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Glioblastoma (GBM) is the deadliest adult brain cancer. Under the current standard of care, almost all patients succumb to the disease and novel treatments are urgently needed. Recognizing that GBMs are addicted to cholesterol, past clinical trials have repurposed statins against GBM but failed. The purpose of this study was to test whether treatments that upregulate the cholesterol biosynthesis pathway in GBM would generate a metabolic vulnerability that can be exploited using statins and to determine the underlying mechanisms.Effects of radiotherapy and temozolomide or dopamine receptor antagonists on the mevalonate pathway in GBM were assessed in vitro and in vivo. The impact of statins on self-renewal of glioma stem cells and median survival was studied. Branches of the mevalonate pathway were probed to identify relevant effector proteins.Cells surviving combination treatments that converge in activating the immediate early response, universally upregulated the mevalonate pathway and increased stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 was inhibited by statins, which led to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.We conclude that a combination of dopamine receptor antagonists and statins could potentially improve radiotherapy outcome and warrants further investigation.SignificanceCombination therapies that activate the mevalonate pathway in GBM cells after sublethal treatment enhance self-renewal and migratory capacity through Rac-1 activation, which creates a metabolic vulnerability that can be further potentially exploited using statins.

Background: Tardive dyskinesia (TD) is a persisting, and potentially irreversible, movement disorder associated with treatment with dopamine receptor antagonists. Few data are available on the risk of TD in children and adolescents treated with antipsychotic medication. Objective: To review the literature on incidence, risk factors, and treatment options for antipsychotic-associated TD in children and adolescents (aged < 18 years). Methods: Relevant articles were identified through a systematic search of Embase and Medline performed in January 2024. Methodological quality was assessed using the Newcastle-Ottawa Scale and Joanna Briggs Institute Critical Appraisal tools. Results: Thirteen studies were identified. The reported TD point prevalence was 5–20%, with higher rates in studies involving typical antipsychotics. Lower estimates (around 1%) emerged from analyses of clinical database data suggesting underdiagnosis in clinical practice. Risk factors included treatment with typical antipsychotics, higher doses, longer duration of exposure, older age, female gender, higher baseline Abnormal Involuntary Movements Scale (AIMS) scores, intellectual impairment, and perinatal complications. Conclusion: Although relatively few cases have been reported in children and adolescents, TD remains a risk in this population. Individuals receiving antipsychotics should be monitored carefully for the emergence of abnormal movements. Other than dose reduction, discontinuation, or switch to a lower-risk antipsychotic, few interventions have demonstrated efficacy. The strongest evidence for pharmacological treatment is for VMAT-2 inhibitors (valbenazine and deutetrabenazine), but these drugs are not licensed for use in children. To reduce risk, antipsychotics should be prescribed only if necessary, at the minimum effective dose and for the minimum necessary duration. [ABSTRACT FROM AUTHOR]

Headaches are a common condition seen in the Emergency Department (ED), with numerous trials focused on improving care for these patients. However, there is limited recent large-scale, robust data available on the incidence, admission rates, evaluation, and treatment in the ED setting. This was a cross-sectional study of ED presentations for headache from 1/1/2016 to 12/31/2023 using the Epic Cosmos national database. All ED visits with headache-relevant ICD-10 coding were included. Outcomes included percentage of total ED visits, admission rates, computed tomography (CT) brain imaging, lumbar puncture (LP) performance, and medication administration. Medications were analyzed by class (NSAIDs, acetaminophen, dopamine antagonists, diphenhydramine, opioids, intravenous fluids, caffeine, and magnesium sulfate). Subgroup analyses were performed by specific types of dopamine antagonists. Of 188,482,644 ED encounters, 6,007,090 (3.2%) were due to headache. Of these, 246,082 (4.1%) were admitted. Nearly half (46.6%) of patients received at least one CT. Rates of CT head without contrast increased from 38.2% to 47.9% over time, while rates of CT angiography rose from 2.8% to 10.2%. 1.4% of all patients received an LP, with rates decreasing from 1.8% to 1.1% over time. The most common medication was NSAIDs (45.3%), followed by dopamine antagonists (44.8%), diphenhydramine (38.1%), acetaminophen (24.8%), opioids (16.3%), magnesium sulfate (0.2%), and caffeine (0.1%). 50.8% of patients received intravenous fluids. Rates of opioids declined over time, while dopamine antagonists, acetaminophen, and intravenous fluid administration increased. Headaches represent a common reason for ED presentation, with approximately 4% of patients being admitted. Imaging is frequently performed, with rises in CT without contrast and CT angiography rates over time, while LP rates have been declining. NSAIDs remain the most common medication given, with opioids declining over time while non-opioid agents such as dopamine antagonists have increased. These findings can help inform health policy initiatives, such as those focused on radiologic imaging and evidence-based medication administration. [ABSTRACT FROM AUTHOR]

Achieving optimal treatment outcomes for individuals living with schizophrenia remains challenging, despite 70 years of drug development efforts. Many chemically distinct antipsychotics have been developed over the past 7 decades with improved safety and tolerability but with only slight variation in efficacy. All antipsychotics currently approved for the treatment of schizophrenia act as antagonists or partial agonists at the dopamine D 2 receptor. With only a few possible exceptions, antipsychotic drugs have similar and modest efficacy for treating positive symptoms and are relatively ineffective in addressing the negative and cognitive symptoms of the disease. The development of novel treatments focused on targeting muscarinic acetylcholine receptors (mAChRs) has been of interest for more than 25 years following reports that treatment with a dual M 1 /M 4 –preferring mAChR agonist resulted in antipsychotic-like effects and procognitive properties in individuals living with Alzheimer's disease and schizophrenia; more recent clinical trials have confirmed these findings. In addition, advances in our understanding of the receptor binding and activation properties of xanomeline at specific mAChRs have the potential to inform future drug design targeting mAChRs. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the potency and efficacy of a library of dopamine receptor D2 (D2R) antagonists in the mitigation of fibrotic activation in retinal pigment epithelial (RPE) cells. Methods: ARPE-19 cells were cultured and treated with methotrexate or 27 district D2R antagonists using a fibronectin deposition assay. The most potent compounds were then further assessed in assays measuring cellular proliferation, cellular migration, and profibrotic gene expression. Results: The previously established antifibrotic D2R antagonist loxapine exerted a robust and dose-dependent inhibition of fibronectin deposition, whereas methotrexate exerted minimal inhibition. The most potent D2R antagonist identified, fluphenazine, effectively blocked in vitro models of fibrosis at 300–1,000 nM concentrations. Conclusions: Here we found multiple FDA-approved D2R antagonists that potently block RPE cell fibrogenesis. These findings further support the potential of D2R antagonism as a potential therapeutic for retinal fibrotic disease. [ABSTRACT FROM AUTHOR]

Rationale: Motivational dysfunctions related to effort exertion are common in psychiatric disorders. Dopamine systems regulate exertion of effort and effort-based choice in humans and rodents. Objectives: Previous rodent studies mainly employed male rats, and it is imperative to conduct studies in male and female rats. Methods: The present studies compared the effort-related effects of IP injections of the dopamine antagonists ecopipam and haloperidol, and the vesicular monoamine transport-2 inhibitor tetrabenazine (TBZ), in male and female rats using the fixed ratio 5/chow feeding choice task. Results: Ecopipam (0.05–0.2 mg/kg) and haloperidol (0.05–0.15 mg/kg) induced a low-effort bias, decreasing lever pressing and increasing chow intake in males and females in the same dose range. With lever pressing, there was a modest but significant dose x sex interaction after ecopipam injection, but there was no significant interaction after administration of haloperidol. In the first study with TBZ (0.25-1.0 mg/kg), there was a robust sex difference. TBZ shifted choice from lever pressing to chow intake in male rats, but was ineffective in females. In a second experiment, 2.0 mg/kg affected choice behavior in both males and females. TBZ increased accumbens c-Fos immunoreactivity in a sex-dependent manner, with males significantly increasing at 1.0 mg/kg, while females showed augmented immunoreactivity at 2.0 mg/kg. Conclusions: The neural and behavioral effects of TBZ differed across sexes, emphasizing the importance of conducting studies in male and female rats. This research has implications for understanding the effort-related motivational dysfunctions seen in psychopathology. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the perception of community pharmacists on the down-scheduling of 5-HT3 antagonists to pharmacist-only-medicine for treatment of acute nausea and/or vomiting in Australia. Methods: A nationwide anonymous survey targeting Australian community pharmacists was conducted from April to May 2023. Responses were collected and analysed quantitively or qualitatively, where appropriate. Key findings: Participants reported that 5-HT3 antagonists were effective at treating nausea and/or vomiting and would likely recommend their use. Training is required to manage supply due to concerns related to their side effects. Conclusion: Participants supported down-scheduling of 5-HT3 antagonists for the treatment of nausea and/or vomiting in Australia. A pilot study on the provision of 5-HT3 antagonists by pharmacists is recommended as is the development of guidelines for pharmacist-only supply before down-scheduling is considered. [ABSTRACT FROM AUTHOR]

