed feeding test (NSFT) (50 mg/kg) and elevated plus-maze test (EPMT) (25 and 50 mg/kg). In the EPMT, anxiolytic-like effects of SeBZF3 (50 mg/kg) were abolished by pretreatment with p-chlorophenylalanine, a selective tryptophan hydroxylase inhibitor (100 mg/kg, i.p. for 4 days), suggesting the involvement of serotonergic mechanisms. Furthermore, we conducted experiments to investigate the synergistic effects of SeBZF3 subeffective doses (5 mg/kg, i.g.) in combination with fluoxetine (a selective serotonin reuptake inhibitor, 5 mg/kg, i.p.) or buspirone (a partial agonist of the 5-HT1A receptor, 2 mg/kg, i.p.). This coadministration resulted in pronounced synergistic effects. We also examined the effects of repeated oral treatment with SeBZF3 at doses of 1 and 5 mg/kg over 14 days and both reduced anxiety signals. In vitro and ex vivo findings revealed that SeBZF3 inhibited cerebral MAO-A activity. These findings collectively imply the potential involvement of serotonergic mechanisms in the anxiolytic-like activity of SeBZF3 in mice. These data offer contributions to the research field of organoselenium compounds and anxiolytics, encouraging the broadening of the search for new effective drugs while offering improved side effect profiles.

The role of the serotonergic system in atropine’s anti-myopic effects

The muscarinic cholinergic antagonist atropine is the most widely used pharmacological treatment for the visual disorder myopia (short-sightedness), the leading cause of low-vision worldwide. This study sought to better define the mechanism by which atropine inhibits myopic growth. Although classified as a muscarinic-cholinergic antagonist, atropine has been found to bind and modulate the activity of several non-cholinergic systems (e.g., serotonin). Thus, this study investigated whether the serotonergic system could underly atropine’s anti-myopic effects. Using a chick model of myopia, we report that atropine’s growth-inhibitory effects can be attenuated by pharmacological stimulation of the serotonin system. This may suggest that atropine can slow the development of myopia through inhibiting serotonergic receptor activity. We also observed that pharmacological antagonism of serotonergic receptors inhibits the development of experimental myopia in a dose-dependent manner, further demonstrating that modulation of serotonergic receptor activity can alter ocular growth rates. Finally, we found that neither experimental myopia, nor atropine treatment, induced a significant change in retinal serotonergic output (i.e., synthesis, transport, release and catabolism). This may suggest that, although myopic growth can be inhibited through modulation of serotonergic receptor activity (by atropine or serotonergic antagonists), this does not require a change in serotonin levels. These findings regarding a serotonergic mechanism for atropine may have significant ramifications for the treatment of human myopia. This includes assessing the use of atropine in patients who are also undergoing treatment to upregulate serotonergic signaling (e.g., serotonergic anti-depressants).

Involvement of 5-HT1A receptors of the thalamic descending pathway in the analgesic effect of intramuscular heating-needle stimulation in a rat model of lumbar disc herniation.

Intramuscular (IM) heating-needle therapy, a non-painful thermal therapy, has been found to exert an analgesic effect via the thalamic ventromedial (VM) nucleus, solely by reducing the triggering threshold for descending inhibition; this could be modulated by intracephalic 5-hydroxytryptamine-1A (5-HT1A) receptors, rather than via the regular analgesia pathway. In this study, the effect and the potential serotonergic mechanism of IM heating-needle stimulation at 43°C were explored in the case of the pathological state of lumbar disc herniation (LDH). A modified classic rat model of LDH, induced via autologous nucleus pulposus implantation, was utilized. IM inner heating-needles were applied at the attachment point of skeletal muscle on both sides of the L4 and L5 spinous processes. WAY-100635 and 8-OH-DAPT, 5-HT1A receptor antagonist and agonist, were separately injected into the bilateral thalamic mediodorsal (MD) and VM nucleus via an intrathalamic catheter. Nociception was assessed by bilateral paw withdrawal reflexes elicited by noxious mechanical and heat stimulation. IM heating-needle stimulation at a temperature of 43°C for 30 or 45 min significantly relieved both mechanical and heat hyperalgesia in the rat model of LDH (P < 0.05). Heat hyperalgesia was found to be significantly enhanced by administration of WAY-100635 into the thalamic VM nucleus, blocking the effect of heating-needle stimulation in a dose-dependent manner (P < 0.05), while no effects were detected after injection into the thalamic MD nucleus (P > 0.05). Injection of 8-OH-DAPT into the thalamic MD nucleus exerted no modulating effects on either mechanical or heat hyperalgesia (P > 0.05). IM heating-needle stimulation at 43°C for 30 min may activate 5-HT1A mechanisms, via the thalamic VM nucleus, to attenuate hyperalgesia in a rat model of LDH. This innocuous form of thermal stimulation is speculated to selectively activate the descending inhibition mediated by the thalamic VM nucleus, exerting an analgesic effect, without the involvement of descending facilitation of the thalamic MD nucleus.

