Dopamine Uptake Inhibitor Research Articles

Use of methylphenidate in alzheimer’s dementia: Effect on apathy

IntroductionAlzheimer’s Disease (AD) is associated with neuropsychiatric symptoms such as agitation depression and apathy. It has been proposed that the pathophysiology of apathy, that is defined as quantitative reduction in goal-directed activity compared with previous functioning, in AD is associated with degeneration of prefrontal cortex and dysfunction of dopamine and norepinephrine neurons in the brain. Methylphenidate (MPH) is a dopamine and norepinephrine reuptake inhibitor and its action increase the availability of these neurotransmitters in the extracellular space of striatum and prefrontal cortex. Over the past decade there has been an effort to study the benefit of the use of MPH for treatment of apathy in patients with Alzheimer’s dementia.ObjectivesStudy the benefit of methylphenidate in the treatment of apathy in AD.MethodsBasic literature review collecting data from PubMed (2010-2020) using the words “Methylphenidate”, “Apathy”, “Alzheimer”, “Dementia”.ResultsClinical trials using 10 to 20mg of MPH per day, for 6 weeks, demonstrated a mitigation in apathy symptoms in one third of patients, with good tolerability. Another clinical trial using the same dosage, for 12 weeks, led to improvement in cognition, functional status, depression and caregiver burden.ConclusionsNew clinical trials with larger groups of patients over a longer period are needed to consolidate the existing results. Although there are still many questions concerning the usefulness of methylphenidate in this population that need to be answered, methylphenidate might be an option to deal with one of the most prevalent neuropsychiatric symptoms, apathy, in some AD patients.

Physiologically Based Pharmacokinetic Modeling of Bupropion and Its Metabolites in a CYP2B6 Drug-Drug-Gene Interaction Network.

The noradrenaline and dopamine reuptake inhibitor bupropion is metabolized by CYP2B6 and recommended by the FDA as the only sensitive substrate for clinical CYP2B6 drug–drug interaction (DDI) studies. The aim of this study was to build a whole-body physiologically based pharmacokinetic (PBPK) model of bupropion including its DDI-relevant metabolites, and to qualify the model using clinical drug–gene interaction (DGI) and DDI data. The model was built in PK-Sim® applying clinical data of 67 studies. It incorporates CYP2B6-mediated hydroxylation of bupropion, metabolism via CYP2C19 and 11β-HSD, as well as binding to pharmacological targets. The impact of CYP2B6 polymorphisms is described for normal, poor, intermediate, and rapid metabolizers, with various allele combinations of the genetic variants CYP2B6*1, *4, *5 and *6. DDI model performance was evaluated by prediction of clinical studies with rifampicin (CYP2B6 and CYP2C19 inducer), fluvoxamine (CYP2C19 inhibitor) and voriconazole (CYP2B6 and CYP2C19 inhibitor). Model performance quantification showed 20/20 DGI ratios of hydroxybupropion to bupropion AUC ratios (DGI AUCHBup/Bup ratios), 12/13 DDI AUCHBup/Bup ratios, and 7/7 DDGI AUCHBup/Bup ratios within 2-fold of observed values. The developed model is freely available in the Open Systems Pharmacology model repository.

Experimental Dopamine Reuptake Inhibitors in Parkinson's Disease: A Review of the Evidence.

Parkinson’s disease (PD) is the second most chronic neurodegenerative disorder worldwide. Deficit of monoamines, particularly dopamine, causes an individually varying compilation of motor and non-motor features. Constraint of presynaptic uptake extends monoamine stay in the synaptic cleft. This review discusses possible benefits of dopamine reuptake inhibition for the treatment of PD. Translation of this pharmacologic principle into positive clinical study results failed to date. Past clinical trial designs did not consider a mandatory, concomitant stable inhibition of glial monoamine turnover, i.e. with monoamine oxidase B inhibitors. These studies focused on improvement of motor behavior and levodopa associated motor complications, which are fluctuations of motor and non-motor behavior. Future clinical investigations in early, levodopa- and dopamine agonist naïve patients shall also aim on alleviation of non-motor symptoms, like fatigue, apathy or cognitive slowing. Oral levodopa/dopa decarboxylase inhibitor application is inevitably necessary with advance of PD. Monoamine reuptake (MRT) inhibition improves the efficacy of levodopa, the blood brain barrier crossing metabolic precursor of dopamine. The pulsatile brain delivery pattern of orally administered levodopa containing formulations results in synaptic dopamine variability. Ups and downs of dopamine counteract the physiologic principle of continuous neurotransmission, particularly in nigrostriatal, respectively mesocorticolimbic pathways, both of which regulate motor respectively non-motor behavior. Thus synaptic dopamine pulsatility overwhelms the existing buffering capacity. Onset of motor and non-motor complications occurs. Future MRT inhibitor studies shall focus on a stabilizing and preventive effect on levodopa related fluctuations of motor and non-motor behavior. Their long-term study designs in advanced levodopa treated patients shall allow a cautious adaptation of oral l-dopa therapy combined with a mandatory inhibition of glial monoamine turnover. Then the evidence for a preventive and beneficial, symptomatic effect of MRT inhibition on motor and non-motor complications will become more likely.