Dopamine-based reward and learning mechanisms have been suggested to contribute to placebo effects. However, the exact role of dopaminergic neurotransmission in their generation and maintenance is still unclear. This study aimed to shed light on the causal role of dopamine in establishing positive treatment expectations, as well as on the magnitude and duration of their effect on pain. To this end, we used an established placebo analgesia paradigm in combination with 2 opposing pharmacological modulations of dopaminergic tone, i.e., the dopamine antagonist sulpiride and the dopamine precursor L-dopa which were both applied in an experimental, double-blind, randomized, placebo-controlled trial with a between-subject design in N = 168 healthy volunteers. The study medication successfully altered dopaminergic tone during the conditioning procedure. Contrary to our hypotheses, the medication did not modulate the formation of positive treatment expectation and placebo analgesia tested 1 day later. Placebo analgesia was no longer detectable on day 8 after conditioning. Using a combined frequentist and Bayesian approach, our data provide strong evidence against a direct dopaminergic influence on the generation and maintenance of placebo effects. Further exploration of the neurochemical mechanisms underlying placebo analgesia remains paramount in the quest to exploit these effects for optimal treatment outcomes. Trial registration: ClinicalTrials.gov German Clinical Trials Register, ID: DRKS00029366, https://drks.de/search/en/trial/DRKS00029366. Dopamine signalling has been linked to pain analgesia and placebo effects but whether there is causal relationship remains unclear. This pre-registered study shows that enhancing dopaminergic tone does not alter the generation of positive treatment expectations or placebo analgesia. [ABSTRACT FROM AUTHOR]

For several decades, the dopamine hypothesis contributed to the discovery of numerous typical and atypical antipsychotics and was the sole hypothesis for the pathophysiology of schizophrenia. However, neither typical nor atypical antipsychotics, other than clozapine, have been effective in addressing negative symptoms and cognitive impairments, which are indices for the prognostic and disability outcomes of schizophrenia. Following the development of atypical antipsychotics, the therapeutic targets for antipsychotics expanded beyond the blockade of dopamine D2 and serotonin 5-HT2A receptors to explore the partial agonism of the D2 receptor and the modulation of new targets, such as D3, 5-HT1A, 5-HT7, and metabotropic glutamate receptors. Despite these efforts, to date, psychiatry has not successfully developed antipsychotics with antipsychotic properties proven to be superior to those of clozapine. The glutamate hypothesis, another hypothesis regarding the pathophysiology/pathomechanism of schizophrenia, was proposed based on clinical findings that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, such as phencyclidine and ketamine, induce schizophrenia-like psychotic episodes. Large-scale genome-wide association studies (GWASs) revealed that approximately 30% of the risk genes for schizophrenia (the total number was over one hundred) encode proteins associated with glutamatergic transmission. These findings supported the validation of the glutamate hypothesis, which was inspired by the clinical findings regarding NMDAR antagonists. Additionally, these clinical and genetic findings suggest that schizophrenia is possibly a syndrome with complicated pathomechanisms that are affected by multiple biological and genetic vulnerabilities. The glutamate hypothesis has been the most extensively investigated pathophysiology/pathomechanism hypothesis, other than the dopamine hypothesis. Studies have revealed the possibility that functional abnormalities of the NMDAR play important roles in the pathophysiology/pathomechanism of schizophrenia. However, no antipsychotics derived from the glutamatergic hypothesis have yet been approved for the treatment of schizophrenia or treatment-resistant schizophrenia. Considering the increasing evidence supporting the potential pro-cognitive effects of glutamatergic agents and the lack of sufficient medications to treat the cognitive impairments associated with schizophrenia, these previous setbacks cannot preclude research into potential novel glutamate modulators. Given this background, to emphasize the importance of the dysfunction of the NMDAR in the pathomechanism and/or pathophysiology of schizophrenia, this review introduces the increasing findings on the functional abnormalities in glutamatergic transmission associated with the NMDAR. [ABSTRACT FROM AUTHOR]

Background: 6‐Nitrodopamine (6‐ND) is a novel endogenous catecholamine that has a potent relaxant action on vascular smooth muscle in vitro. Objectives: To evaluate the basal release of 6‐ND and noradrenaline from rabbit‐isolated corpus cavernosum (RbCC) and its relaxing action on this tissue. Methods: Rabbit corpus cavernosa were dissected and suspended in a 5‐mL organ bath containing oxygenated Krebs‐Henseleit's solution. 6‐ND and noradrenaline release was quantified by liquid chromatography coupled to tandem mass spectrometry. The relaxant activity of 6‐ND was assessed in RbCC strips pre‐contracted with endothelin‐1 (10 nM). Results: Rabbit corpus cavernosum presented basal release of both 6‐ND (2.9 ± 0.8 ng/mL, n = 12) and noradrenaline (1.7 ± 1.3 ng/mL, n = 12). The 6‐ND release was reduced by pre‐treatment with Nω‐nitro‐l‐arginine methyl ester (l‐NAME) (100 µM), whereas that of noradrenaline was unaffected. Tetrodotoxin (TTX, 1 µM) abolished the noradrenaline release but had no effect on 6‐ND release, indicating a non‐neurogenic origin for 6‐ND. 6‐ND and the selective dopamine D2‐agonist L‐741,626 caused concentration‐dependent RbCC relaxations (pEC50 of 11 ± 0.15 and 11.15 ± 0.28, respectively). Pre‐treatment with either l‐NAME or the soluble guanylate cyclase inhibitor 1H‐[1,2,4] oxadiazolo[4,3‐a]quinoxalin‐1‐on (ODQ) (100 µM) caused a rightward shift of the concentration–response curve to 6‐ND, without affecting the L‐741,626 responses. In TTX (100 nM)‐pre‐treated preparations, neither l‐NAME nor ODQ shifted the 6‐ND concentration–response curve. Dopamine, noradrenaline, and adrenaline caused concentration‐dependent RbCC contractions. Pre‐incubation with 6‐ND concentration‐dependently inhibited the dopamine‐induced contractions, without affecting those induced by either noradrenaline or adrenaline. Discussion and conclusion: 6‐Nitrodopamine is the most potent endogenous relaxant agent in RbCC ever described and represents a novel mechanism by which NO causes corpus cavernosum smooth muscle relaxation. The finding that 6‐ND acts as a truly selective dopamine D2‐receptor antagonist indicates that the balance of dopamine and 6‐ND release/synthesis may be the main mechanism that modulates corpus cavernosum smooth muscle tonus in vivo. [ABSTRACT FROM AUTHOR]

Sulpiride (Sul) is a medication that blocks dopamine D2 receptors. It is used to treat gastrointestinal disturbances and has antipsychotic effects depending on the dose given. Sulpiride is subject to P-glycoprotein efflux, resulting in limited bioavailability and erratic absorption. Hence, the aim of this study was to generate a glycerosomal in situ gel of sulpiride for intranasal administration, specifically targeting children with schizophrenia who may have difficulty swallowing traditional solid medications, for enhancing its bioavailability. This study aimed to demonstrate the efficacy of intranasal administration of glycerin-encapsulated lipid-nanovesicles (glycerosomes) mixed with in situ gels for prolonged release of anti-psychotic medication. A Box–Behnken design was utilized to create sulpiride-loaded glycerosomes (Sul-GMs), with the lipid amount (A), glycerin concentration (B), and sonication time (C) acting as independent variables. Their impact on the entrapment efficiency, EE% (Y1), and in vitro drug release (Y2) were evaluated. The sulpiride EE% showed an increase when the glycerin concentration was raised to 25% v/v. Nevertheless, when the glycerin concentration was raised to 40% v/v, there was a notable decrease in the EE%. The optimized glycerosome was added to pH triggered carbopol 974P in situ gel formulations including HPMC K15M with different concentrations. The in situ gel formulation (G3) comprising 0.6% carbopol 974P and 0.6% hydroxypropyl methyl cellulose-K15M (HPMC K15M) demonstrated suitable pH, viscosity, desired gel strength, spreadability, and mucoadhesive strength. Consequently, it was selected for in vitro study, ex vivo permeation investigation, and in vivo evaluations. The glycerosomal in situ gel exhibited favorable ex vivo permeability of SU when applied to the nasal mucosa. The pharmacokinetic investigation revealed that the optimized Sul-loaded glycerosomal in situ gel exhibited a significant fourfold and twofold enhancement in systemic bioavailability compared to both the control gel and the commercially available formulation. Finally, the intranasal administration of Sul-loaded glycerosomal in situ gel is a promising alternative to oral treatment for pediatric patients with psychosis. [ABSTRACT FROM AUTHOR]

