Search Results (31)

Background/Objectives: As the prevalence of depression and the use of antidepressants have risen steadily in the last decade, new treatment options are needed. Aloysia gratissima var. gratissima ethanol extract has previously shown antidepressant-like activity, and the present study was conducted to identify the active fraction and clarify the possible mechanisms of action. Methods: Tail suspension (TST) and forced swimming (FST) behavioral tests were performed, and possible mechanisms of action were elucidated using serotonergic, dopaminergic, adrenergic, and GABAergic system antagonists. UPLC-DAD-MS analyses were performed to identify compounds in active fractions, and molecular docking studies were carried out to determine the binding affinities of these compounds to serotonergic and dopaminergic receptors (5-HT_1A, 5-HT_2A, 5-HT₃, and D₂R). Results: Ethyl acetate and butanol fractions were found to decrease immobility time in FST. The reduction in immobility time during the FST caused by the ethyl acetate fraction was reversed by pretreating mice with WAY100635 (5-HT_1A antagonist), ketanserin (a 5-HT_2A antagonist, ondansetron (5-HT₃ antagonist), or haloperidol (D₂ antagonist). UPLC-DAD-MS analysis revealed a similar composition for the ethyl acetate and butanol fractions of A. gratissima var. gratissima. Pharmacokinetic predictions suggest that only a few of the identified compounds have the potential to permeate the blood–brain barrier, and molecular docking simulations showed that compounds such as 13-oxooctadecadienoic acid, ferulic acid, and coumaric acid have binding affinities to the druggable site of serotonergic and dopaminergic receptors. Conclusions: These results suggest that the Agg ethyl acetate fraction possesses antidepressant-like activities, altering dopaminergic and serotonergic system functions. Computational simulations also suggest that some of the identified compounds have binding affinities to the 5-HT_1A, 5-HT_2A, 5-HT₃, and D₂R receptors. Full article

Background: Ketamine and magnesium sulfate are commonly used perioperatively to prevent shivering, a frequent and clinically relevant complication of spinal and general anesthesia. Although their hypothermic effects are well documented, the neurotransmitter mechanisms underlying these effects remain insufficiently understood. This study examines whether serotonergic, adrenergic (α₂), and GABAergic (GABA_A) systems contribute to hypothermia induced by ketamine and a ketamine–magnesium sulfate combination. Methods: Body temperature was measured in Wistar rats after administration of ketamine (10 mg/kg) or the ketamine (5 mg/kg)–magnesium sulfate (5 mg/kg) combination. To assess neurotransmitter involvement, animals received yohimbine (α₂ antagonist), methysergide (non-selective 5-HT antagonist), or bicuculline (GABA_A antagonist) prior to ketamine or the drug combination. Data were analyzed using two-way repeated measures ANOVA followed by Tukey’s post hoc test. Results: Yohimbine at 0.5 and 1 mg/kg significantly potentiated ketamine-induced hypothermia, while only 3 mg/kg enhanced the effect of the ketamine–magnesium sulfate combination. Methysergide had a bidirectional influence: 1 mg/kg methysergide deepened ketamine-induced hypothermia, whereas 0.5 mg/kg methysergide attenuated the hypothermic effect of the ketamine–magnesium sulfate combination. Bicuculline (1–2 mg/kg) did not alter the hypothermic responses to ketamine or the combination. Conclusions: These findings indicate that ketamine- and ketamine–magnesium sulfate-induced hypothermia is primarily modulated by serotonergic and adrenergic mechanisms, whereas GABA_A receptor-dependent pathways do not appear to play a major role under the experimental conditions used. These results provide new mechanistic insights into NMDA antagonist–related thermoregulation and may help inform anesthetic strategies for shivering prevention and maintenance of perioperative thermal stability. Full article