Profiling the structural determinants of aminoketone derivatives as hNET and hDAT reuptake inhibitors by field-based QSAR based on molecular docking

BACKGROUND: Bupropion, one of the dual norepinephrine and dopamine reuptake inhibitors (NDRIs), is an aminoketone derivative performed effect in improving cognitive function for depression. However, its therapeutic effect is unsatisfactory due to poor clinical response, and there are only few derivatives in pre-clinical settings.OBJECTIVE: This work attempted to elucidate the essential structural features for the activity and designed a series of novel derivatives with good inhibitive ability, pharmacokinetic and medicinal chemistry properties.METHODS: The field-based QSAR of aminoketone derivatives of two targets were established based on docking poses, and the essential structural properties for designing novel compounds were supplied by comparing contour maps.RESULTS: The selected two models performed good predictability and reliability with R of 0.8479 and 0.8040 for training set, Q of 0.7352 and 0.6266 for test set respectively, and the designed 29 novel derivatives performed no less than the highest active compound with good ADME/T pharmacokinetic properties and medicinal chemistry friendliness.CONCLUSIONS: Bulky groups in R, bulky groups with weak hydrophobicity in R, and potent hydrophobic substituted group with electronegative in R from contour maps provided important insights for assessing and designing 29 novel NDRIs, which were considered as candidates for cognitive dysfunction with depression or other related neurodegenerative disorders.

Discriminative stimulus effects of 3,4-methylenedioxypyrovalerone (MDPV) and structurally related synthetic cathinones.

The 3,4-methylenedioxypyrovalerone (MDPV), and other structurally related synthetic cathinones, are popular alternatives to prototypical illicit psychostimulants, such as cocaine and methamphetamine. These drugs are often referred to as 'bath salts' and function either as cocaine-like inhibitors of monoamine uptake, or amphetamine-like substrates for dopamine, norepinephrine and serotonin transporters. These studies used male Sprague-Dawley rats trained to discriminate MDPV from saline to evaluate the substitution profiles of structurally related synthetic cathinones, cocaine, and other direct-acting dopamine and noradrenergic receptor agonists in order to characterize the relative contributions of dopamine, norepinephrine and serotonin to the discriminative stimulus effects of MDPV. As expected, each of the cathinones and cocaine dose-dependently increased MDPV-appropriate responding, with a rank-order potency that was positively correlated with their potency to inhibit dopamine and norepinephrine, but not serotonin, a relationship that is consistent with the rank order to maintain self-administration. The dopamine D2/3 receptor-preferring agonist quinpirole produced a modest increase in MDPV-appropriate responding, whereas the dopamine D1/5 receptor agonist, SKF 82958, nonselective dopamine receptor agonist, apomorphine, as well as the α-1, and α-2 adrenergic receptor agonists, phenylephrine and clonidine, respectively, failed to increase MDPV-appropriate responding at doses smaller than those that suppressed responding altogether. Although these studies do not support a role for serotonergic or adrenergic systems in mediating/modulating the discriminative stimulus effects of MDPV, convergent evidence is provided to suggest that the discriminative stimulus effects of MDPV are primarily mediated by its capacity to inhibit dopamine uptake, and the subsequent activation of dopamine D2 or D3 receptors.