While all reversible receptor-targeting radioligands for positron emission tomography (PET) can be displaced by competition with an antagonist at the receptor, many radiotracers show limited occupancies using agonists even at high doses. [11C]Raclopride, a D2/D3 receptor radiotracer with rapid kinetics, can identify the direction of changes in the neurotransmitter dopamine, but quantitative interpretation of the relationship between dopamine levels and radiotracer binding has proven elusive. Agonist-induced receptor desensitization and internalization, a homeostatic mechanism to downregulate neurotransmitter-mediated function, can shift radioligand-receptor binding affinity and confound PET interpretations of receptor occupancy. In this study, we compared occupancies induced by amphetamine (AMP) in drug-naive wild-type (WT) and internalization-compromised β-arrestin-2 knockout (KO) mice using a within-scan drug infusion to modulate the kinetics of [11C]raclopride. We additionally performed studies at 3 h following AMP pretreatment, with the hypothesis that receptor internalization should markedly attenuate occupancy on the second challenge, because dopamine cannot access internalized receptors. Without prior AMP treatment, WT mice exhibited somewhat larger binding potential than KO mice but similar AMP-induced occupancy. At 3 h after AMP treatment, WT mice exhibited binding potentials that were 15 % lower than KO mice. At this time point, occupancy was preserved in KO mice but suppressed by 60 % in WT animals, consistent with a model in which most receptors contributing to binding potential in WT animals were not functional. These results demonstrate that arrestin-mediated receptor desensitization and internalization produce large effects in PET [11C]raclopride occupancy studies using agonist challenges.

Summary This study aimed to investigate sex‐related differences in the response to ropinirole and pramipexole in patients with restless legs syndrome (RLS). By analysing clinical parameters and polysomnographic (PSG) findings, we sought to elucidate the potential factors related to sex disparities modulating treatment responses and sleep quality in RLS. A total of 41 drug‐free patients with RLS, aged ≥18 years, underwent two consecutive nocturnal PSG recordings, without medication at baseline; before the second night, 26 patients received an oral dose of 0.25 mg pramipexole whereas 15 received 0.5 mg ropinirole. After each PSG recording, patients self‐evaluated the severity of their previous night symptoms by means of an ad hoc visual analogue scale (VAS). At baseline, sleep efficiency and percentage of Stage N2 tended to be higher in females while wakefulness after sleep onset was significantly higher in males. After treatment, total leg movements during sleep (LMS), periodic LMS (PLMS), and periodicity indexes were significantly lower in females than in males. The VAS score was lower after treatment in all patients, without differences between the two sexes. This study demonstrates a higher acute responsiveness of PLMS to dopamine agonists (pramipexole and ropinirole) in females than in males with RLS. These findings might be explained by differential sex‐related expression of dopamine receptors, especially D3, within the central nervous system. In addition, our findings provide translational hints toward a better tailored and sex‐specific approach to the treatment of RLS associated with PLMS, with dopamine agonist possibly associated with a better outcome in females than in males. [ABSTRACT FROM AUTHOR]

Schizophrenia is a frequently debilitating and complex mental disorder affecting approximately 1% of the global population, characterized by symptoms such as hallucinations, delusions, disorganized thoughts and behaviors, cognitive dysfunction, and negative symptoms. Traditional treatment has centered on postsynaptic dopamine antagonists, commonly known as antipsychotic drugs, which aim to alleviate symptoms and improve functioning and the quality of life. Despite the availability of these medications, significant challenges remain in schizophrenia therapeutics, including incomplete symptom relief, treatment resistance, and medication side effects. This opinion article explores advancements in schizophrenia treatment, emphasizing molecular mechanisms, novel drug targets, and innovative delivery methods. One promising approach is novel strategies that target neural networks and circuits rather than single neurotransmitters, acknowledging the complexity of brain region interconnections involved in schizophrenia. Another promising approach is the development of biased agonists, which selectively activate specific signaling pathways downstream of receptors, offering potential for more precise pharmacological interventions with fewer side effects. The concept of molecular polypharmacy, where a single drug targets multiple molecular pathways, is exemplified by KarXT, a novel drug combining xanomeline and trospium to address both psychosis and cognitive dysfunction. This approach represents a comprehensive strategy for schizophrenia treatment, potentially improving outcomes for patients. In conclusion, advancing the molecular understanding of schizophrenia and exploring innovative therapeutic strategies hold promise for addressing the unmet needs in schizophrenia treatment, aiming for more effective and tailored interventions. Future research should focus on these novel approaches to achieve better clinical outcomes and improve the functional level and quality of life for individuals with schizophrenia. [ABSTRACT FROM AUTHOR]

Rationale: Internally perceived stimuli evoked by morphine administration can form Pavlovian associations such that they can function as occasion setters (OSs) for externally perceived reward cues in rats, coming to modulate reward-seeking behaviour. Though much research has investigated mechanisms underlying opioid-related reinforcement and analgesia, neurotransmitter systems involved in the functioning of opioids as Pavlovian interoceptive discriminative stimuli remain to be disentangled despite documented differences in the development of tolerance to analgesic versus discriminative stimulus effects. Objectives: Dopamine has been implicated in many opioid-related behaviours, so we aimed to investigate the role of this neurotransmitter in expression of morphine occasion setting. Methods: Male and female rats were assigned to positive- (FP) or negative-feature (FN) groups and received an injection of morphine or saline before each training session. A 15-s white noise conditioned stimulus (CS) was presented 8 times during every training session; offset of this stimulus was followed by 4-s access to liquid sucrose on morphine, but not saline, sessions for FP rats. FN rats learned the reverse contingency. Following stable discrimination, rats began generalization testing for expression of morphine-guided sucrose seeking after systemic pretreatment with different doses of the non-selective dopamine receptor antagonist, flupenthixol, and the non-selective dopamine receptor agonist, apomorphine, combined with training doses of morphine or saline in a Latin-square design. Results: The morphine discrimination was acquired under both FP and FN contingencies by males and females. Neither flupenthixol nor apomorphine at any dose substituted for morphine, but both apomorphine and flupenthixol disrupted expression of the morphine OS. This inhibition was specific to sucrose seeking during CS presentations rather than during the period before CS onset and, in the case of apomorphine more so than flupenthixol, to trials on which access to sucrose was anticipated. Conclusions: Our findings lend support to a mechanism of occasion setting involving gating of CS-induced dopamine release rather than by direct dopaminergic modulation by the morphine stimulus. [ABSTRACT FROM AUTHOR]

• Age-related cognitive decline was detected through rodent temporal order recognition. • Poor temporal order memory is rescued by D 1 dopamine agonists. • Optimal effective doses vary markedly among individual rats of different age groups. • Population effectiveness may be influenced by agonist functional selectivity. Dopamine D 1 receptor agonists improve spatial working memory, but their effects on temporal order memory, particularly prone to the effects of aging, have not been studied. Two D 1 agonists, PF6256142 (PF) and 2-methyldihydrexidine (2MDHX), were examined for their effects in a rodent temporal order recognition task. Our results are consistent with the hypothesis that there is an age-related decline in rodent temporal order memory. The data also show that either agonist rescues the poor memory performance with a large effective size. Interestingly, the optimal effective dose varied among individual rats of different age groups. PF showed greater potency for older rats, whereas 2MDHX showed better overall population effectiveness. Both PF and 2MDHX have high intrinsic activity at rodent D 1 -mediated cAMP synthesis. Conversely, at D 1 -mediated β-arrestin recruitment, PF has essentially no intrinsic activity, whereas 2MDHX is a super-agonist. These findings suggest that D 1 agonists have potential to treat age-related cognitive decline, and the pattern of functional selectivity may be useful for developing drugs with an improved therapeutic index. [ABSTRACT FROM AUTHOR]