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by motor and phonic tics, often including attention deficit, hyperactivity, and obsessive–compulsive behaviours. The pathophysiology involves the dysfunction of cortico-striato-thalamo-cortical circuits, primarily implicating dopaminergic hyperactivity, but also involving multiple different neurotransmitter systems. Treatment of GTS is complex, highly individualized, and influenced by considerable variability in symptom presentation. Behavioural approaches, such as Habit Reversal Therapy (HRT), play a key role, especially in milder cases. Pharmacological therapy is largely empirical and varies across countries, influenced by drug availability and the perceived risks of certain classes of drugs, particularly dopamine receptor blocking agents. Drug options for managing tics include dopamine receptor antagonists, monoamine depleting agents, and alpha-2 agonists, all of which require close monitoring for metabolic, cardiovascular, and neurological side effects. Botulinum toxin injections represent an effective solution for focal tics that are resistant to systemic treatments. Cannabinoids and antiepileptics have limited efficacy, yet they may still offer relevant therapeutic potential in selected cases. Serotonergic drugs are useful for treating obsessive–compulsive symptoms. For patients with refractory tics, deep brain stimulation (DBS) represents an intervention of last-resort; however, DBS remains off-label and consensus on optimal targets is lacking. This narrative review draws on both the relevant literature and extensive personal clinical experience to explore the complexities of managing GTS, with a focus on evidence-based treatments for tics and associated neuropsychiatric symptoms. A therapeutic algorithm is proposed, emphasizing a “start low, go slow” approach, combining pharmacological interventions with cognitive behavioural and surgical therapies, when needed. We underscore the importance of tailoring treatments to individual patient profiles and symptom variability over time, highlighting the need for further research in GTS management. Full article

Individuals with severe mental illness face a substantially higher risk of suicide compared with the general population, with drug overdose representing one of the most common and potentially lethal methods. This narrative review explores toxidromes frequently encountered in psychiatric populations, such as opioid, anticholinergic, and serotonergic toxicity, highlighting the clinical presentation in intentional overdose. Emphasis is placed on clinical recognition, antidote-based treatment, and systems-level strategies for the prevention of lethal overdose. We conducted a comprehensive literature search of PubMed, Google Scholar, and Web of Science for English-language articles using combinations of the following keywords: mental disorders; persons with psychiatric disorders; drug overdose; poisoning; serotonin syndrome; neuroleptic malignant syndrome; anticholinergic agents/poisoning; cholinergic antagonists/poisoning; psychotropic drugs/adverse effects; substance-related disorders; drug-related side effects and adverse reactions; polypharmacy; suicide, attempted; emergency service, hospital. By embedding toxidrome awareness into routine emergency and psychiatric practice, we aim to expedite treatment and improve patient outcomes. Full article

The serotonergic system, originating in the raphe nuclei, differentially modulates the dorsal and ventral hippocampus, which are implicated in cognition and emotion, respectively. Emerging evidence from rodent models (e.g., neonatal ventral hippocampal lesion, pharmacological NMDA receptor antagonist exposure) and human postmortem studies indicates dorsoventral serotonergic alterations in schizophrenia. These data include elevated 5-HT1A receptor expression in the dorsal hippocampus, linking serotonergic hypofunction to cognitive deficits, and hyperactive 5-HT2A/3 receptor signaling and denser serotonergic innervation in the ventral hippocampus driving local hyperexcitability associated with psychosis and stress responsivity. These dorsoventral serotonergic alterations are shown to disrupt the excitation–inhibition balance, impair synaptic plasticity, and disturb network oscillations, as established by in vivo electrophysiology and functional imaging. Synthesizing these multi-level findings, we propose a novel “dorsoventral serotonin imbalance” model of schizophrenia, in which ventral hyperactivation predominantly contributes to psychotic symptoms and dorsal hypoactivity underlies cognitive deficits. We further highlight promising preclinical evidence that selective targeting of region- and receptor-specific targeting, using both pharmacological agents and emerging delivery technologies, may offer novel therapeutic opportunities enabling symptom-specific strategies in schizophrenia. Full article