Underlying pharmacological mechanisms of psilocin-induced broadband desynchronization and disconnection of EEG in rats.

Psilocybin is one of the most extensively studied psychedelic drugs with a broad therapeutic potential. Despite the fact that its psychoactivity is mainly attributed to the agonism at 5-HT2A receptors, it has high binding affinity also to 5-HT2C and 5-HT1A receptors and indirectly modulates the dopaminergic system. Psilocybin and its active metabolite psilocin, as well as other serotonergic psychedelics, induce broadband desynchronization and disconnection in EEG in humans as well as in animals. The contribution of serotonergic and dopaminergic mechanisms underlying these changes is not clear. The present study thus aims to elucidate the pharmacological mechanisms underlying psilocin-induced broadband desynchronization and disconnection in an animal model. Selective antagonists of serotonin receptors (5-HT1A WAY100635, 5-HT2A MDL100907, 5-HT2C SB242084) and antipsychotics haloperidol, a D2 antagonist, and clozapine, a mixed D2 and 5-HT receptor antagonist, were used in order to clarify the underlying pharmacology. Psilocin-induced broadband decrease in the mean absolute EEG power was normalized by all antagonists and antipsychotics used within the frequency range 1-25 Hz; however, decreases in 25-40 Hz were influenced only by clozapine. Psilocin-induced decrease in global functional connectivity and, specifically, fronto-temporal disconnection were reversed by the 5-HT2A antagonist while other drugs had no effect. These findings suggest the involvement of all three serotonergic receptors studied as well as the role of dopaminergic mechanisms in power spectra/current density with only the 5-HT2A receptor being effective in both studied metrics. This opens an important discussion on the role of other than 5-HT2A-dependent mechanisms underlying the neurobiology of psychedelics.

The Role of Serotonergic and Noradrenergic Descending Pathways on Performance-Based Cognitive Functioning at Rest and in Response to Exercise in People with Chronic Whiplash-Associated Disorders: A Randomized Controlled Crossover Study.

(1) Background: Dysregulation in serotonergic and noradrenergic systems may be implicated in the neurobiophysiological mechanisms underlying pain-related cognitive impairment in chronic whiplash-associated disorders (CWAD). This study aimed to unravel the role of serotonergic and noradrenergic descending pathways in cognitive functioning at rest and in response to exercise in people with CWAD. (2) Methods: 25 people with CWAD were included in this double-blind, randomized, controlled crossover study. Endogenous descending serotonergic and noradrenergic inhibitory mechanisms were modulated by using a single dose of a selective serotonin reuptake inhibitor (Citalopram) or a selective norepinephrine reuptake inhibitor (Atomoxetine). Cognitive performance was studied at rest and in response to exercise (1) without medication intake; (2) after intake of Citalopram; and (3) after intake of Atomoxetine. (3) Results: After Atomoxetine intake, selective attention improved compared with the no medication day (p < 0.05). In contrast, a single dose of Citalopram had no significant effect on cognitive functioning at rest. When performing pairwise comparisons, improvements in selective attention were found after exercise for the no medication condition (p < 0.05). In contrast, after intake of Citalopram or Atomoxetine, selective and sustained attention worsened after exercise. (4) Conclusions: A single dose of Atomoxetine improved selective attention only in one Stroop condition, and a single dose of Citalopram had no effect on cognitive functioning at rest in people with CWAD. Only without medication intake did selective attention improve in response to exercise, whereas both centrally acting medications worsened cognitive performance in response to a submaximal aerobic exercise bout in people with CWAD.