Mutations of Human DopamineTransporter at Tyrosine88, Aspartic Acid206, and Histidine547 Influence Basal and HIV-1 Tat\u2010inhibited Dopamine Transport

HIV-1 transactivator of transcription (Tat) has a great impact on the development of HIV-1 associated neurocognitive disorders through disrupting dopamine transmission. This study determined the mutational effects of human dopamine transporter (hDAT) on basal and Tat-induced inhibition of dopamine transport. Compared to wild-type hDAT, the maximal velocity (Vmax) of [3H]dopamine uptake was decreased in D381L and Y88F/D206L/H547A, increased in D206L/H547A, and unaltered in D206L. Recombinant TatR1 − 86 inhibited dopamine uptake in wild-type hDAT, which was attenuated in either DAT mutants (D206L, D206L/H547A, and Y88F/D206L/H547A) or mutated TatR1 − 86 (K19A and C22G), demonstrating perturbed Tat-DAT interaction. Mutational effects of hDAT on the transporter conformation were evidenced by attenuation of zinc-induced increased [3H]WIN35,428 binding in D206L/H547A and Y88F/D206A/H547A and enhanced basal MPP+ efflux in D206L/H547A. H547A-induced outward-open transport conformational state was further validated by enhanced accessibility to MTSET ([2-(trimethylammonium)ethyl]-methanethiosulfonate) of an inserted cysteine (I159C) on a hDAT background.. Furthermore, H547A displayed an increase in palmitoylation inhibitor-induced inhibition of dopamine uptake relative to wide-type hDAT, indicating a change in basal palmitoylation in H547A. These results demonstrate that Y88F, D206L, and H547A attenuate Tat inhibition while preserving DA uptake, providing insights into identifying targets for improving DAT-mediated dopaminergic dysregulation.Graphical HIV-1 Tat inhibits dopamine uptake through human dopamine transporter (hDAT) on the presynaptic terminal through a direct allosteric interaction. Key hDAT residues D-H547, D-Y88, and D-D206 are predicted to be involved in the HIV-1 Tat-DAT binding. Mutating these residues attenuates this inhibitory effect by disrupting the Tat-hDAT interaction

Using Computational and Neurobiological Methods to Characterise the Stimulant Properties of Novel Psychoactive Substances (NPS) at the Dopamine Transporter

Stimulant drugs, including novel psychoactive substances (NPS, formerly “legal highs”) have addictive potential which their users may not realize. Stimulants elevate extracellular dopamine (DA) by inducing DA efflux via the dopamine transporter (DAT) and inhibition of DA reuptake. In this work we aim to assess DAT responses to stimulant NPS by means of in vitro, in vivo and in silico approaches. We compared how NPS bind to rat DAT, using autoradiography assessment of [125I]RTI-121 displacement in rat striatal sections.

Cocaine-induced locomotor stimulation involves autophagic degradation of the dopamine transporter.

Cocaine exerts its stimulant effect by inhibiting dopamine reuptake leading to increased dopamine signaling. This action is thought to reflect binding of cocaine to the dopamine transporter (DAT) to inhibit its function. However, cocaine is a relatively weak inhibitor of DAT, and many DAT inhibitors do not share the behavioral actions of cocaine. We previously showed that toxic levels of cocaine induce autophagic neuronal cell death. Here, we show that subnanomolar concentrations of cocaine elicit neural autophagy in vitro and in vivo. Autophagy inhibitors reduce the locomotor stimulant effect of cocaine in mice. Cocaine-induced autophagy degrades transporters for dopamine but not serotonin in the nucleus accumbens. Autophagy inhibition impairs cocaine conditioned place preference in mice. Our findings indicate that autophagic degradation of DAT modulates behavioral actions of cocaine.