The adaptation of the body when exposed to a lower-than-usual temperature is a challenge that involves neuro-endocrine–immune mechanisms and affects the pharmacokinetics and/or pharmacodynamics of drugs taken before or after cold exposure. The experiments presented in this study clearly show differences in the analgesic effect of an exogenously introduced model substance (C-terminal fragment of calcium-binding protein, spermatid-specific 1) before and after cold exposure compared to its effect at an ambient temperature. The model substance used for the experiments is an octapeptide, TDIFELLK, which was synthesized via standard solid-phase peptide synthesis. Preliminary studies proved TDIFELLK’s analgesic activity. The ANOVA analysis performed showed statistically significant differences in the pain thresholds, measured by a paw pressure test, in 109 rats distributed among 14 groups and subjected to cold exposure according to different set-ups. Cold exposure immediately after TDIFELLK administration appears to enhance its analgesic effect, while cold exposure before administration reduces the effect. In some of the set-ups, antagonists of the most significant for analgesia receptors, i.e., opioid, cannabinoid, and serotonergic, were also introduced. The results showed that cold exposure had a modulating influence on the effect of the exogenously administered substances. The modulating effect was manifested differently depending on whether the intake occurred before or after cold exposure. The results also showed that the interaction with individual mediator systems was also subjected to differences depending on intake occurring before and after cold exposure. Full article

Background/Objectives: Non-response to initial treatment options for major depressive disorder (MDD) is a common clinical challenge with profound deleterious impacts for affected patients. Few treatments have received regulatory approval for treatment-resistant depression (TRD). Methods: A systematic search of United States and European Union clinical trials registries was conducted to identify Phase II, III, or IV clinical trials, with a last update posted on or after 1 January 2020, that were evaluating medications for TRD. For both the US and EU registries, the condition term “treatment resistant depression” and associated lower-level terms (per registry search protocol) were used. For the US registry, a secondary search using the condition term “depressive disorders” and the modifying term “inadequate” was also performed to capture registrations not tagged as TRD. Two additional searches were also conducted in the US registry for the terms “suicide” and “anhedonia” as transdiagnostic targets of investigational medications. Trials were categorized based on the primary mechanism of action of the trial’s investigational medication. Results: Fifty clinical trials for TRD, 20 for anhedonia, and 25 for suicide were identified. Glutamate system modulation was the mechanism currently with the most compounds in development, including antagonists and allosteric modulators of NMDA receptors, AMPA receptors, metabotropic type 2/3 glutamate receptors, and intracellular effector molecules downstream of glutamate signaling. Psychedelics have seen the greatest surge among mechanistic targets in the past 5 years, however, with psilocybin in particular garnering significant attention. Other mechanisms included GABA modulators, monoamine modulators, anti-inflammatory/immune-modulating agents, and an orexin type 2 receptor antagonist. Conclusions: These investigations offer substantial promise for more efficacious and potentially personalized medication approaches for TRD. Challenges for detecting efficacy in TRD include the heterogeneity within the TRD population stemming from the presumed variety of biological dysfunctions underlying the disorder, comorbid disorders, chronic psychosocial stressors, and enduring effects of prior serotonergic antidepressant medication treatments. Full article

Autism spectrum disorder is a complex neurodevelopmental disorder. The available medical treatment options for autism spectrum disorder are very limited. While the etiology and pathophysiology of autism spectrum disorder are still not fully understood, recent studies have suggested that wide alterations in the GABAergic, glutamatergic, cholinergic, and serotonergic systems play a key role in its development and progression. Histamine neurotransmission is known to have complex interactions with other neurotransmitters that fit perfectly into the complex etiology of this disease. Multitarget-directed compounds with an affinity for the histamine H₃ receptor indicate an interesting profile of activity against autism spectrum disorder in animal models. Here, we present the results of our research on the properties of (4-piperazin-1-ylbutyl)guanidine derivatives acting on histamine H₃ receptors as potential multitarget ligands. Through the virtual screening approach, we identified promising ligands among 32 non-imidazole histamine H₃ receptor antagonists/inverse agonists with potential additional activity against the dopamine D₂ receptor and/or cholinesterases. The virtual screening protocol integrated predictions from SwissTargetPrediction, SEA, and PPB2 tools, along with molecular docking simulations conducted using GOLD 5.3 and Glide 7.5 software. Among the selected ligands, compounds 25 and 30 blocked radioligand binding to the D₂ receptor at over 50% at a screening concentration of 1 µM. Further experiments allowed us to determine the pK_i value at the D₂ receptor of 6.22 and 6.12 for compounds 25 and 30, respectively. Our findings suggest that some of the tested compounds could be promising multitarget-directed ligands for the further research and development of more effective treatments for autism spectrum disorder. Full article

