-
Archives of Razi Institute Oct 2023Since depression is a common mental illness affecting an estimated 5% of people worldwide, investigators are encouraged to develop effective antidepressants. According...
Since depression is a common mental illness affecting an estimated 5% of people worldwide, investigators are encouraged to develop effective antidepressants. According to the monoamine-deficiency hypothesis, the underlying pathophysiology of depression is a deficiency of some neurotransmitters (serotonin, norepinephrine, or dopamine) in the central nervous system. The neurotransmitter serotonin has drawn the most attention concerning depression. As per research, 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) elevates inter-synaptic serotonin levels when administered as a single inhalation of vapor from dried toad secretion and leads to higher life satisfaction, convergent thinking, higher ratings of mindfulness, lower ratings of depression, and anxiety. Furthermore, although 5-MeO-DMT lowers stress biomarkers such as cortisol, it is a psychedelic with hallucinogenic effects. In the present study, analogues of 5-MeO-DMT are designed with the hope that they might have better therapeutic activity and lower psychedelic side effects. The current study aimed to look at 5-MeO-DMT analogues as possible antidepressants. We used 70,000 5-MeO-DMT analogues that were sketched using Marvin to conduct a High Throughput Virtual Screening method in hopes of finding potential 5-MeO-DMT analogues against the 5-Hydroxytryptamine 1A receptor (5-HT1AR; 7E2Y.pdb) as an agonist. The prediction of the analogue-protein interaction and the evaluation of the binding affinity is accomplished by employing molecular docking. The Glide XP docking data indicated that a total of 21 compounds had Glide gscores ranging from -11.41 to -6.53 kcal/mol. When compared to the standard 5-MeO-DMT with the binding affinity of -7.75 kcal/mol, 14 compounds showed better binding affinity. Furthermore, Molecular Mechanics -Generalised Born and Surface Area solvation (MM-GBSA) indicated a binding free energy range of -63.55 to -35.37 kcal/mol, and 18 compounds showed better binding free energy than standard 5-MeO-DMT (-41.42 kcal/mol). Through ligand binding interactions with Asp116, Phe361, Phe362, Ser190, Ser199, Val117, Trp358, Ala365, Pro369, Ile189, Tyr195, Ala203, Ile167, Tyr390, Cys120, Trp358, Val364, Ala365, and Leu368, these complexes were stabilized, according to the molecular dynamic simulation of 20453/7E2Y in 100ns.
Topics: Humans; Hallucinogens; Molecular Docking Simulation; Serotonin; Molecular Dynamics Simulation; Methoxydimethyltryptamines; Antidepressive Agents
PubMed: 38590677
DOI: 10.22092/ARI.2023.78.5.1603 -
Frontiers in Neuroscience 2024Estradiol, the most potent and prevalent member of the estrogen class of steroid hormones and is expressed in both sexes. Functioning as a neuroactive steroid, it plays... (Review)
Review
Estradiol, the most potent and prevalent member of the estrogen class of steroid hormones and is expressed in both sexes. Functioning as a neuroactive steroid, it plays a crucial role in modulating neurotransmitter systems affecting neuronal circuits and brain functions including learning and memory, reward and sexual behaviors. These neurotransmitter systems encompass the serotonergic, dopaminergic, and glutamatergic signaling pathways. Consequently, this review examines the pivotal role of estradiol and its receptors in the regulation of these neurotransmitter systems in the brain. Through a comprehensive analysis of current literature, we investigate the multifaceted effects of estradiol on key neurotransmitter signaling systems, namely serotonin, dopamine, and glutamate. Findings from rodent models illuminate the impact of hormone manipulations, such as gonadectomy, on the regulation of neuronal brain circuits, providing valuable insights into the connection between hormonal fluctuations and neurotransmitter regulation. Estradiol exerts its effects by binding to three estrogen receptors: estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and G protein-coupled receptor (GPER). Thus, this review explores the promising outcomes observed with estradiol and estrogen receptor agonists administration in both gonadectomized and/or genetically knockout rodents, suggesting potential therapeutic avenues. Despite limited human studies on this topic, the findings underscore the significance of translational research in bridging the gap between preclinical findings and clinical applications. This approach offers valuable insights into the complex relationship between estradiol and neurotransmitter systems. The integration of evidence from neurotransmitter systems and receptor-specific effects not only enhances our understanding of the neurobiological basis of physiological brain functioning but also provides a comprehensive framework for the understanding of possible pathophysiological mechanisms resulting to disease states. By unraveling the complexities of estradiol's impact on neurotransmitter regulation, this review contributes to advancing the field and lays the groundwork for future research aimed at refining understanding of the relationship between estradiol and neuronal circuits as well as their involvement in brain disorders.