Background: Neuropsychopharmacological compounds may exert complex brain-wide effects due to an anatomically and genetically broad expression of their molecular targets and indirect effects via interconnected brain circuits. Electrophysiological measurements in multiple brain regions using electroencephalography (EEG) or local field potential (LFP) depth-electrodes may record fingerprints of such pharmacologically-induced changes in local activity and interregional connectivity (pEEG/pLFP). However, in order to reveal such patterns comprehensively and potentially derive mechanisms of therapeutic pharmacological effects, both activity and connectivity have to be estimated for many brain regions. This entails the problem that hundreds of electrophysiological parameters are derived from a typically small number of subjects, making frequentist statistics ill-suited for their analysis. Methods: We here present an optimized interpretable machine-learning (ML) approach which relies on predictive power in individual recording sequences to extract and quantify the robustness of compound-induced neural changes from multi-site recordings using Shapley additive explanations (SHAP) values. To evaluate this approach, we recorded LFPs in mediodorsal thalamus (MD), prefrontal cortex (PFC), dorsal hippocampus (CA1 and CA3), and ventral hippocampus (vHC) of mice after application of amphetamine or of the dopaminergic antagonists clozapine, raclopride, or SCH23390, for which effects on directed neural communication between those brain structures were so far unknown. Results: Our approach identified complex patterns of neurophysiological changes induced by each of these compounds, which were reproducible across time intervals, doses (where tested), and ML algorithms. We found, for example, that the action of clozapine in the analysed cortico-thalamohippocampal network entails a larger share of D1--as opposed to D2-receptor induced effects, and that the D2-antagonist raclopride reconfigures connectivity in the delta-frequency band. Furthermore, the effects of amphetamine and clozapine were surprisingly similar in terms of decreasing thalamic input to PFC and vHC, and vHC activity, whereas an increase of dorsal-hippocampal communication and of thalamic activity distinguished amphetamine from all tested anti-dopaminergic drugs. Conclusion: Our study suggests that communication from the dorsal hippocampus scales proportionally with dopamine receptor activation and demonstrates, more generally, the high complexity of neuropharmacological effects on the circuit level. We envision that the presented approach can aid in the standardization and improved data extraction in pEEG/pLFP-studies. [ABSTRACT FROM AUTHOR]

In everyday life, we encounter situations that require tradeoffs between potential rewards and associated costs, such as time and (physical) effort. The literature indicates a prominent role for dopamine in discounting of both delay and effort, with mixed findings for delay discounting in humans. Moreover, the reciprocal antagonistic interaction between dopaminergic and cholinergic transmission in the striatum suggests a potential opponent role of acetylcholine in these processes. We found opposing effects of dopamine D2 (haloperidol) and acetylcholine M1 receptor (biperiden) antagonism on specific components of effort-based decision-making in healthy humans: haloperidol decreased, whereas biperiden increased the willingness to exert physical effort. In contrast, delay discounting was reduced under haloperidol, but not affected by biperiden. Together, our data suggest that dopamine, acting at D2 receptors, modulates both effort and delay discounting, while acetylcholine, acting at M1 receptors, appears to exert a more specific influence on effort discounting only. Tradeoffs between potential rewards and associated costs involves the dopaminergic system, which antagonistically interacts with the cholinergic system. This study describes that dopamine and acetylcholine have opposing effects on the modulation of specific components of cost-benefit decision making in humans. [ABSTRACT FROM AUTHOR]

Rationale: Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is a novel molecule in development for treatment of substance use disorders, psychiatric comorbidities, and pain. Objective: Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays. Methods: Cell-based assays were used to measure receptor binding and intrinsic efficacy of ITI-333; animal models were employed to assess effects on opioid reinstatement, precipitated oxycodone withdrawal, and drug abuse liability. Results: In vitro, ITI-333 is a potent 5-HT2A receptor antagonist (Ki = 8 nM) and a biased, partial agonist at μ-opioid (MOP) receptors (Ki = 11 nM; lacking β-arrestin agonism) with lesser antagonist activity at adrenergic α1A (Ki = 28 nM) and dopamine D1 (Ki = 50 nM) receptors. In vivo, ITI-333 blocks 5-HT2A receptor-mediated head twitch and MOP receptor-mediated effects on motor hyperactivity in mice. ITI-333 alone is a naloxone-sensitive analgesic (mice) which suppresses somatic signs of naloxone-precipitated oxycodone withdrawal (mice) and heroin cue-induced reinstatement responding without apparent tolerance or physical dependence after chronic dosing (rats). ITI-333 did not acutely impair gastrointestinal or pulmonary function (rats) and was not intravenously self-administered by heroin-maintained rats or rhesus monkeys. Conclusions: ITI-333 acts as a potent 5-HT2A receptor antagonist, as well a biased MOP receptor partial agonist with low intrinsic efficacy. ITI-333 mitigates opioid withdrawal/reinstatement, supporting its potential utility as a treatment for OUD. [ABSTRACT FROM AUTHOR]

Objective: Levodopa (L-dopa) therapy is the principal pharmacological treatment for Parkinson's disease (PD). Nevertheless, prolonged use of this drug may result in different involuntary movement symptoms caused by the medication, referred to as levodopa-induced dyskinesia (LID). LID is associated with changes in synaptic plasticity of the D1 medium spiny neurons (MSNs) located in the dorsal striatum (dStr). Within the striatum, the amount of Dopamine D3 receptor (D3R) is notably increased in LID, demonstrating colocalization with D1R expression in neurons, and the level of D3R expression is directly related to the intensity of LID. IRL 790, as a D3R antagonist, can ameliorate LID. This study aims to explore if IRL 790 improves LID by regulating the synaptic plasticity of D1+ MSNs in dStr. Methods: The electrophysiology and synaptic spine density of D1+ MSNs in dStr were recorded for sham mice, LID mice, and LID mice treated with IRL 790. The regulation of synaptic plasticity in LID D1+ MSNs by IRL 790 was analyzed. Behavioral tests were conducted to confirm the treatment effect of IRL 790 on LID. Results: In LID D1+ MSNs, there was persistent abnormal LTP, absence of LTD, and an increase in spontaneous excitatory postsynaptic currents (sEPSCs). IRL 790 treatment restored normal LTP, LTD, and sEPSCs. Treatment with IRL 790 also restored the reduced dendritic spine density in D1+ MSNs of LID mice. IRL790 improved dyskinetic manifestations in LID mice. Conclusion: IRL790 ameliorates LID by regulating the synaptic structure and functional plasticity of striatal D1+ MSNs. [ABSTRACT FROM AUTHOR]

For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there has been limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal senescence, brain volume loss, the attenuation of gamma oscillations in electroencephalograms, and the oxidation of lipids in the plasma and mitochondrial membranes. We surmise that the aberrant activation of the aryl hydrocarbon receptor by toxins derived from gut microbes or the environment drives premature cellular and neuronal senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including the impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: (1) to summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders, and (2) to discuss novel strategies for improving long-term outcomes in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor antagonists. [ABSTRACT FROM AUTHOR]

Aim: The therapeutic potential of N‐methyl‐D‐aspartate glutamate receptor (NMDAR) antagonists, particularly ketamine, in mood disorders, is linked to their modulation of dopamine dynamics in the medial prefrontal cortex (mPFC). However, conflicting effects of distinct NMDAR antagonists, like ketamine and phencyclidine, on mPFC dopamine levels stem from variances in their receptor affinity profiles. This study investigates the impact of intermittent subchronic administration of an NMDAR antagonist on dopamine synthesis capacity and responsiveness within the mPFC, focusing on Dizocilpine (MK‐801), a highly selective NMDAR antagonist. Methods: In vivo microdialysis and high‐performance liquid chromatography assessed extracellular dopamine levels in the mPFC following subchronic MK‐801 treatment. Locomotor activity was measured using a computed video tracking system. Results: Intermittent subchronic MK‐801 administration, followed by a 24‐h withdrawal, preserved both dopamine synthesis capacity and responsiveness to MK‐801 challenge in the mPFC. However, altered locomotor activity was observed, deviating from previous findings indicating impaired dopamine synthesis and responsiveness in the mPFC with twice‐daily subchronic NMDAR antagonist treatment. Conclusion: These findings offer crucial biochemical insights into the diverse impacts of NMDAR antagonists on dopamine dynamics and the distinct therapeutic mechanisms associated with ketamine in depression treatment. However, further investigation is imperative to pinpoint potential inconsistencies stemming from variances in drug type, dosage, or administration frequency. [ABSTRACT FROM AUTHOR]