Stanhopea tigrina Bateman ex Lindl. (Orchidaceae) is an orchid endemic to Mexico, known as “Calavera” or “calaverita”, in the Huasteca Potosina (central region of Mexico). This plant species is used for the folk treatment of mental disorders and urological kidney disorders, according to the ethnomedicinal information obtained in this study. Ethanolic extracts of leaves (HE) and pseudobulb (PE) were obtained by microwave-assisted extraction (MAE). Gas Chromatography coupled with Mass Spectrometry (GC-MS) was used to carry out the chemical characterization of HE and PE. The pharmacological effects (antioxidant, diuretic, anxiolytic, locomotor, hypnotic, and sedative) of HE and PE were evaluated. The possible mechanism of action of the anxiolytic-like activity induced by HE was assessed using inhibitors of the GABAergic, adrenergic, and serotonergic systems. The possible mechanism of the diuretic action of HE was assessed using prostaglandin inhibitory antagonists and nitric oxide synthase (NOS) blockers. HE at 50 and 100 mg/kg exerted anxiolytic-like activity without inducing hypnosis or sedation. Flumazenil, prazosin, and ketanserin inhibited the anxiolytic-like activity shown by HE, which suggests the participation of GABA, α₁-adrenergic receptors, and 5-HT₂ receptors, respectively. The diuretic effect was reversed by the non-selective NOS inhibitor L-NAME, which caused the reduction in nitric oxide (NO). These results demonstrate that the ethanolic extract of S. tigrina leaves exhibited anxiolytic-like activity and diuretic effects without inducing hypnosis or sedation. This work validates the medicinal uses of this orchid species. Full article

The core symptoms of attention deficit hyperactivity disorder (ADHD) are due to the hypofunction of the brain’s adrenergic (NE) and dopamine (DA) systems. Drugs that enhance DA and NE neurotransmission in the brain by blocking their transporters or receptors are the current therapeutic strategies. Of late, the emerging results point out the serotonergic (5-HT) system, which indirectly modulates the DA activity in reducing the core symptoms of ADHD. On this basis, second-generation antipsychotics, which utilize 5-HT receptors, were prescribed to children with ADHD. However, it is not clear how serotonergic receptors modulate the DA activity to minimize the symptoms of ADHD. The present study investigates the efficacy of serotonergic and alpha-2 adrenergic receptor manipulation in tackling the core symptoms of ADHD and how it affects the DA neuroreceptors in the brain regions involved in ADHD. Fifteen-day-old male spontaneously hypertensive rats (SHRs) received 5-HT1A agonist (ipsapirone) or 5-HT2A antagonist (MDL 100907) (i.p.) or alpha-2 agonist (GFC) from postnatal days 15 to 42 along with age-matched Wistar Kyoto rats (WKY) (n = 8 in each group). ADHD-like behaviors were assessed using a battery of behavioral tests during postnatal days 44 to 65. After the behavioral tests, rat brains were processed to estimate the density of 5-HT1A, 5-HT2A, DA-D1, and DA-D2 neuroreceptors in the prefrontal cortex, the striatum, and the substantia nigra. All three neuroreceptor manipulations were able to minimize the core symptoms of ADHD in SHRs. The positive effect was mainly associated with the upregulation of 5-HT2A receptors in all three areas investigated, while 5-HT1A was in the prefrontal cortex and the substantia nigra. Further, the DA-D1 receptor expression was downregulated by all three neuroreceptor manipulations except for alpha-2 adrenergic receptor agonists in the striatum and 5-HT2A antagonists in the substantia nigra. The DA-D2 expression was upregulated in the striatum while downregulated in the prefrontal cortex and the substantia nigra. In this animal model study, the 5-HT1A agonist or 5-HT2A antagonist monotherapies were able to curtail the ADHD symptoms by differential expression of DA receptors in different regions of the brain. Full article