Synthesis and anxiolytic effect of europium metallic complex containing lapachol [Eu(DBM)3. LAP] in adult zebrafish through serotonergic neurotransmission: in vivo and in silico approach

Anxiety-related mental health problems are estimated at 3.6% globally, benzodiazepines (BZDs) are the class of drugs indicated for the treatment of anxiety, including lorazepam and diazepam. However, concerns have been raised about the short- and long-term risks associated with BZDs. Therefore, despite anxiolytic and antidepressant drugs, there is a need to develop more effective pharmacotherapies with fewer side effects than existing drugs. The present work reported the synthesis, anxiolytic activity, mechanism of action in Adult Zebrafish (Danio rerio) and in silico study of a europium metallic complex with Lapachol, [Eu(DBM)3. LAP]. Each animal (n = 6/group) was treated intraperitoneally (i.p.; 20 µL) with the synthesized complex (4, 20 and 40 mg/Kg) and with the vehicle (DMSO 3%; 20 µL), being submitted to the tests of locomotor activity and 96h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5-HT) was evaluated through the antagonists of the 5-HTR1, 5-HTR2A/2C and 5-HTR3A/3B receptors. The complex was characterized using spectrometric techniques, and the anxiolytic effect of complex may be involved the neuromodulation of receptors 5-HT3A/3B, since the pre-treatment with pizotifen and cyproheptadine did not block the anxiolytic effect of [Eu(DBM)3. LAP], unlike fluoxetine had its anxiolytic effect reversed. In addition, molecular docking showed interaction between the [Eu(DBM)3. LAP] and 5HT3A receptor with binding energy −7.8 kcal/mol and the ADMET study showed that complex has low toxic risk. It is expected that the beginning of this study will allow the application of the new anxiolytic drugs, given the pharmacological potential of the lapachol complex. Communicated by Ramaswamy H. Sarma

SEROTONIN SYNDROME AFTER HIGH DOSAGE QUETIAPINE INTAKE: CASE REPORT AND BRIEF LITERATURE REVIEW

IntroductionSerotonin syndrome is a potentially life-threatening condition due to increased serotonergic activity in the CNS. Its most well-known causes are the ingestion of large amounts of serotonergic drugs or the inappropriate combination of two or more serotonergic antidepressants. Rarer causes of serotonin syndrome have been reported in the literature.ObjectivesThe aim of this paper is to highlight, through case presentation, rarer causes of serotonin syndrome.MethodsCase presentation (woman, 39 years old) who was hospitalized with clinical presentation of Serotonin syndrome, after pharmaceutical self-poisoning with a large amount of quetiapine (&gt;20g). The search of the case data (clinical and paraclinical examination findings) was performed from the medical records and files of the 3rd Internal Medicine Clinic and the Liaison Psychiatry Department of our hospital. A literature search of similar cases (through PubMed) was performed.ResultsA patient with a history of mood disorders, under treatment with venlafaxine, lamotrigine, quetiapine and aripiprazole, was admitted to the hospital ICU due to a decreased level of consciousness (GCS 11/15). Ingestion of approximately 100 tablets of Quetiapine 200mg was reported. The patient developed upper and lower limb myoclonus, supraventricular tachycardia (130bpm), nystagmus, bilateral mydriasis with normal photomotor reflexes, increased tendon reflexes, excessive sweating, upper limb muscle rigidity and abdominal flatulence with the presence of loud bowel sounds. Gastric lavage was performed and admission to the Internal Medicine department followed. Intravenous diazepam was administered, 30mg on the 1st 24 hour period and 20mg on the 2nd, with gradual tapering. From the very 2nd 24 hour period of hospitalization, her clinical condition showed significant improvement, with complete remission of symptoms and recovery of a satisfactory level of consciousness.ConclusionsSerotonin syndrome can be effectively treated if early recognition of symptoms is made. Clinicians should be particularly alert and suspect the possibility of serotonin syndrome in a patient with compatible symptoms by clinical examination, especially in case of overdose of a drug, with or without a serotonergic mechanism of action.Disclosure of InterestNone Declared