Dopamine antagonists, 5-HT 3 antagonists, and dexamethasone are frequently used in obstetrics to prevent postoperative nausea and vomiting (PONV). However, the superiority of any drug class is yet to be established. This network meta-analysis aimed to compare the efficacy of these antiemetics for PONV prophylaxis in women receiving neuraxial morphine for Caesarean delivery. We searched PubMed, Embase, CENTRAL, Web of Science, and Wanfang Data for eligible randomised controlled trials. Primary outcomes were the incidences of postoperative nausea (PON) and postoperative vomiting (POV) within 24 h after surgery. We used a Bayesian random-effects model and calculated odds ratios with 95% credible intervals for dichotomous data. We performed sensitivity and subgroup analyses for primary outcomes. A total of 33 studies with 4238 women were included. In the primary analyses of all women, 5-HT 3 antagonists, dopamine antagonists, dexamethasone, and 5-HT 3 antagonists plus dexamethasone significantly reduced PON and POV compared with placebo, and 5-HT 3 antagonists plus dexamethasone were more effective than monotherapy. In the subgroup analyses, similar results were seen in women receiving epidural morphine or intrathecal morphine alone but not in women receiving intrathecal morphine with fentanyl or sufentanil. However, most included studies had some concerns or a high risk of bias, and the overall certainty of the evidence was low or very low. Combined 5-HT 3 antagonists plus dexamethasone are more effective than monotherapy in preventing PONV associated with neuraxial morphine after Caesarean delivery. Future studies are needed to determine the role of prophylactic antiemetics in women receiving intrathecal morphine and lipophilic opioids. PROSPERO CRD42023454602. [ABSTRACT FROM AUTHOR]

Voriconazole is a second-generation azole used to treat serious fungal infections. Visual hallucinations constitute a representative adverse event caused by voriconazole. However, its mechanism of action remains unclear. In patients with schizophrenia or Parkinson's disease, the frequency of visual hallucinations is associated with brain dopamine levels. This study investigated the frequency of visual hallucinations in patients treated with voriconazole alone or in combination with dopaminergic medicines or dopamine antagonists, using data collected from the Food and Drug Administration Adverse event Reporting System (FAERS). The frequency of visual hallucinations with voriconazole alone and in combination with a dopaminergic medicine (levodopa) or dopamine antagonists (risperidone and chlorpromazine) was compared using data from the FAERS between 2004 and 2023, using the reporting odds ratio (ROR) with relevant 95% confidence intervals (CI). The reference group comprised patients who had been administered voriconazole without dopaminergic medication or dopamine antagonists. Of the patients, 22,839, 90,810, 109,757, 6,435, 20, 83, and 26, respectively were treated with voriconazole, levodopa, risperidone, chlorpromazine, voriconazole plus levodopa, voriconazole plus risperidone, and voriconazole plus chlorpromazine. The occurrence of visual hallucinations increased when used in combination with levodopa (ROR = 12.302, 95% CI = 3.587–42.183). No increase in incidence was associated with the concomitant use of dopamine antagonists (risperidone, ROR = 1.721, 95% CI = 0.421–7.030; chlorpromazine, ROR = none, 95% CI = none). Dopaminergic medicine may increase the risk of visual hallucinations in patients treated with voriconazole. Whether voriconazole positively modulates dopamine production warrants further investigation using a translational research approach. [ABSTRACT FROM AUTHOR]

Background: Adults with cannabis hyperemesis syndrome (CHS) are increasingly presenting to the emergency department (ED), and this systematic review will evaluate the direct evidence on the effectiveness of capsaicin and dopamine antagonists in its clinical management. Methods: A bibliographic search was conducted to address the following population–intervention–control–outcome (PICO) question: (P) adults >18 years old with a diagnosis of acute CHS presenting to the ED; (I) dopamine antagonists (e.g., haloperidol, droperidol) and topical capsaicin; (C) usual care or no active comparator; and (O) symptoms improvement/resolution in ED, ED length of stay, admission rate, ED recidivism, need for rescue medication, and adverse events. This systematic review was conducted in accordance with PRISMA reporting recommendations. Results: From 53 potentially relevant articles, seven articles were included: five observational studies and two randomized controlled trials, including a total of 492 patients. Five of these studies evaluated the efficacy of capsaicin cream (n = 386), and two examined dopamine antagonists (haloperidol, droperidol; n = 106). There was mixed evidence for the efficacy of capsaicin for reducing nausea and emesis. Both studies evaluating dopamine antagonists detected clinical benefit to usual care or no active comparator. Conclusions: There is limited direct evidence on the efficacy of dopamine antagonists or capsaicin for treating CHS in the ED. Current evidence is mixed for capsaicin and potentially beneficial for dopamine antagonists. Because of the small number of studies, small number of participants, lack of standardization of treatment administration, and risk of bias of the included studies, methodologically rigorous trials on both types of intervention are needed to directly inform ED management of CHS. [ABSTRACT FROM AUTHOR]

The inhibitory effects of veralipride, a benzamide‐class antipsychotic acting as dopamine D2 receptors antagonist incorporates a primary sulfonamide moiety and was investigated for its interactions with carbonic anhydrase (CA) isoforms. In vitro profiling using the stopped‐flow technique revealed that veralipride exhibited potent inhibitory activity across all tested hCA isoforms, with exception of hCA III. Comparative analysis with standard inhibitors, acetazolamide (AAZ), and sulpiride, provided insights for understanding the relative efficacy of veralipride as CA inhibitor. The study reports the X‐ray crystal structure analysis of the veralipride adduct with three human (h) isoforms, hCA I, II, and CA XII mimic, allowing the understanding of the molecular interactions rationalizing its inhibitory effects against each isoform. These findings contribute to our understanding of veralipride pharmacological properties and for the design of structural analogs endowed with polypharmacological properties. [ABSTRACT FROM AUTHOR]

The excitation‐inhibition imbalance manifesting as epileptic activities in Alzheimer's disease is gaining more and more attention, and several potentially involved cellular and molecular pathways are currently under investigation. Based on in vitro studies, dopamine D1‐type receptors in the anterior cingulate cortex and the hippocampus have been proposed to participate in this peculiar co‐morbidity in mouse models of amyloidosis. Here, we tested the implication of dopaminergic transmission in vivo in the Tg2576 mouse model of Alzheimer's disease by monitoring epileptic activities via intracranial EEG before and after treatment with dopamine antagonists. Our results show that neither the D1‐like dopamine receptor antagonist SCH23390 nor the D2‐like dopamine receptor antagonist haloperidol reduces the frequency of epileptic activities. While requiring further investigation, our results indicate that on a systemic level, dopamine receptors are not significantly contributing to epilepsy observed in vivo in this mouse model of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Presently, there is limited guidance on the maximal dosing of psychosis drugs that is based on effectiveness rather than safety or toxicity. Current maximum dosing recommendations may far exceed the necessary degree of dopamine D2 receptor blockade required to treat psychosis. This may lead to excess harm through cognitive impairment and side effects. Aims: This analysis aimed to establish guidance for prescribers by optimally dosing drugs for psychosis based on efficacy and benefit. Methods: We used data from two dose–response meta-analyses and reviewed seven of the most prescribed drugs for psychosis in the UK. Where data were not available, we used appropriate comparison techniques based on D2 receptor occupancy to extrapolate our recommendations. Results: We found that the likely threshold dose for achieving remission of psychotic symptoms was often significantly below the currently licensed dose for these drugs. We therefore recommend that clinicians are cautious about exceeding our recommended doses. Individual factors, however, should be accounted for. We outline potentially relevant factors including age, ethnicity, sex, smoking status and pharmacogenetics. Additionally, we recommend therapeutic drug monitoring as a tool to determine individual pharmacokinetic variation. Conclusions: In summary, we propose a new set of maximum target doses for psychosis drugs based on efficacy. Further research through randomised controlled trials should be undertaken to evaluate the effect of reducing doses from current licensing maximums or from doses that are above our recommendations. However, dose reductions should be implemented in a manner that accounts for and reduces the effects of drug withdrawal. [ABSTRACT FROM AUTHOR]

Rationale: Cabergoline (CAB) is an ergot derivative typically prescribed for the treatment of hyperprolactinemia. It suppresses the release of prolactin through agonist actions on dopamine (DA) D2 receptors; however, it possesses binding affinity for other DA and 5-HT receptors. Side effects that exacerbate valvular heart disease can occur with high doses. Objective: The present study examined the acute, subchronic, and chronic dose–response effects of CAB and a derivative dimethylcabergoline (DMC) which acts as an antagonist instead of agonist at 5-HT 2B receptors, on appetitive and consummatory sexual behaviors of male rats. Methods: CAB (0, 0.03, 0.15, or 0.3 mg/kg/ml) was administered daily to sexually experienced male rats (N = 10/dose) by oral gavage for a total of 68 days. Sexual behavior was tested every 4 days during this period for a total of 16 trials. On the 17th trial, rats were administered their dose of CAB, and 4 h after were overdosed with sodium pentobarbital, perfused intracardially, and their brains processed for Fos immunohistochemistry. DMC (0, 0.03, 0.15, 0.3 mg/kg/ml) was administered daily to sexually experienced male rats (N = 10/dose) by oral gavage for a total of 36 days. Sexual behavior was tested every 4 days for a total of 9 trials. Results: CAB increased anticipatory level changes, intromissions, and ejaculations significantly across all timepoints, with the medium and high doses being most potent. The medium and high doses also increased Fos protein significantly within the medial preoptic area, whereas in the nucleus accumbens shell, the low and medium doses decreased Fos protein but the high dose increased it significantly from control. Similar to CAB, the medium and high doses of DMC increased the number of ejaculations significantly. Rats in all drug dose groups appeared healthy for the duration of the experiments. Conclusions: Both CAB and DMC facilitate ejaculations, and CAB further facilitates measures of anticipatory sexual motivation and intromissions. These data suggest that both could be used as treatments for sexual arousal disorders and ejaculation/orgasm disorders with little or no untoward side effects at low doses. [ABSTRACT FROM AUTHOR]