The perception of „stress” triggers many physiological and behavioral responses, collectively called the stress response. Such a complex process allows for coping with stress and also triggers severe pathology. Because of the multidirectional effect of stress on the body, multiple systems participate in its pathogenesis, with the endogenous cannabinoid and the serotoninergic ones among them. These two systems also take part in the pain perception decrease, known as stress-induced analgesia (SIA), which can then be taken as an indirect indicator of the stress response. The aim of our study was to study the changes in cold SIA (c-SIA) resulting from the exogenous activation of cannabinoid receptor type 1 (CB1) and 5-hydroxytryptamine (5-HT, serotonin) receptor type 1_A (5-HT1A). Various combinations of agonists and/or antagonists of CB1 and 5-HT1A, before or after 1 h of cold exposure, were applied, since we presumed that the exogenous activation of the receptors before the cold exposure would influence the pathogenesis of the stress response, while their activation after the stressful trigger would influence the later development. Our results show that the serotonergic system “maintained” c-SIA in the pre-stress treatment, while the cannabinoids’ modulative effect was more prominent in the post-stress treatment. Here, we show the interactions of the two systems in the stress response. The interpretation and understanding of the mechanisms of interaction between CB1 and 5-HT1A may provide information for the prevention and control of adverse stress effects, as well as suggest interesting directions for the development of targeted interventions for the control of specific body responses. Full article

Intense species-specific locomotion changes the behavioural and cognitive states of various vertebrates and invertebrates. However, whether and how reproductive behaviour is affected by previous increased motor activity remains largely unknown. We addressed this question using a model organism, the pond snail Lymnaea stagnalis. Intense crawling in shallow water for two hours had previously been shown to affect orienting behaviour in a new environment as well as the state of the serotonergic system in L. stagnalis. We found that the same behaviour resulted in an increased number of egg clutches and the total number of eggs laid in the following 24 h. However, the number of eggs per clutch was not affected. This effect was significantly stronger from January to May, in contrast to the September–December period. Transcripts of the egg-laying prohormone gene and the tryptophan hydroxylase gene, which codes for the rate-limiting enzyme in serotonin synthesis, were significantly higher in the central nervous system of snails that rested in clean water for two hours after intense crawling. Additionally, the neurons of the left (but not the right) caudo-dorsal cluster (CDC), which produce the ovulation hormone and play a key role in oviposition, responded to stimulation with a higher number of spikes, although there were no differences in their resting membrane potentials. We speculate that the left–right asymmetry of the response was due to the asymmetric (right) location of the male reproductive neurons having an antagonistic influence on the female hormonal system in the hermaphrodite mollusc. Serotonin, which is known to enhance oviposition in L. stagnalis, had no direct effect on the membrane potential or electrical activity of CDC neurons. Our data suggest that (i) two-hour crawling in shallow water enhances oviposition in L. stagnalis, (ii) the effect depends on the season, and (iii) the underlying mechanisms may include increased excitability of the CDC neurons and increased expression of the egg-laying prohormone gene. Full article