PubMed: 38586193
DOI: 10.3389/fnins.2024.1348551 -
Case Reports in Psychiatry 2024This is a case report of three cases of trazodone-induced buccal-lingual dyskinesias. Each case demonstrated the distinct pattern of the development of this dyskinesia...
This is a case report of three cases of trazodone-induced buccal-lingual dyskinesias. Each case demonstrated the distinct pattern of the development of this dyskinesia after trazodone exposure for several months. All cases showed abrupt cessation of the movement disorder when the drug was discontinued. One of the three cases demonstrated a highly unusual presentation of an on/off pattern of buccal dyskinesia directly related to repetitive exposure and termination of the drug trazodone. Two of the three cases had no prior exposure to any dopamine blocking agents. One of the three had a distant exposure to a dopamine antagonist. As opposed to other antidepressants, trazodone has a mechanism of action which can account for both the development and treatment of dyskinetic movements. Its metabolite, M/chlorophenylpiperazine (M-CPP) is a 5HT2C agonist capable of causing abnormal oral-facial movements in rodent models. The presence of oromandibular dyskinetic movements can occur spontaneously with age, with trazodone being a potential predisposing factor. This article will discuss proposed mechanisms for trazodone's action with an emphasis on case reports of dystonic movements.
PubMed: 38585414
DOI: 10.1155/2024/5543023 -
Therapie Mar 2024The past twenty years have seen a rise in cocaine-related statistics in France, including cocaine use in the general population, emergency ward presentations of acute...
AIM OF THE STUDY
The past twenty years have seen a rise in cocaine-related statistics in France, including cocaine use in the general population, emergency ward presentations of acute cocaine intoxication, cocaine use disorders related outpatient appointments and cocaine-related deaths. This study's objectives were to describe trends in patients' admission for specific cocaine detoxification as well as changes in patients' characteristics in the Assistance publique-Hôpitaux de Paris (AP-HP) hospitals group located in Paris region, France.
METHODS
We reviewed the international classification of diseases 10 edition (ICD-10) discharge codes of the AP-HP hospitals group between 2011 and 2021. In addition, medical reports of the largest addiction medicine ward were also analysed for changes across the years 2009, 2014, 2019 and 2022.
RESULTS
The regional database showed an almost 3-fold increase in cocaine-related disorders discharge codes between 2011 and 2019. This occurred due to a rise in hospital stays for cocaine dependence or cocaine acute intoxication prior to the fall in levels of inpatient stays associated with the coronavirus disease 2019 (COVID-19) pandemic. The in-depth analysis of inpatients' stays in the specialized addiction medicine ward also showed an increase in admissions for cocaine detoxification programs, with a prevalence of 1.19% in 2009 to 15.73% in 2022 (P=1.44×10). Inpatient characteristics showed significant changes, especially in 2022, namely: more daily users, less intravenous administration and less comorbid illicit substances use disorders, with heightened levels of cured hepatitis C patients (P<0.05). Inpatient prescriptions were primarily dopaminergic antagonists with sedatives properties (cyamemazine, loxapine and chlorpromazine), dopamine-receptors partial agonist (aripiprazole) and serotonin reuptake inhibitors.
CONCLUSION
The referral to hospital care for cocaine detoxification has increased in Paris region since 2011, coupled with changes in inpatients' characteristics. This trend has significant implications for the management of inpatient hospital services.
PubMed: 38582619
DOI: 10.1016/j.therap.2024.03.001 -
Schizophrenia Research May 2024Sleep problems are common and related to a worse quality of life in patients with schizophrenia. Almost all patients with schizophrenia use antipsychotic medications,...
BACKGROUND
Sleep problems are common and related to a worse quality of life in patients with schizophrenia. Almost all patients with schizophrenia use antipsychotic medications, which usually increase sleep. Still, the differences in subjective sleep outcomes between different antipsychotic medications are not entirely clear.
METHODS
This study assessed 5466 patients with schizophrenia and is part of the nationwide Finnish SUPER study. We examined how the five most common antipsychotic medications (clozapine, olanzapine, quetiapine, aripiprazole, and risperidone) associate with questionnaire-based sleep problems in logistic regression analyses, including head-to-head analyses between different antipsychotic medications. The sleep problems were difficulties initiating sleep, early morning awakenings, fatigue, poor sleep quality, short (≤6 h) and long sleep duration (≥10 h).
RESULTS
The average number of antipsychotic medications was 1.59 per patient. Clozapine was associated with long sleep duration (49.0 % of clozapine users vs 30.2 % of other patients, OR = 2.05, 95 % CI 1.83-2.30, p < .001). Olanzapine and risperidone were in head-to-head analyses associated with less sleep problems than patients using aripiprazole, quetiapine, or no antipsychotic medication. Aripiprazole and quetiapine were associated with more insomnia symptoms and poorer sleep quality. Patients without antipsychotic medications (N = 159) had poorer sleep quality than patients with antipsychotic use, and short sleep duration was common (21.5 % of patients not using antipsychotics vs 7.8 % of patients using antipsychotics, OR = 2.97, 95 % CI 1.98-4.44, p < .001).