Efficacy, Safety, and Tolerability of Ansofaxine (Ly03005) Extended-Release Tablet for Major Depressive Disorder: A Randomized, Double-Blind, Placebo Controlled, Dose-Finding, Phase 2 Clinical Trial

BACKGROUND Ansofaxine (LY03005) extended-release (ER) tablet is a potential triple reuptake inhibitor of serotonin, norepinephrine, and dopamine. This study assessed the efficacy, safety, and appropriate dosage of ansofaxine for the treatment of major depressive disorder (MDD). METHOD A multicenter, randomized, double-blind, placebo-controlled, dose-finding, Phase 2 clinical trial was conducted in China. Eligible patients with MDD (18-65 years) were randomly assigned to receive fixed-dose ansofaxine ER tablets (40, 80, 120, or 160 mg/day) or placebo for 6 weeks. The primary outcome measure was a change in the total score on the 17-item Hamilton Depression Rating Scale (HAMD17) from baseline to week 6. RESULT A total of 260 patients were recruited from October 2015 to September 2017. 255 patients received the study drug as the following: 40 mg (n = 52), 80 mg (n = 52), 120 mg (n = 51), and 160 mg (n = 51) ansofaxine and placebo (n = 49). Significant differences were found in mean changes in HAMD17 total scores at week 6 in the four ansofaxine groups vs. placebo (-12.46; χ 2 = -9.71, p = 0.0447). All doses of ansofaxine were generally well-tolerated. Treatment-related adverse events (TRAEs) occurred in 141 patients (303 cases), giving TRAEs incidence rates of 51.92%, 65.38%, 56.86%, and 62.75%in the 40, 80, 120, and 160 mg ansofaxine groups and 38.78% in the placebo group. CONCLUSION Active doses (40, 80, 120, and 160 mg per day) of ansofaxine in a controlled setting were safe, tolerated, and effective in improving depression symptoms in MDD patients.

Profile of Solriamfetol in the Management of Excessive Daytime Sleepiness Associated with Narcolepsy or Obstructive Sleep Apnea: Focus on Patient Selection and Perspectives.

Excessive sleepiness (ES) is a symptom of obstructive sleep apnea (OSA) and narcolepsy that has severe consequences. Wake-promoting drugs and stimulants are utilized as accessory treatment in OSA to reduce propensity to sleep but they do not improve sleep-disordered breathing. Solriamfetol is a first-line therapeutic agent to combat sleepiness in OSA and narcolepsy patients that is approved both by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). For excessively sleepy adult patients with OSA despite primary treatment or narcolepsy patients without cataplexy, solriamfetol may be used as initial therapy or as replacement therapy in patients who fail treatment or experience unacceptable side effects with modafinil, armodafinil, pitolisant, or stimulants. It can also be used as add-on therapy in OSA or narcolepsy patients when ES is only partially controlled with modafinil, armodafinil, pitolisant, sodium oxybate, or stimulants. Solriamfetol is a phenylalanine derivative whose wake-promoting action may be mediated through its selective dopamine and norepinephrine reuptake inhibition. This paper reviews the profile of solriamfetol in treating ES associated with OSA or narcolepsy and discusses patient selection and clinical perspectives. Mechanism of action, pharmacology, pharmacokinetics, clinical efficacy, and tolerability of solriamfetol are described. The Treatment of OSA and Narcolepsy Excessive Sleepiness (TONES) solriamfetol trials demonstrated the efficacy of solriamfetol in reducing propensity to sleep and maintaining wakefulness, with significant improvements in mean maintenance of wakefulness test (MWT) sleep latencies and significant reduction in Epworth Sleepiness Scale (ESS) scores compared to placebo. With solriamfetol, significantly higher percentages of patients showed improvement in patient’s and clinician’s global impression of change.

The Role of a Dopaminergic Component in the Analgesic Effect of the Low-Affinity NMDA Receptor Antagonist Hemantane

The role of dopaminergic transmission in the mechanism of analgesic action of the low-affinity NMDAreceptor antagonist hemantane [N-(2-adamantyl)hexamethyleneimine hydrochloride] was demonstrated experimentally. A single i.p. injection of hemantane at a dose of 20 mg/kg has the ability to inhibit dopamine reuptake and exhibits an analgesic effect in the somatic thermal pain model (tail-flick test) and visceral pain model (acetic-acid-induced writhing test) in ICR mice. The dopamine D1 receptor antagonist R(+)-SCH-23390 at a dose of 0.005 mg/kg and dopamine D2 receptor antagonist sulpiride at a dose of 5 mg/kg administered by a single i.p. injection 30 min before hemantane injection prevented manifestation of the antinociceptive activity of the NMDA receptor antagonist in the used methods, which was more pronounced for the spinal reflex (tail-flick test).

