Dopamine Reuptake Research Articles

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.

Excessive Daytime Sleepiness in Obstructive Sleep Apnea. Mechanisms and Clinical Management.

Many patients with obstructive sleep apnea (OSA) experience excessive daytime sleepiness (EDS), which can negatively affect daily functioning, cognition, mood, and other aspects of well-being. Although EDS can be reduced with primary OSA treatment, such as continuous positive airway pressure (CPAP) therapy, a significant proportion of patients continue to experience EDS despite receiving optimized therapy for OSA. This article reviews the pathophysiology and clinical evaluation and management of EDS in patients with OSA. The mechanisms underlying EDS in CPAP-treated patients remain unclear. Experimental risk factors include chronic intermittent hypoxia and sleep fragmentation, which lead to oxidative injury and changes in neurons and brain circuit connectedness involving noradrenergic and dopaminergic neurotransmission in wake-promoting regions of the brain. In addition, neuroimaging studies have shown alterations in the brain’s white matter and gray matter in patients with OSA and EDS. Clinical management of EDS begins with ruling out other potential causes of EDS and evaluating its severity. Tools to evaluate EDS include objective and self-reported assessments of sleepiness, as well as cognitive assessments. Patients who experience residual EDS despite primary OSA therapy may benefit from wake-promoting pharmacotherapy. Agents that inhibit reuptake of dopamine or of dopamine and norepinephrine (modafinil/armodafinil and solriamfetol, respectively) have demonstrated efficacy in reducing EDS and improving quality of life in patients with OSA. Additional research is needed on the effects of wake-promoting treatments on cognition in these patients and to identify individual or disorder-specific responses.

Effect of palmitoylation on the dimer formation of the human dopamine transporter

The human dopamine transporter (hDAT) is one in three members of the monoamine transporter family (MAT). hDAT is essential for regulating the dopamine concentration in the synaptic cleft through dopamine reuptake into the presynaptic neuron; thereby controlling hDAT dopamine signaling. Dysfunction of the transporter is linked to several psychiatric disorders. hDAT and the other MATs have been shown to form oligomers in the plasma membrane, but only limited data exists on which dimeric and higher order oligomeric states are accessible and energetically favorable. In this work, we present several probable dimer conformations using computational coarse-grained self-assembly simulations and assess the relative stability of the different dimer conformations using umbrella sampling replica exchange molecular dynamics. Overall, the dimer conformations primarily involve TM9 and/or TM11 and/or TM12 at the interface. Furthermore, we show that a palmitoyl group (palm) attached to hDAT on TM12 modifies the free energy of separation for interfaces involving TM12, suggesting that S-palmitoylation may change the relative abundance of dimers involving TM12 in a biological context. Finally, a comparison of the identified interfaces of hDAT and palmitoylated hDAT to the human serotonin transporter interfaces and the leucine transporter interface, suggests similar dimer conformations across these protein family.

A mathematical model of circadian rhythms and dopamine

BackgroundThe superchiasmatic nucleus (SCN) serves as the primary circadian (24hr) clock in mammals and is known to control important physiological functions such as the sleep-wake cycle, hormonal rhythms, and neurotransmitter regulation. Experimental results suggest that some of these functions reciprocally influence circadian rhythms, creating a highly complex network. Among the clock’s downstream products, orphan nuclear receptors REV-ERB and ROR are particularly interesting because they coordinately modulate the core clock circuitry. Recent experimental evidence shows that REV-ERB and ROR are not only crucial for lipid metabolism but are also involved in dopamine (DA) synthesis and degradation, which could have meaningful clinical implications for conditions such as Parkinson’s disease and mood disorders.MethodsWe create a mathematical model consisting of differential equations that express how the circadian variables are influenced by light, how REV-ERB and ROR feedback to the clock, and how REV-ERB, ROR, and BMAL1-CLOCK affect the dopaminergic system. The structure of the model is based on the findings of experimentalists.ResultsWe compare our model predictions to experimental data on clock components in different light-dark conditions and in the presence of genetic perturbations. Our model results are consistent with experimental results on REV-ERB and ROR and allow us to predict the circadian variations in tyrosine hydroxylase and monoamine oxidase seen in experiments. By connecting our model to an extant model of dopamine synthesis, release, and reuptake, we are able to predict circadian oscillations in extracellular DA and homovanillic acid that correspond well with experimental observations.ConclusionsThe predictions of the mathematical model are consistent with a wide variety of experimental observations. Our calculations show that the mechanisms proposed by experimentalists by which REV-ERB, ROR, and BMAL1-CLOCK influence the DA system are sufficient to explain the circadian oscillations observed in dopaminergic variables. Our mathematical model can be used for further investigations of the effects of the mammalian circadian clock on the dopaminergic system. The model can also be used to predict how perturbations in the circadian clock disrupt the dopaminergic system and could potentially be used to find drug targets that ameliorate these disruptions.