CONCLUSIONS
Prevalence of sleep problems is markedly related to the antipsychotic medication the patient uses. These findings underline the importance of considering and assessing sleep problems when treating schizophrenia patients with antipsychotics.
Topics: Humans; Schizophrenia; Antipsychotic Agents; Male; Female; Sleep Wake Disorders; Adult; Middle Aged; Finland; Aripiprazole
PubMed: 38579432
DOI: 10.1016/j.schres.2024.03.015 -
ELife Apr 2024Psychosis is characterized by a diminished ability of the brain to distinguish externally driven activity patterns from self-generated activity patterns. Antipsychotic...
Psychosis is characterized by a diminished ability of the brain to distinguish externally driven activity patterns from self-generated activity patterns. Antipsychotic drugs are a class of small molecules with relatively broad binding affinity for a variety of neuromodulator receptors that, in humans, can prevent or ameliorate psychosis. How these drugs influence the function of cortical circuits, and in particular their ability to distinguish between externally and self-generated activity patterns, is still largely unclear. To have experimental control over self-generated sensory feedback, we used a virtual reality environment in which the coupling between movement and visual feedback can be altered. We then used widefield calcium imaging to determine the cell type-specific functional effects of antipsychotic drugs in mouse dorsal cortex under different conditions of visuomotor coupling. By comparing cell type-specific activation patterns between locomotion onsets that were experimentally coupled to self-generated visual feedback and locomotion onsets that were not coupled, we show that deep cortical layers were differentially activated in these two conditions. We then show that the antipsychotic drug clozapine disrupted visuomotor integration at locomotion onsets also primarily in deep cortical layers. Given that one of the key components of visuomotor integration in cortex is long-range cortico-cortical connections, we tested whether the effect of clozapine was detectable in the correlation structure of activity patterns across dorsal cortex. We found that clozapine as well as two other antipsychotic drugs, aripiprazole and haloperidol, resulted in a strong reduction in correlations of layer 5 activity between cortical areas and impaired the spread of visuomotor prediction errors generated in visual cortex. Our results are consistent with the interpretation that a major functional effect of antipsychotic drugs is a selective alteration of long-range layer 5-mediated communication.
Topics: Humans; Animals; Mice; Antipsychotic Agents; Clozapine; Haloperidol; Brain; Aripiprazole
PubMed: 38578678
DOI: 10.7554/eLife.86805 -
Archives of Endocrinology and Metabolism Apr 2024Dopamine agonists are the first line of treatment for patients with symptomatic hyperprolactinemia due to prolactinomas and in those with idiopathic hyperprolactinemia....
Treatment of hyperprolactinemia in women: A Position Statement from the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and the Brazilian Society of Endocrinology and Metabolism (SBEM).
Dopamine agonists are the first line of treatment for patients with symptomatic hyperprolactinemia due to prolactinomas and in those with idiopathic hyperprolactinemia. Treatment with these agents is effective in 80%-90% of the cases. Infertility treatment of patients with hyperprolactinemia is also carried out with dopamine agonists, aiming for the normalization of prolactin levels. The risk of symptomatic growth of prolactinomas during pregnancy is dependent on the tumor's size, duration of previous treatments, and prolactin levels. Notably, the corresponding risk is relatively low in cases of microprolactinomas (<5%). Remission of hyperprolactinemia occurs in about 30% of the patients after drug treatment and may also occur after pregnancy and menopause. The use of some drugs, such as antidepressants and antipsychotics, is a frequent cause of hyperprolactinemia, and managing this occurrence involves unique considerations. This position statement by the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and Brazilian Society of Endocrinology and Metabolism (SBEM) addresses the recommendations for measurement of serum prolactin levels and the investigations of symptomatic and asymptomatic hyperprolactinemia and drug-induced hyperprolactinemia in women.
Topics: Pregnancy; Humans; Female; Hyperprolactinemia; Prolactinoma; Dopamine Agonists; Prolactin; Pituitary Neoplasms; Brazil
PubMed: 38578473
DOI: 10.20945/2359-4292-2023-0504 -
Pharmacological Inhibition of the Nucleus Accumbens Increases Dyadic Social Interaction in Macaques.ENeuro Apr 2024The nucleus accumbens (NAc) is a central component of the brain circuitry that mediates motivated behavior, including reward processing. Since the rewarding properties...