PRIAPISM AS A COMPLICATION OF PSYCHOPHARMACOTHERAPY

Priapism is a serious complication of psychopharmacotherapy, which can result in erectile dysfunction if there is no timely diagnosis and treatment. Purpose: to study cases of priapism in patients taking psychotropic drugs which were described in the literature. Articles were searched in the Medline database (1969-2020) in English by keywords – priapism and psychotropic drugs. 265 articles were found, most of which were devoted to the use of trazodone (81 articles) and resperidone (50) in patients with mental disorders with the development of priapism. There were cases of such complication associated with taking 12 antipsychotics (six – of the first generation and six – of the second; three – drugs of prolonged action) and 12 antidepressants (from the group of tricyclic, tetracyclic, selective serotonin and dopamine reuptake inhibitors, monoamine oxidase inhibitors, serotonin and norepinephrine reuptake antagonists/inhibitors, selective serotonin reuptake inhibitors), as well as four mood stabilizing agents. The prescribed doses of drugs varied widely. Often these medications were used in various combinations. Priapism most often occurred in the first days (month) of treatment with low doses of drugs. Cases of priapism against the background of psychopharmacotherapy are described not only in adults and elderly men, but also in children starting from the age of two, as well as in women who developed clitorism (female version of priapism). Although priapism is caused by many factors, caution should be exercised when adding other psychotropic drugs to treatment, when increasing their single (daily) dose, passing from the tablet to the injectable form, including appointment of depot drugs, and canceling treatment. Special attention should be paid to patients having episodes of prolonged erections and hematological pathology (hemoglobinopathies and thrombophilias) in their medical history. Priapism is a rare but dangerous complication that requires urgent urological care. This condition can develop when taking almost all psychotropic drugs that have serotoninergic, dopaminergic and alpha-adrenergic antagonistic properties.

Dopamine release, diffusion and uptake: A computational model for synaptic and volume transmission.

Computational modeling of dopamine transmission is challenged by complex underlying mechanisms. Here we present a new computational model that (I) simultaneously regards release, diffusion and uptake of dopamine, (II) considers multiple terminal release events and (III) comprises both synaptic and volume transmission by incorporating the geometry of the synaptic cleft. We were able to validate our model in that it simulates concentration values comparable to physiological values observed in empirical studies. Further, although synaptic dopamine diffuses into extra-synaptic space, our model reflects a very localized signal occurring on the synaptic level, i.e. synaptic dopamine release is negligibly recognized by neighboring synapses. Moreover, increasing evidence suggests that cognitive performance can be predicted by signal variability of neuroimaging data (e.g. BOLD). Signal variability in target areas of dopaminergic neurons (striatum, cortex) may arise from dopamine concentration variability. On that account we compared spatio-temporal variability in a simulation mimicking normal dopamine transmission in striatum to scenarios of enhanced dopamine release and dopamine uptake inhibition. We found different variability characteristics between the three settings, which may in part account for differences in empirical observations. From a clinical perspective, differences in striatal dopaminergic signaling contribute to differential learning and reward processing, with relevant implications for addictive- and compulsive-like behavior. Specifically, dopaminergic tone is assumed to impact on phasic dopamine and hence on the integration of reward-related signals. However, in humans DA tone is classically assessed using PET, which is an indirect measure of endogenous DA availability and suffers from temporal and spatial resolution issues. We discuss how this can lead to discrepancies with observations from other methods such as microdialysis and show how computational modeling can help to refine our understanding of DA transmission.

The effects of acute dopamine reuptake inhibition on cognitive function during passive hyperthermia.