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.

Striatal Dopamine Induced ERK Phosphorylation Is Altered in Mouse Models of Monogenic Dystonia.

Similar to some monogenic forms of dystonia, levodopa-induced dyskinesia is a hyperkinetic movement disorder with abnormal nigrostriatal dopaminergic neurotransmission. Molecularly, it is characterized by hyper-induction of phosphorylation of extracellular signal-related kinase in response to dopamine in medium spiny neurons of the direct pathway. The objective of this study was to determine if mouse models of monogenic dystonia exhibit molecular features of levodopa-induced dyskinesia. Western blotting and quantitative immunofluorescence was used to assay baseline and/or dopamine-induced levels of the phosphorylated kinase in the striatum in mouse models of DYT1, DYT6, and DYT25 expressing a reporter in dopamine D1 receptor-expressing projection neurons. Cyclic adenosine monophosphate (cAMP) immunoassay and adenylyl cyclase activity assays were also performed. In DYT1 and DYT6 models, blocking dopamine reuptake with cocaine leads to enhanced extracellular signal-related kinase phosphorylation in dorsomedial striatal medium spiny neurons in the direct pathway, which is abolished by pretreatment with the N-methyl-d-aspartate antagonist MK-801. Phosphorylation is decreased in a model of DYT25. Levels of basal and stimulated cAMP and adenylyl cyclase activity were normal in the DYT1 and DYT6 mice and decreased in the DYT25 mice. Oxotremorine induced increased abnormal movements in the DYT1 knock-in mice. The increased dopamine induction of extracellular signal-related kinase phosphorylation in 2 genetic types of dystonia, similar to what occurs in levodopa-induced dyskinesia, and its decrease in a third, suggests that abnormal signal transduction in response to dopamine in the postsynaptic nigrostriatal pathway might be a point of convergence for dystonia and other hyperkinetic movement disorders, potentially offering common therapeutic targets. © 2021 International Parkinson and Movement Disorder Society.

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.

Potential Role of Dexamphetamine in the Treatment of Non-alcoholic Fatty Liver Disease: Hopes and Pitfalls.

Non-alcoholic fatty liver disease (NAFLD) is one of most frequent causes of chronic liver disease. Global prevalence of NAFLD and nonalcoholic steatohepatitis (NASH) with advanced fibrosis is increasing day by day. Patients with NAFLD are more susceptible to encounter cardiovascular morbidity and mortality. Apart from lifestyle changes and dietary modifications, no effective pharmacotherapy is available to prevent the progression of NAFLD to NASH and advanced stages of hepatic fibrosis and cirrhosis. Dexamphetamine is the d-isomer of amphetamine, which acts by inhibiting monoamine reuptake and direct stimulation of dopamine and noradrenaline release. Presently, dexamphetamine is indicated for the treatment of attention deficit hyperactivity disorder and narcolepsy, but since its use was found to be associated with weight loss, it is also now used as an off-label drug for the treatment of obesity. Direct or indirect evidence is present in the form case reports, case series and from effects of related drugs to support the potential role of dexamphetamine in NAFLD. There is an urgent need to initiate preclinical and clinical studies involving robust methodology and adequate sample sizes to explore the potential of dexamphetamine in patients with NAFLD. In this review, we will discuss the therapeutic potential of dexamphetamine for the treatment of NAFLD.

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.

It takes two—or more—to tango: Revisiting the role of dopamine transporter oligomerization

The dopamine transporter utilizes the transmembrane sodium gradient to mediate reuptake of dopamine from the extracellular space. The dopamine transporter can form dimers and possibly also higher order structures in the plasma membrane, and this oligomerization has been implicated in both trafficking and transport. However, we still do not fully understand its biological importance. A study by Sorkina et al. now describes a series of small molecules that link transporter conformation to oligomerization and endocytosis, providing an interesting step forward in an intricate dance.

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.