The nucleus accumbens (NAc) is a central component of the brain circuitry that mediates motivated behavior, including reward processing. Since the rewarding properties of social stimuli have a vital role in guiding behavior (both in humans and nonhuman animals), the NAc is likely to contribute to the brain circuitry controlling social behavior. In rodents, prior studies have found that focal pharmacological inhibition of NAc and/or elevation of dopamine in NAc increases social interactions. However, the role of the NAc in social behavior in nonhuman primates remains unknown. We measured the social behavior of eight dyads of male macaques following (1) pharmacological inhibition of the NAc using the GABA agonist muscimol and (2) focal application of quinpirole, an agonist at the D2 family of dopamine receptors. Transient inhibition of the NAc with muscimol increased social behavior when drug was infused in submissive, but not dominant partners of the dyad. Focal application of quinpirole was without effect on social behavior when infused into the NAc of either dominant or submissive subjects. Our data demonstrate that the NAc contributes to social interactions in nonhuman primates.
PubMed: 38575350
DOI: 10.1523/ENEURO.0085-24.2024 -
Cell Communication and Signaling : CCS Apr 2024Desensitization of G protein-coupled receptors (GPCRs) refers to the attenuation of receptor responsiveness by prolonged or intermittent exposure to agonists. The...
BACKGROUND
Desensitization of G protein-coupled receptors (GPCRs) refers to the attenuation of receptor responsiveness by prolonged or intermittent exposure to agonists. The binding of β-arrestin to the cytoplasmic cavity of the phosphorylated receptor, which competes with the G protein, has been widely accepted as an extensive model for explaining GPCRs desensitization. However, studies on various GPCRs, including dopamine D-like receptors (DR, DR, DR), have suggested the existence of other desensitization mechanisms. The present study employed DR/DR variants with different desensitization properties and utilized loss-of-function approaches to uncover the mechanisms underlying GPCRs homologous desensitization, focusing on the signaling cascade that regulates the ubiquitination of AKT.
RESULTS
AKT undergoes K8/14 ubiquitination by TRAF6, which occurs in the nucleus and promotes its membrane recruitment, phosphorylation and activation under receptor desensitization conditions. The nuclear entry of TRAF6 relies on the presence of the importin complex. Src regulates the nuclear entry of TRAF6 by mediating the interaction between TRAF6 and importin β1. Ubiquitinated AKT translocates to the plasma membrane where it associates with Mdm2 to phosphorylate it at the S166 and S186 residues. Thereafter, phosphorylated Mdm2 is recruited to the nucleus, resulting in the deubiquitination of β-Arr2. The deubiquitinated β-Arr2 then forms a complex with Gβγ, which serves as a biomarker for GPCRs desensitization. Like in DR, ubiquitination of AKT is also involved in the desensitization of β adrenoceptors.
CONCLUSION
Our study proposed that the property of a receptor that causes a change in the subcellular localization of TRAF6 from the cytoplasm to the nucleus to mediate AKT ubiquitination could initiate the desensitization of GPCRs.
Topics: TNF Receptor-Associated Factor 6; Proto-Oncogene Proteins c-akt; Receptors, G-Protein-Coupled; Ubiquitination; Phosphorylation; Karyopherins
PubMed: 38566235
DOI: 10.1186/s12964-024-01592-z -
Psychiatria Polska Dec 2023In this article, we present the case of an adult patient, whose main problem is episodes of fantasizing and rocking lasting up to 12 hours a day and completely...
In this article, we present the case of an adult patient, whose main problem is episodes of fantasizing and rocking lasting up to 12 hours a day and completely preventing school development. The nature of the disorder in the patient is related to the sinking into fantasies, and not typical obsessions as in OCD. The patient was previously treated with drugs from the SSRI group, neuroleptics (without aripiprazole) and methylphenidate. Only methylphenidate showed some improvement; however, it made the patient feel ‟stiff in thinking". The patient was hospitalized because of a suicide attempt, which, as it later turned out, was self-harm with no intention of killing himself. During hospitalization, a differential diagnosis was performed and the diagnosis of Asperger's syndrome was made, which was accompanied by immersion in the world of one's fantasies and stereotypical behavior. The patient was administered aripiprazole at a dose of 15 mg/d and after three weeks, a significant improvement in health was achieved, including a reduction in the duration of episodes from several hours to several dozen seconds. The drug is well tolerated by the patient. The patient was discharged from the hospital and continues his school education. In the article, we present single case reports in which similar spectacular results were achieved in similar cases. We also describe a possible physiological explanation for this response to this drug.
Topics: Adult; Humans; Asperger Syndrome; Aripiprazole; Antipsychotic Agents; Suicide, Attempted; Methylphenidate
PubMed: 38564518
DOI: 10.12740/PP/152316