Dopamine activity can modulate physical performance in the heat, but less is known about its effects on cognition during thermal stress. Twelves males completed a randomized, double-blinded protocol consisting of oral ingestion of 20 mg of methylphenidate (MPH) or placebo (lactose pill) during passive heating using a water-perfused suit (water temperature ∼49 °C). To identify the impact of peripheral versus central thermal strain, a cognitive test battery was completed at 4 different thermal states: baseline (BASE; 37.2 ± 0.6 °C core, 32.9 ± 0.7 °C skin), neutral core-hot skin (NC-HS; 37.2 ± 0.3 °C, 37.4 ± 0.3 °C), hyperthermic core-hot skin (HC-HS; 38.7 ± 0.4 °C, 38.7 ± 0.2 °C), and hyperthermic core-cooled skin (HC-CS; 38.5 ± 0.4 °C, 35.1 ± 0.8 °C). The cognitive test battery consisted of the 2-back task (i.e., working memory), set-shifting (i.e., executive function), Groton Maze Learning Task (i.e., executive function) and detection task (i.e., psychomotor processing). MPH led to significantly higher heart rates (∼5-15 b·min-1) at BASE, NC-HS, and HC-HS (all p < 0.05). There were no significant differences in the number of errors made on each task (all p < 0.05). Participants were significantly faster (p < 0.05) on the set-shifting task in the HC-HS timepoint, irrespective of drug condition (p > 0.05). In summary, we demonstrated that 20 mg of MPH did not significantly alter cognitive function during either normothermia or moderate hyperthermia. Novelty: Twenty milligrams of MPH did not significantly alter cognitive function during passive heat stress. MPH led to significant higher heart rates (∼5-15 b·min-1) in thermoneutral and during passive heat stress. Future studies are needed to determine the mechanisms of why MPH improves physical but not cognitive performance during heat stress.

Imaging synaptic dopamine availability in individuals at clinical high-risk for psychosis: a [11C]-(+)-PHNO PET with methylphenidate challenge study.

Patients at clinical high-risk (CHR) for psychosis show elevations in [18F]DOPA uptake, an estimate of dopamine (DA) synthesis capacity, in the striatum predictive of conversion to schizophrenia. Intrasynaptic DA levels can be inferred from imaging the change in radiotracer binding at D2 receptors due to a pharmacological challenge. Here, we used methylphenidate, a DA reuptake inhibitor, and [11C]-(+)-PHNO, to measure synaptic DA availability in CHR both in striatal and extra-striatal brain regions. Fourteen unmedicated, nonsubstance using CHR individuals and 14 matched control subjects participated in the study. Subjects underwent two [11C]-(+)-PHNO scans, one at baseline and one following administration of a single oral dose (60 mg) of methylphenidate. [11C]-(+)-PHNO BPND, the binding potential relative to the nondisplaceable compartment, was derived using the simplified reference tissue model with cerebellum as reference tissue. The percent change in BPND between scans, ΔBPND, was computed as an index of synaptic DA availability, and group comparisons were performed with a linear mixed model. An overall trend was found for greater synaptic DA availability (∆BPND) in CHR than controls (p = 0.06). This was driven entirely by ∆BPND in ventral striatum (-34 ± 14% in CHR, -20 ± 12% in HC; p = 0.023). There were no significant group differences in any other brain region. There were no significant differences in DA transmission in any striatal region between converters and nonconverters, although this finding is limited by the small sample size (N = 2). There was a strong and negative correlation between ΔBPND in VST and severity of negative symptoms at baseline in the CHR group (r = -0.66, p < 0.01). We show abnormally increased DA availability in the VST in CHR and an inverse relationship with negative symptoms. Our results suggest a potential early role for mesolimbic dopamine overactivity in CHR. Longitudinal studies are needed to ascertain the significance of the differential topography observed here with the [18F]DOPA literature.

Drug-induced dystonia

Drug-induced dystonia (DID) is a rarely diagnosed adverse reaction to a sufficiently large number of drugs. Acute DID (ADID) occurs soon after starting to take a drug or raising its dose, and switching from one antipsychotic medication to another, especially to its injectable dosage form. Tardive DID (TDID) develops a few months or years after starting drug intake or 3 months after stopping therapy. The diagnosis of TDID is based on the persistence of dystonic hyperkinesis for more than 1 month, the use of a dopamine receptor blocking agent, and the absence of other causes of its development. The risk factors for DID are male sex; young age (less than 30 years of age); a history of dystonic reactions; hypocalcemia, alcohol use while taking the drug. DID is most commonly related to therapy with antipsychotics, metoclopramide, antidepressants, and antiepileptic drugs. The short-term use of anticholinergic drugs (benzotropin, diphenhydramine) is effective in treating ADID. Anticholinergic drugs and atypical antipsychotics (clozapine, quetiapine), benzodiazepines, muscle relaxants (baclofen), and dopamine reuptake inhibitors (tetrabenazine) are used to treat TDID. To prevent DID, it is very important that a physician should be aware of that this unwanted adverse reaction may occur and that a drug with the lowest risk for DID should be chosen.