The understanding of the pathophysiology of schizophrenia as well as the mechanisms of action of antipsychotic drugs remains a challenge for psychiatry. The demonstration of the therapeutic efficacy of several new atypical drugs targeting multiple different receptors, apart from the classical dopamine D2 receptor as initially postulated unique antipsychotic target, complicated even more conceptualization efforts. Here we discuss results suggesting a main role of the islands of Calleja, still poorly studied GABAergic granule cell clusters in the ventral striatum, as cellular targets of several innovative atypical antipsychotics (clozapine, cariprazine, and xanomeline/emraclidine) effective in treating also negative symptoms of schizophrenia. We will emphasize the potential role of dopamine D3 and M4 muscarinic acetylcholine receptor expressed at the highest level by the islands of Calleja, as well as their involvement in schizophrenia-associated neurocircuitries. Finally, we will discuss the implications of new data showing ongoing adult neurogenesis of the islands of Calleja as a very promising antipsychotic target linking long-life neurodevelopment and dopaminergic dysfunction in the striatum. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This article discusses the effects of opioid withdrawal on striatal dopamine levels. The study found that in laboratory rats exposed to morphine injections, extracellular dopamine concentrations decreased in the ventral striatum during withdrawal, but increased in the dorsal striatum during naloxone-triggered withdrawal. These findings suggest that withdrawal symptoms can become paired with opioid availability, enhancing the incentive salience of the drug and promoting conditioned approach. The article also explores the implications of these findings for addiction treatment, suggesting that a medication that offsets the aversive effects of withdrawal while diminishing dopamine surges could be beneficial. [Extracted from the article]

Astrocytes, the most abundant glial cells in the central nervous system, respond to a wide variety of neurotransmitters binding to metabotropic receptors. Here, we investigated the intracellular calcium responses of spinal cord astrocytes to dopamine and noradrenaline, two catecholamines released by specific descending pathways. In a slice preparation from the spinal cord of neonatal mice, puff application of dopamine resulted in intracellular calcium responses that remained in the endfeet. Noradrenaline induced stronger responses that also started in the endfeet but spread to neighbouring compartments. The intracellular calcium responses were unaffected by blocking neuronal activity or inhibiting various neurotransmitter receptors, suggesting a direct effect of dopamine and noradrenaline on astrocytes. The intracellular calcium responses induced by noradrenaline and dopamine were inhibited by the D1 receptor antagonist SCH 23390. We assessed the functional consequences of these astrocytic responses by examining changes in arteriole diameter. Puff application of dopamine or noradrenaline resulted in vasoconstriction of spinal arterioles. However, blocking D1 receptors or manipulating astrocytic intracellular calcium levels did not abolish the vasoconstrictions, indicating that the observed intracellular calcium responses in astrocyte endfeet were not responsible for the vascular changes. Our findings demonstrate a compartmentalized response of spinal cord astrocytes to catecholamines and expand our understanding of astrocyte–neurotransmitter interactions and their potential roles in the physiology of the central nervous system. [ABSTRACT FROM AUTHOR]

Introduction The complex nature of neurocognitive impairment in schizophrenia has been discussed in light of the mixed effects of antipsychotic drugs, psychotic symptoms, dopamine D2 receptor blockade, and intelligence quotient (IQ). These factors have not been thoroughly examined before. Methods This study conducted a comprehensive re-analysis of the CATIE data using machine learning techniques, in particular Conditional Inference Tree (CTREE) analysis, to investigate associations between neurocognitive functions and moderating factors such as estimated trough dopamine D2 receptor blockade with risperidone, olanzapine, or ziprasidone, Positive and Negative Syndrome Scale (PANSS), and baseline IQ in 573 patients with schizophrenia. Results The study reveals that IQ, age, and education consistently emerge as significant predictors across all neurocognitive domains. Furthermore, higher severity of PANSS-negative symptoms was associated with lower cognitive performance scores in several domains. CTREE analysis, in combination with a genetic algorithm approach, has been identified as particularly insightful for illustrating complex interactions between variables. Lower neurocognitive function was associated with factors such as age>52 years, IQ<94/95,<12/13 education years, and more pronounced negative symptoms (score<26). Conclusions These findings emphasize the multifaceted nature of neurocognitive functioning in patients with schizophrenia, with the PANSS-negative score being an important predictor. This gives rise to a role in addressing negative symptoms as a therapeutic objective for enhancing cognitive impairments in these patients. Further research must examine nonlinear relationships among various moderating factors identified in this work, especially the role of D2 occupancy. [ABSTRACT FROM AUTHOR]

This article discusses the case of a 17-year-old Hispanic adolescent boy who developed psychosis after immigrating to the United States. The article explores the patient's background and history, including his psychiatric, developmental, educational, social, and family background. The patient was diagnosed with schizophreniform disorder with catatonia and received treatment with medications. The article also discusses the factors that contribute to the development of psychosis, including genetic and environmental factors. The case highlights the importance of early recognition and targeted pharmacotherapy in improving outcomes for youth with psychosis. [Extracted from the article]

Aim: Impairments in emotional memory are frequently observed in several mental disorders, highlighting their significance as potential therapeutic targets. Recent research on the cued fear conditioning model has elucidated the neural circuits involved in fear memory processing. However, contradictory findings have been reported concerning the role of dopamine and the impact of dopamine D2 receptor (D2R) antagonists. There is notably limited knowledge regarding the clinical utility of chronic D2R antagonist treatments. This study aimed to uncover how such treatments affect fear memory processing. Methods: We utilized a cued fear conditioning rat model and conducted chronic haloperidol treatment for 14 days. Subsequently, to investigate the effect of chronic haloperidol treatment on fear‐conditioned memory expression and extinction, we observed freezing behavior under exposure to a conditioned stimulus for 14 days. Results: Chronic haloperidol treatment suppressed freezing time on the fear memory expression. In contrast, a single haloperidol administration enhanced the freezing time on fear memory expression and delayed extinction. Conclusion: The results of this study suggest that chronic administration of antipsychotic drugs affects fear memory processing differently from single‐dose administration. This indicates that the effects of chronic D2R antagonist treatment are distinct from the nonspecific effects of the drugs. This study provides fundamental insights that may contribute to our understanding of therapeutic mechanisms for fear memory disorders related to D2R in the future. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment are among the core features of schizophrenia, experienced by up to 75% of patients. Available treatment options for schizophrenia including dopamine antagonists and traditional antipsychotic medications have not been shown to confer significant benefits on cognitive deficits. Contrary to the focus on management of positive symptoms in schizophrenia, cognitive abilities are main predictor of independent living skills, functional abilities, employment, engagement in relapse prevention, and patients' subjective sense of well‐being and quality of life. This review aims to provide a summary of recent literature on pharmacological options for the treatment of cognitive deficits in schizophrenia. Methods: We conducted a literature search of studies from 2011 to 2021 across four electronic databases including PubMed, PsycInfo, MEDLINE, and Embase. Human studies using a pharmacological treatment for cognitive impairment in schizophrenia were included. Results: Fifty‐eight eligible publications, representing 11 pharmacological classes, were included in this review. Major limitations involved small sample size, methodological limitations as well as heterogeneity of participants and outcome measures. Conclusions: Overall evidence remains inconclusive for any pharmacological classes studied for the treatment of cognitive deficits in schizophrenia. Methodological limitations in a majority of the studies rendered their findings preliminary. We further discuss possible explanations for these findings that could guide future research. [ABSTRACT FROM AUTHOR]