Infantile parkinsonism-dystonia, type 1 (case report)

Infantile parkinsonism-dystonia, type 1 (DTDS) (OMIM 613135) is a rare inherited autosomal recessive disease that manifests in infancy. The development of the disease is caused by a homozygous or compound-heterozygous mutation in theSLC6A3gene (OMIM 126455), which encodes a dopamine Transporter localized on the short arm of chromosome 5 (5p15). The main pathogenetic mechanism of the disease is the loss of the function of the main dopamine transporter at the presynaptic level, which leads to a decrease in the reuptake of dopamine in the synaptic cleft, depletion of presynaptic dopamine reserves, and an increase in the amount of extraneuronal dopamine. Currently, there are 20 cases of this disease in children in the world. The main clinical manifestations of DTDS are various hyperkinesis patterns (dystonia, chorea, athetosis, etc.), followed by hypokinesia and rigidity, developing against the background of axial hypotension. Difficulties in differential diagnosis lead to the fact that many patients are observed for years with erroneous clinical diagnoses, including cerebral palsy, regularly receiving rehabilitation treatment without clinical effect. The mentioned above explains the need for clinicians to be aware of a rare disease DTDS, which will avoid diagnostic errors, prescribe adequate therapy promptly, and thereby significantly improve the quality of life of patients and their families. The article contains an overview of the etiological, pathogenetic, epidemiological, diagnostic, and therapeutic aspects of DTDS. For the first time in Russia, there is reported a clinical case of this rare disease, which presents the own experience with DTDS patient.

A case study on escitalopram induced QTc prolongation and adverse drug reaction

Antagonistic medication response (ADR) can be characterized as any toxic change which is suspected to be because of a medication, happens at dosages ordinarily utilized in man, requires treatment or decline in portion or shows alert later on the utilization of similar medication. Escitalopram is a medication which goes under the classification of particular serotonin reuptake inhibitors (SSRIs) (antidepressants). It is the S-enantiomer of the racemic subsidiary of citalopram, which specifically restrains the reuptake of serotonin with practically no impact on norepinephrine or dopamine reuptake. Practically all the antidepressants and antipsychotics have been connected to QT prolongation. In a patient with previously diagnosed congenital QTS, we present a drug-induced QT extension owing to the escitalopram overdose. A 15-year-old Caucasian woman was presented with an escalopram overdose after a suicide attempt. The patient has a lengthy QT period of torsade de point incidents. The patient was received and monitored in the telemetry facility. She proceeded to exhibit the persistently extended QT period after the resolution of torsades de punes. She was diagnosed with a congenital QT condition by the cardiology clinic. In this situation, an escitalopram overdose is seen to trigger an immediate QT extension for a patient who has congenital LQTS and the value of an electrocardiogram before SSRIs are started, particularly for those at high risk of QT prolongation.

The Ketamine Antidepressant Story: New Insights.

Ketamine is a versatile agent primarily utilized as a dissociative anesthetic, which acts by blocking the excitatory receptor N-methyl-d-aspartate receptor (NMDA). It functions to inhibit the current of both Na+ and K+ voltage-gated channels, thus preventing serotonin and dopamine reuptake. Studies have indicated that administering a single subanesthetic dose of ketamine relieves depression rapidly and that the effect is sustained. For decades antidepressant agents were based on the monoamine theory. Although ketamine may not be the golden antidepressant, it has opened new avenues toward mechanisms involved in the pathology of treatment-resistant depression and achieving rapid antidepressant effects. Thus, preclinical studies focusing on deciphering the molecular mechanisms involved in the antidepressant action of ketamine will assist in the development of a new antidepressant. This review was conducted to elucidate the emerging pathways that can explain the complex dose-dependent mechanisms achieved by administering ketamine to treat major depressive disorders. Special attention was paid to reviewing the literature on hydroxynorketamines, which are ketamine metabolites that have recently attracted attention in the context of depression.

Effect of fasting on dopamine neurotransmission in subregions of the nucleus accumbens in male and female mice

ABSTRACT Diets high in saturated fat (HFD) disrupt dopamine neurotransmission, whereas fasting alters tonic and phasic dopamine release to drive motivation and food consumption. However, functional compartments in the nucleus accumbens (NAc) influencing these effects are not well characterized, and sex comparisons have not been made. This study sought to determine whether consumption of a HFD, sex, or being fed versus fasted altered baseline dopamine release and reuptake throughout NAc subregions. Male and female C57BL/6 mice were fed a control diet or nutrient matched HFD for six weeks. Ex-vivo fast-scan cyclic voltammetry revealed females had significantly slower dopamine reuptake in the NAc core than males when fed ad lib control diet. Fasting enhanced dopamine release and reuptake in the NAc core but not the medioventral shell. Further, being fasted versus fed significantly increased dopamine release throughout the NAc core in control males but specifically promoted release and reuptake in only the ventrolateral core of HF-fed males, effects which were lacking in females. Finally, fasting promoted dopamine release and reuptake in the rostral NAc core of controls and more caudally in HFD groups. These data support that dopamine neurotransmission is heterogeneous in NAc subregions and suggest the ventrolateral core is responsive to energy state. Furthermore, a rostrocaudal gradient in the NAc core might control valence responses to fasting that could promote overeating after chronic HFD consumption.