Cardiohemodynamic and Arrhythmogenic Effects of the Anti-Atrial Fibrillatory Compound Vanoxerine in Halothane-Anesthetized Dogs.

While vanoxerine (GBR-12909) is a synaptosomal dopamine uptake inhibitor, it also suppresses IKr, INa and ICa,L in vitro. Based on these profiles on ionic currents, vanoxerine has been developed as a candidate compound for treating atrial fibrillation. To investigate electropharmacological profiles, vanoxerine dihydrochloride was intravenously administered at 0.03 and 0.3 mg/kg to halothane-anesthetized dogs (n = 4), possibly providing subtherapeutic and therapeutic concentrations, respectively. The low dose increased the heart rate and cardiac output, whereas it prolonged the ventricular refractoriness. The high dose decreased the heart rate but increased the total peripheral vascular resistance, whereas it delayed the ventricular repolarization and increased the atrial refractoriness in addition to further enhancing the ventricular refractoriness. The extent of increase in the refractoriness in the atrium was 0.8 times of that in the ventricle. The high dose also prolonged the early and late repolarization periods of the ventricle as well as the terminal repolarization period. Meanwhile, no significant change was detected in the mean blood pressure, ventricular contraction, preload to the left ventricle, or the intra-atrial, intra-ventricular or atrioventricular conductions. The high dose can be considered to inhibit IKr, but it may not suppress INa or ICa in the in situ heart, partly explaining its poor atrial selectivity for increasing refractoriness. The prolongation of early repolarization period may reflect enhancement of net inward current, providing potential risk for intracellular Ca2+ overload. Thus, vanoxerine may provide both trigger and substrate toward torsade de pointes, which would make the drug less promising as an anti-atrial fibrillatory drug.

Acute and chronic bupropion treatment does not prevent morphine-induced conditioned place preference in mice

A substantial barrier to the treatment of Opioid Use Disorder (OUD) is the elevated relapse rates in affected patients, and a significant contributor to these events of relapse is exposure to cues and contexts that are intensely associated with prior drug abuse. The neurotransmitter dopamine plays a key role in reward-related behaviors, and previous studies have illustrated that dopamine hypofunction in periods of abstinence serves to prompt drug craving and seeking. We hypothesized that restoration of dopaminergic signaling could attenuate drug-seeking behaviors. Therefore, we investigated whether use of an FDA-approved drug, bupropion, an inhibitor of the dopamine transporter (DAT), or a dopamine uptake inhibitor with high affinity for DAT, JHW 007, was able to decrease preference for a drug-paired context. In these experiments, mice underwent 5 days of non-contingent morphine (10 mg/kg) exposure in a conditioned place preference (CPP) paradigm. We found that systemic injection of bupropion (20 mg/kg, i. p.) or intracranial injection of JHW 007 into the nucleus accumbens shell did not prevent the expression of morphine CPP. We then investigated whether chronic bupropion treatment (via implanted osmotic pumps) would influence morphine CPP. We observed that chronic bupropion treatment for 21 days following morphine conditioning did not attenuate the prolonged preference for morphine-paired contexts. Overall, with our dose and paradigm, neither acute nor chronic bupropion diminishes morphine CPP. Continued studies should address FDA-approved medications and their potential for recovery in OUD patients.

Effect of citicoline as adjuvant therapy in Parkinson disease: A systematic review

Introduction: Citicoline is a natural precursor of phospholipid synthesis. Its aids in cerebral metabolism and facilitating neuroplasticity. Particularly in Parkinson's disease, citicoline has been shown to increase dopamine synthesis and inhibit dopamine uptake.

Secondary and side effects of particular Selective Serotonin Reuptake Inhibitors (SSRIs) antidepressants - literature review

Serotonin reuptake inhibitors (SSRIs), along with serotonin norepinephrine reuptake inhibitors (SNRIs) and norepinephrine dopamine reuptake inhibitors (NDRIs), are the first-line drugs in the treatment of depression. Pharmacotherapy of psychiatric disorders with SSRIs is widely practised. Although SSRIs are thought to be relatively safe group of drugs, it is worth to remember that particular SSRIs agents are related to unique secondary and side effects. Knowledge about basic differences between each medication in this group is essential to choose suitable treatment for every patient.