Symptoms of nausea and vomiting are common in palliative care and hospice patients. One of the many classes of medications used for the treatment of nausea and vomiting is dopamine receptor antagonists which are particularly helpful for treating nausea mediated by the chemoreceptor trigger zone (CTZ) and impaired gastrointestinal function. While dopamine antagonists can be very effective treatments for nausea they should be used with caution as they carry the risk of QTc prolongation, have a FDA black box warning for tardive dyskinesia (TD), and increased risk of precipitating psychosis and death in patients with dementia. This review will cover haloperidol, olanzapine, prochlorperazine, and metoclopramide for treatment of nausea and vomiting including evidence of efficacy, pharmacokinetics, and pharmacodynamics to improve safe and effective utilization in clinical practice. This includes medication receptor site affinities at histaminic, muscarinic, serotonergic, and alpha-adrenergic receptors which can help providers anticipate potential adverse effects and risk of extrapyramidal symptoms (EPS), TD, and QTc prolongation. This review also includes considerations for dose adjustments based on renal function, hepatic function, and age. Understanding the pharmacology of dopamine antagonists can help providers choose the best treatment for control of nausea and vomiting and subsequently improve patients' quality of life. [ABSTRACT FROM AUTHOR]

Decades of pharmacogenetic research have revealed genetic biomarkers of clinical response to antipsychotics. Genetic variants in antipsychotic targets, dopamine and serotonin receptors in particular, and in metabolic enzymes have been associated with the efficacy and toxicity of antipsychotic treatments. However, genetic prediction of antipsychotic response based on these biomarkers is far from accurate. Despite the clinical validity of these findings, the clinical utility remains unclear. Nevertheless, genetic information on CYP metabolic enzymes responsible for the biotransformation of most commercially available antipsychotics has proven to be effective for the personalisation of clinical dosing, resulting in a reduction of induced side effects and in an increase in efficacy. However, pharmacogenetic information is rarely used in psychiatric settings as a prescription aid. Lack of studies on cost-effectiveness, absence of clinical guidelines based on pharmacogenetic biomarkers for several commonly used antipsychotics, the cost of genetic testing and the delay in results delivery hamper the implementation of pharmacogenetic interventions in clinical settings. This narrative review will comment on the existing pharmacogenetic information, the clinical utility of pharmacogenetic findings, and their current and future implementations. [ABSTRACT FROM AUTHOR]

End-of-life (EOL) care for Parkinson's disease (PD) can be challenging when oral medications are no longer tolerated. To assess EOL prescribing for people with PD (PWP), focusing on rotigotine dosing and proxy measures of distress: benzodiazepine and opioid use. A retrospective audit of patient records from PWP who died between January 2019 and May 2022 at the Royal Hobart Hospital (RHH), Australia, was conducted. Data was systematically collated on demographics, symptoms, levodopa equivalent daily dose (LEDD) and rotigotine, oral morphine equivalent (OME) and benzodiazepine doses in the last 72 hours of life. Pain (72%), respiratory secretions (66%) and agitation (66%) were the most documented EOL symptoms. 83% (n = 52) of PWP were eligible for rotigotine and, of those, 13% (n = 7) received the correct dose, 38% (n = 20) a lower dose, 12% (n = 6) a higher dose and 37% (n = 19) did not receive any. Rotigotine dose was positively associated with total (P = 0.016) and PRN (P = 0.037) benzodiazepine dose. LEDD was positively associated with total benzodiazepine (P = 0.018) and total OME dose (P = 0.046). Contraindicated dopamine antagonists were prescribed for 43% of PWP and administered in 31% of those cases. Rotigotine dose and admission LEDD were both associated with proxy measures of distress in the last 72 hours of life. This suggests cautious use of rotigotine at EOL. LEDD may help identify patients at risk of distress. Rates of inappropriate prescribing and symptom prevalence were high, indicating a need for further staff education to optimize the care of PWP. [ABSTRACT FROM AUTHOR]

Rationale: Dopamine antagonists induce dopamine receptor supersensitivity. This may manifest in late-appearing movement disorders (tardive dyskinesia (TD). VMAT-2 inhibitors reduce dopaminergic transmission but have limited activity at postsynaptic receptors and so may have antipsychotic activity with lower risk of tardive dyskinesia. Methods: We conducted a systematic database search from inception to September 2022 for articles describing the use of VMAT-2 inhibitors in psychosis. Inclusion criteria were as follows: Population: adults diagnosed with psychosis or schizophrenia; Intervention: treatment with tetrabenazine, deutetrabenazine or valbenazine; Comparison: comparison with placebo or/and antipsychotic drug; Outcomes: with efficacy outcomes (e.g. Brief Psychiatric Rating Scale (BPRS) change or clinician assessment) and adverse effects ratings (e.g. rating scale or clinician assessment or dropouts); and Studies: in randomised controlled trials and non-randomised studies. Results: We identified 4892 records relating to VMAT-2 inhibitor use of which 5 (173 participants) met our a priori meta-analysis inclusion criteria. VMAT-2 inhibitors were more effective than placebo for the outcome 'slight improvement' (risk ratio (RR) = 1.77 (95% CI 1.03, 3.04)) but not for 'moderate improvement' (RR 2.81 (95% CI 0.27, 29.17). VMAT-2 inhibitors were as effective as active comparators on both measures for—'slight improvement' (RR 1.05 (95% CI 0.6, 1.81)) and 'moderate improvement' (RR 1.11 (95% CI 0.51, 2.42). Antipsychotic efficacy was also suggested by a narrative review of 37 studies excluded from the meta-analysis. Conclusions: VMAT-2 inhibitors may have antipsychotic activity and may offer promise for treatment of psychosis with the potential for a reduced risk of TD. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to determine the clinical impact of a specialized pharmacist-led medication assessment on the incidence of dopamine antagonists administered for patients with Parkinson's disease after deep brain stimulation (DBS). METHODS: This was a single-center, Institutional Review Board-approved, two-phase study with pre- and postimplementation cohorts of patients who were 18 years of age or older who underwent DBS for treatment of Parkinson's disease. The primary endpoint was the incidence of dopamine antagonists administered after DBS procedure. Secondary endpoints included the incidence of dopamine antagonists ordered; restarting home Parkinson's disease regimen; rate of tardive dyskinesia; length of hospital stay; and incidence of sitters, restraints, and medications administered for acute agitation. Statistical analysis included Fisher's exact test for categorical data, unpaired t-test for continuous data, and descriptive statistics for all other data. RESULTS: The incidence of dopamine antagonists administered was 1 (1.2%) versus 1 (25%) for the pre- and post-implementation groups, respectively (P = 0.09). Restarting of home Parkinson's disease regimen was 30 (36.1%) versus 4 (100%); P = 0.021. The average length of stay was 1.9 days versus 1.3 days. Incidence of sitters was 1 (1.2%) versus 0 (0%), and incidence of restraints was 0 (0%) versus 0 (0%). Incidence of acute agitation medications administered was 9 (10.8%) versus 0 (0%). The secondary endpoints were not significant except for the restarting of home medication regimen. CONCLUSION: The specialized pharmacist-led medication review service identified a single incident of inappropriate medications administered for Parkinson's disease patients status post DBS. However, it did significantly increase the incidence of the restart of Parkinson's disease home regimen. [ABSTRACT FROM AUTHOR]

Background Rats emit 50-kHz ultrasonic vocalizations (USVs) in response to nonpharmacological and pharmacological stimuli, with addictive psychostimulants being the most effective drugs that elicit calling behavior in rats. Earlier investigations found that dopamine D1-like and D2-like receptors modulate the emission of 50-kHz USVs stimulated in rats by the acute administration of addictive psychostimulants. Conversely, information is lacking on how dopamine D1-like and D2-like receptors modulate calling behavior in rats that are repeatedly treated with addictive psychostimulants. Methods We evaluated the emission of 50-kHz USVs in rats repeatedly treated (×5 on alternate days) with amphetamine (1 mg/kg, i.p.) either alone or together with (1) SCH 23390 (0.1–1 mg/kg, s.c.), a dopamine D1 receptor antagonist; (2) raclopride (0.3–1 mg/kg, s.c.), a selective dopamine D2 receptor antagonist; or (3) a combination of SCH 23390 and raclopride (0.1 + 0.3 mg/kg, s.c.). Calling behavior of rats was recorded following pharmacological treatment, as well as in response to the presentation of amphetamine-paired cues and to amphetamine challenge (both performed 7 days after treatment discontinuation). Results Amphetamine-treated rats displayed a sensitized 50-kHz USV emission during repeated treatment, as well as marked calling behavior in response to amphetamine-paired cues and to amphetamine challenge. Antagonism of D1 or D2 receptors either significantly suppressed or attenuated the emission of 50-kHz USVs in amphetamine-treated rats, with a maximal effect after synergistic antagonism of both receptors. Conclusions These results shed further light on how dopamine transmission modulates the emission of 50-kHz USVs in rats treated with psychoactive drugs. [ABSTRACT FROM AUTHOR]