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.

(Invited) Near Infrared Nanosensors to Image Brain Neurochemistry

Neurons communicate through chemical neurotransmitter signals that either terminate at the postsynaptic process (“wired transmission”) or diffuse beyond the synaptic cleft to modulate the activity of larger neuronal networks (“volume transmission”). Molecules such as dopamine belong to the latter class of neurotransmitters, and have been the pharmacological targets of antidepressants and antipsychotics for decades. Owing to the central role of dopamine over a range of behaviors and psychiatric disorders, real-time imaging of the signal’s spatial propagation would constitute a valuable advance in neurochemical imaging. To this end, we present a nanoscale near-infrared fluorescent nanosensor for dopamine and demonstrate its efficacy for imaging dopamine volume transmission in the extracellular space of the brain striatum and prefrontal cortex (Beyene et al. ACS Chem. Neuro. 2017). The sensor is developed from polymers pinned to the surface of single wall carbon nanotubes (SWNT) in which the surface-adsorbed polymer is the recognition moiety and the carbon nanotube the fluorescence transduction element. Excitonic transitions in functionalized SWNT yield up to ΔF/F = 4500% near-infrared fluorescence emission in the presence of dopamine (Beyene et al. Nano Letters 2018). We next demonstrate imaging of evoked dopamine release in acute striatal slices, and show altered dopamine reuptake kinetics when brain tissue is exposed to dopamine receptor agonist and antagonist drugs (Beyene et al. Science Advances 2019). Lastly, we discuss how to evolve synthetic molecular recognition for other neuromodulators of interest, such as serotonin (Jeong et al. Science Advances 2019). We characterize our findings in the context of their utility for high spatial and temporal neuromodulator imaging in the brain, describe nanosensor exciton behavior from a molecular dynamics (MD) perspective, and validate nanosensor for use to elucidate dopaminergic signaling variability with disease or pharmacological perturbations at a synaptic scale.

Feeding status alters exploratory and anxiety-like behaviors in zebrafish larvae exposed to quinpirole

The dysfunction of dopaminergic signaling is associated with several neurological disorders. The use of pharmacological agents that interact with this signaling system may be employed to understand mechanisms underlying such disorders. Nutritional status can impact dopamine reuptake, receptor affinity, transporter activity, and the effects of drugs that bind to dopamine receptors or interact with dopaminergic system. Here we evaluated the effects of quinpirole (a dopamine D2/D3 receptor agonist) exposure on fed and non-fed zebrafish larvae. Zebrafish larvae (6 days post-fertilization, dpf) were exposed to quinpirole (5.5, 16.7, and 50.0 μM) or water (control group) for one hour. To evaluate the effect of feeding status on quinpirole exposure, the experiments were performed on fed and non-fed animals, a between subject experimental design. Both fed and non-fed quinpirole treated larvae exhibited increased erratic movements compared to controls in an open tank exploration task. No alterations were observed on the main parameters of exploratory behavior and swim activity for non-fed larvae treated with quinpirole compared to controls. However, fed animals exposed to quinpirole exhibited increased locomotor activity, anxiety-like behavior, and repetitive circular movements when compared to controls and non-fed exposed animals. In addition, we observed quinpirole exposure to have no effects on morphological parameters and heartbeat, but to impair optomotor responses in both fed and non-fed larvae compared to control. We also found quinpirole effects to interact with feeding status, as quinpirole-treated fed larvae improved while quinpirole treated non-fed larvae impaired their avoidance reaction towards an aversive stimulus. These results indicate that the behavioral effects of quinpirole exposure depended upon feeding status. They showed that consumption of food, a naturally rewarding stimulus known to engage the dopaminergic system, made this neurotransmitter system more susceptible to quinpirole's effects.

Ansofaxine Hydrochloride

Ansofaxine hydrochloride (LY03005; LPM570065) is a triple reuptake inhibitor that inhibits serotonin, dopamine and norepinephrine reuptake. This novel triple reuptake inhibitor is a carboxylic acid ester prodrug of desvenlafaxine. It is currently under development for the treatment of major depressive disorder - a frequent and heterogeneous disorder induced by a complex pattern of genetic, epigenetic, developmental, and environmental factors.