Around 700,000 people die from suicide each year in the world. Approximately 90% of suicides have a history of mental illness, and more than two-thirds occur during a major depressive episode. Specific therapeutic options to manage the suicidal crisis are limited and measures to prevent acting out also remain limited. Drugs shown to reduce the risk of suicide (antidepressants, lithium, or clozapine) necessitate a long delay of onset. To date, no treatment is indicated for the treatment of suicidality. Ketamine, a glutamate NMDA receptor antagonist, is a fast-acting antidepressant with significant effects on suicidal ideation in the short term, while its effects on suicidal acts still need to be demonstrated. In the present article, we reviewed the literature on preclinical studies in order to identify the potential anti-suicidal pharmacological targets of ketamine. Impulsive–aggressive traits are one of the vulnerability factors common to suicide in patients with unipolar and bipolar depression. Preclinical studies in rodent models with impulsivity, aggressiveness, and anhedonia may help to analyze, at least in part, suicide neurobiology, as well as the beneficial effects of ketamine/esketamine on reducing suicidal ideations and preventing suicidal acts. The present review focuses on disruptions in the serotonergic system (5-HT_B receptor, MAO-A enzyme), neuroinflammation, and/or the HPA axis in rodent models with an impulsive/aggressive phenotype, because these traits are critical risk factors for suicide in humans. Ketamine can modulate these endophenotypes of suicide in human as well as in animal models. The main pharmacological properties of ketamine are then summarized. Finally, numerous questions arose regarding the mechanisms by which ketamine may prevent an impulsive–aggressive phenotype in rodents and suicidal ideations in humans. Animal models of anxiety/depression are important tools to better understand the pathophysiology of depressed patients, and in helping develop novel and fast antidepressant drugs with anti-suicidal properties and clinical utility. Full article

The antinociceptive activity of the flower extracts of Styrax japonicus was confirmed in our previous study. However, the key compound for analgesia has not been distinguished, and the corresponding mechanism is obscure. In this study, the active compound was isolated from the flower by multiple chromatographic techniques and structurally illustrated using spectroscopic methods and referring to the related literature. The antinociceptive activity of the compound and the underlying mechanisms were investigated using animal tests. The active compound was determined to be jegosaponin A (JA), which showed significant antinociceptive responses. JA was also shown to possess sedative and anxiolytic activities but no anti-inflammatory effect, implying the association of the antinociceptive effects with the sedative and anxiolytic activities. Further antagonists and calcium ionophore tests showed that the antinociceptive effect of JA was blocked by flumazenil (FM, antagonist for GABA-A receptor) and reversed by WAY100635 (WAY, antagonist for 5-HT_1A receptor). Contents of 5-HT and its metabolite (5-HIAA) increased significantly in the hippocampus and striatum tissues after JA administration. The results indicated that the antinociceptive effect of JA was regulated by the neurotransmitter system, especially GABAergic and serotonergic systems. Full article

Renal vasculature, which is highly innervated by sympathetic fibers, contributes to cardiovascular homeostasis. This renal sympathetic outflow is inhibited by 5-HT in normoglycaemic rats. Considering that diabetes induces cardiovascular complications, we aimed to determine whether diabetic state modifies noradrenergic input at renal level and its serotonergic modulation in rats. Alloxan diabetic rats were anaesthetized (pentobarbital; 60 mg/kg i.p.) and prepared for in situ autoperfusion of the left kidney to continuously measure systemic blood pressure (SBP), heart rate (HR), and renal perfusion pressure (RPP). Electrical stimulation of renal sympathetic outflow induces frequency-dependent increases (Δ) in RPP (23.9 ± 2.1, 59.5 ± 1.9, and 80.5 ± 3.5 mm Hg at 2, 4, and 6 Hz, respectively), which were higher than in normoglycaemic rats, without modifying HR or SBP. Intraarterial bolus of 5-HT and 5-CT (5-HT_1/5/7 agonist) reduced electrically induced ΔRPP. Only L-694,247 (5-HT_1D agonist) reproduced 5-CT inhibition on sympathetic-induced vasoconstrictions, whereas it did not modify exogenous noradrenaline-induced ΔRPP. 5-CT inhibition was exclusively abolished by i.v. bolus of LY310762 (5-HT_1D antagonist). An inhibitor of guanylyl cyclase, ODQ (i.v.), completely reversed the L-694,247 inhibitory effect. In conclusion, diabetes induces an enhancement in sympathetic-induced vasopressor responses at the renal level. Prejunctional 5-HT_1D receptors, via the nitric oxide pathway, inhibit noradrenergic-induced vasoconstrictions in diabetic rats. Full article