Daikenchuto significantly improves stool consistency and lower gastrointestinal symptoms in patients with chronic constipation.

A number of basic and clinical studies have confirmed that the traditional Japanese herbal medicine, Daikenchutou (DKT) has a pharmacological effect on cholinergic and serotonergic mechanisms with a favorable safety profile and an improving effect on lower gastrointestinal (GI) symptoms including abdominal pain or bloating. The purpose of this study is to evaluate the efficacy and safety of DKT on chronic constipation. This multicenter, randomized, placebo-controlled, double-blinded clinical trial enrolled 67 patients with chronic constipation fulfilling Rome III criteria. After a 2-week observation period, 63 patients with persistent symptoms were finally randomized to a 4-week course of treatment with DKT or placebo. The primary endpoint consisted of a global assessment of overall treatment effect (OTE), while the secondary endpoints consisted of improvements in stool consistency, spontaneous bowel movements, lower GI symptoms related to constipation, and quality of life. Factors associated with OTE were also investigated. After 4 weeks administration of DKT, OTE was significantly higher than placebo. No side effects were observed. Significant improvement in stool consistency and lower GI symptoms was observed in the DKT group. The improvements in lower GI symptoms as well as stool consistency were associated with OTE. OTE was higher in patients with greater improvement in lower GI symptoms with mental component summary scores close to normal before treatment. DKT was effective and safe in treating chronic constipation, especially in patients having symptoms related to constipation with no impaired mental component summary score.

Behavioral sleep medicine-The need for harmonization of clinical best practice outcome measures in children and adolescents with intellectual or developmental disabilities and restless sleep.

In behavioral medicine, sleep disorders, insomnia in particular, may be considered comorbidities and precipitating factors to intellectual or developmental disabilities (IDD). Nevertheless, sleep alterations have often been neglected in favor of daytime features and symptoms, albeit simple behavioral nighttime observations may disclose hypermotor features that characterize restless sleep. The root of most hypermotor restlessness is linked to central iron deficiency. The latter is often exacerbated by vitamin D deficiency (VDD), which interferes with both dopaminergic and serotonergic mechanisms. In this way, an imbalance affecting daytime behavior and mood is created. Several sleep-related motor disorders such as bruxism, periodic and aperiodic leg movements, Restless Legs Syndrome (RLS), and Restless Sleep Disorder (RSD) are commonly seen in Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorders (ASD). However, they are rarely diagnosed and often overlooked in affected children and adolescents. As a result, not only are these disorders not adequately addressed therapeutically, but their symptoms may be worsened by the side-effects of drugs used to contain disruptive daytime behavior, such as antipsychotics and antidepressants. In children with IDDs, obesity, inactivity and metabolic effects of antipsychotics often lead to Sleep Disordered Breathing (SDB), which is currently understood as an inflammatory state leading to “hyperactive” lethargy and further alterations of the hypoxic chain and vitamin D levels. Endorsing simple routine blood tests, including inflammatory markers such as C-reactive protein, ferritin, transferrin, and vitamin D levels, may favorably complement caregiver observations and ambulatory sleep recordings, leading to a sleep disorder diagnosis and consequent therapy. In fact, the treatment of SDB, RLS, and RSD has been copiously demonstrated to favorably impact vigilance, behavior, social competence, and academic skills in healthy and, to a greater extent, in IDD children. Thus, consulting and deliberating the root causes of functional and categorical diagnoses within a clinical framework may engender a more precise diagnosis and further benefit pediatric daytime and nighttime management of hyperactive behaviors.