This narrative review explores the efficacy and tolerability of third-generation antipsychotics (TGAs)—aripiprazole, cariprazine, brexpiprazole, and lurasidone—for the management of substance-induced psychosis (SIP). SIP is a psychiatric condition triggered by substance misuse or withdrawal, characterized by unique features distinct from those of primary psychotic disorders. These distinctive features include a heightened prevalence of positive symptoms, such as hallucinations and delusions, in addition to a spectrum of mood and cognitive disturbances. This review comprehensively investigates various substances, such as cannabinoids, cocaine, amphetamines, and LSD, which exhibit a greater propensity for inducing psychosis. TGAs exhibit substantial promise in addressing both psychotic symptoms and issues related to substance misuse. This review elucidates the distinctive pharmacological properties of each TGA, their intricate interactions with neurotransmitters, and their potential utility in the treatment of SIP. We advocate for further research to delineate the long-term effects of TGAs in this context and underscore the necessity for adopting an integrated approach that combines pharmacological and psychological interventions. Our findings underscore the intricate and multifaceted nature of treating SIP, highlighting the potential role of TGAs within therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context. Methods: GFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo. Results: Ui-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, inhibited the growth of orthotopic GSC (BG5) derived xenografts in nude mice. Conclusions: DRD1 contributes to GBM invasion and progression by regulating c-Myc entry into the nucleus that affects the transcription of the UHRF1 gene. SKF83566 inhibits the transmembrane protein DRD1, and as such represents a candidate small therapeutic molecule for GBMs. [ABSTRACT FROM AUTHOR]

The available antipsychotics for schizophrenia (SZ) only reduce positive symptoms and do not significantly modify SZ neurobiology. This has raised the question of the robustness and translational value of methods employed during drug development. Electroencephalography (EEG)-based measures like evoked and spontaneous gamma oscillations are considered robust translational biomarkers as they can be recorded in both patients and animal models to probe a key mechanism underlying all SZ symptoms: the excitation/inhibition imbalance mediated by N-methyl-D-aspartate receptor (NMDAr) hypofunction. Understanding the effects of commercialized atypical antipsychotics on such measures could therefore contribute to developing better therapies for SZ. Yet, the effects of such drugs on these EEG readouts are unknown. Here, we studied the effect of the atypical antipsychotic aripiprazole on the gamma-band auditory steady-state response (ASSR), spontaneous gamma oscillations and behavioral features in a SZ rat model induced by the NMDAr antagonist MK-801. Interestingly, we found that aripiprazole could not normalize MK-801-induced abnormalities in ASSR, spontaneous gamma oscillations or social interaction while it still improved MK-801-induced hyperactivity. Suggesting that aripiprazole is unable to normalize electrophysiological features underlying SZ symptoms, our results might explain aripiprazole's inefficacy towards the social interaction deficit in our model but also its limited efficacy against social symptoms in patients. [ABSTRACT FROM AUTHOR]

Several preclinical and clinical studies indicate that exposure to acute stress may decrease pain perception and increases pain tolerance. This phenomenon is called stress-induced analgesia (SIA). A variety of neurotransmitters, including dopamine, is involved in the SIA. Dopaminergic neurons in the mesolimbic circuits, originating from the ventral tegmental area (VTA), play a crucial role in various motivational, rewarding, and pain events. The present study aimed to investigate the modulatory role of VTA dopaminergic receptors in the antinociceptive responses evoked by forced swim stress (FSS) in a model of acute pain. One hundred-five adult male albino Wistar rats were subjected to stereotaxic surgery for implanting a unilateral cannula into the VTA. After one week of recovery, separate groups of animals were given different doses of SCH23390 and Sulpiride (0.25, 1, and 4 µg/0.3 µl) as D1- and D2-like receptor antagonists into the VTA, respectively. Then, the animals were exposed to FSS for a 6-min period, and the pain threshold was measured using the tail-flick test over a 60-min time set intervals. Results indicated that exposure to FSS produces a prominent antinociceptive response, diminishing by blocking both dopamine receptors in the VTA. Nonetheless, the effect of a D1-like dopamine receptor antagonist on FSS-induced analgesia was more prominent than that of a D2-like dopamine receptor antagonist. The results demonstrated that VTA dopaminergic receptors contribute to the pain process in stressful situations, and it might be provided a practical approach to designing new therapeutic agents for pain management. [ABSTRACT FROM AUTHOR]

Halogenated compounds, especially fluorine and chlorine, play a key role in drug development. They account for a large proportion of all approved drug molecules. The importance of these two halogens stems from their remarkable effects on biological activity and pharmacokinetic properties. The study presented here aims to give the results obtained by the DFT methods and in silico medicinal evaluations of a newly synthesized small molecule. The small molecule belongs to the Schiff base class of organic compounds and is substituted with halogen atoms. The tetrahalogenated compound (THSB) Schiff base, 2-(((2,4-dichlorophenyl)imino)methyl)-3,4-difluorophenol, was first synthesized via the classical condensation method and then characterized by spectroscopic techniques. The THSB optimized by the B3LYP method was evaluated in terms of geometrical parameters, surface area (MEP and Hirshfeld analysis) and secondary interaction analysis, NLO properties, and electronic properties (HOMO-LUMO and UV-Vis). Second, THSB was evaluated regarding medicinal chemistry, physicochemical and pharmacokinetic properties, and toxicity (ADMET). Then, we comprehensively investigated the potential biological targets of THSB. Using the results of the SwissSimilarity analysis, we investigated the antagonistic effects of THSB against serotonin 5-HT2A and dopamine D2 receptors. Docking results were compared with the known antipsychotics, clozapine and risperidone. THSB showed a higher antagonistic effect than clozapine for the D2 receptor. However, risperidone proved to be the most effective antagonist for both targets. The binding energies of THSB, risperidone, and clozapine were -8.30, -11.84, and -8.07 kcal/mol, respectively, for D2; those of THSB, risperidone, and clozapine were -6.94, -11.47, and -10.10 kcal/mol, respectively, for 5-HT2A. [ABSTRACT FROM AUTHOR]

This document is an editorial for a special issue of the journal Biomedicines titled "Synaptic Transmission: From Molecular to Neural Network Levels." The editorial highlights six research articles that cover various aspects of synaptic function and plasticity, focusing on the cerebellar network and its role in motor control. One study investigates the preference of Purkinje cells, a type of cerebellar neuron, for specific frequency bands in motor activity control. Another study explores the frequency dependence of cerebellar activity and the dynamic properties of input processing in the cerebellar cortex. Additionally, the editorial discusses research on long-term plasticity at the cerebellar input stage and its impact on transmission along channels. The issue also includes studies on the effects of knocking down the expression of a specific protein in synaptically activated neurons and the effects of an antipsychotic drug on synaptic transmission in vestibular hair cells. Lastly, the editorial mentions a study on the cognitive effects of high-sugar beverage consumption in juvenile rats and its impact on brain-derived neurotrophic factor expression. These findings provide new insights into synaptic mechanisms and their network-level impacts, offering potential applications and therapies for various conditions. [Extracted from the article]

Quetiapine exhibits notable pharmacokinetic and pharmacodynamic (PK/PD) variability, the origins of which are poorly understood. This systematic review summarizes published population PK/PD studies and identifies significant covariates accounting for this variability to inform precision dosing. We systematically searched the PubMed, Web of Science, and Embase databases and compared study characteristics, model parameters, and covariate effects. Visual predictive distributions were used to compare different models. Forest plots and Monte Carlo simulations were used to assess the influence of covariates. Six population PK and three population PK/PD studies were included. The median apparent clearance in adults was 87.7 L/h. Strong and moderate cytochrome P450 3A4 inducers increased the apparent clearance approximately fourfold, while strong cytochrome P450 3A4 inhibitors reduced it by 93%. The half-maximum effect concentrations were 82.8 ng/mL for the Brief Psychiatric Rating Scale and 583 ng/mL for dopamine D2 receptor occupancy. Both treatment duration and quetiapine exposure were associated with weight gain. Concurrent administration of potent or moderate CYP3A4 inducers and inhibitors need to be avoided in quetiapine-treated patients. When co-medication is required, it is recommended to adjust the dosage based on therapeutic drug monitoring. Additional research is warranted to delineate the dose-exposure-response relationships of quetiapine and active metabolite norquetiapine in pediatrics, geriatrics, hepatically-impaired patients, and women using contraceptives or are pregnant or menopausal. CRD42023446654 [ABSTRACT FROM AUTHOR]