Dopamine Reuptake Research Articles

Fluoxetine Potentiates Oral Methylphenidate-Induced Gene Regulation in the Rat Striatum.

Methylphenidate (MP) is combined with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (FLX) to treat various disorders. MP, a dopamine reuptake inhibitor, helps manage attention-deficit hyperactivity disorder (ADHD) and is abused as a cognitive enhancer; it has a reduced addiction liability. We showed that combining FLX (serotonin) with MP potentiates MP-induced gene regulation in the striatum. These studies used intraperitoneal drug administration, which is relevant for MP abuse. Clinically, MP and FLX are taken orally (slower bioavailability). Here, we investigated whether chronic oral administration of MP and FLX also altered striatal gene regulation. MP (30/60mg/kg/day), FLX (20mg/kg/day), and MP + FLX were administered in rats' drinking water for 8h/day over 4weeks. We assessed the expression of dynorphin and substance P (both markers for striatal direct pathway neurons) and enkephalin (indirect pathway) by in situ hybridization histochemistry. Chronic oral MP alone produced a tendency for increased dynorphin and substance P expression and no changes in enkephalin expression. Oral FLX alone did not increase gene expression. In contrast, when given together, FLX greatly enhanced MP-induced expression of dynorphin and substance P and to a lesser degree enkephalin. Thus, FLX potentiated oral MP-induced gene regulation predominantly in direct pathway neurons, mimicking cocaine effects. The three functional domains of the striatum were differentially affected. MP + SSRI concomitant therapies are indicated in ADHD/depression comorbidity and co-exposure occurs with MP misuse as a cognitive enhancer by patients on SSRIs. Our findings indicate that MP + SSRI combinations, even given orally, may enhance addiction-related gene regulation.

Aiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications.

Exogenous administration of inflammatory stimuli to humans and laboratory animals and chronic endogenous inflammatory states lead to motivational deficits and ultimately anhedonia, a core and disabling symptom of depression present in multiple other psychiatric disorders. Inflammation impacts neurotransmitter systems and neurocircuits in subcortical brain regions including the ventral striatum, which serves as an integration point for reward processing and motivational decision-making. Many mechanisms contribute to these effects of inflammation, including decreased synthesis, release and reuptake of dopamine, increased synaptic and extrasynaptic glutamate, and activation of kynurenine pathway metabolites including quinolinic acid. Neuroimaging data indicate that these inflammation-induced neurotransmitter effects manifest as decreased activation of ventral striatum and decreased functional connectivity in reward circuitry involving ventral striatum and ventromedial prefrontal cortex. Neurocircuitry changes in turn mediate nuanced effects on motivation that include decreased willingness to expend effort for reward while maintaining the ability to experience reward. Taken together, the data reveal an inflammation-induced pathophysiologic phenotype that is agnostic to diagnosis. Given the many mechanisms involved, this phenotype represents an opportunity for development of novel and/or repurposed pharmacological strategies that target inflammation and associated cellular and systemic immunometabolic changes and their downstream effects on the brain. To date, clinical trials have failed to capitalize on the unique nature of this transdiagnostic phenotype, leaving the field bereft of interpretable data for meaningful clinical application. However, novel trial designs incorporating established targets in the brain and/or periphery using relevant outcome variables (e.g., anhedonia) are the future of targeted therapy in psychiatry. SIGNIFICANCE STATEMENT: Emerging understanding of mechanisms by which peripheral inflammation can affect the brain and behavior has created unprecedented opportunities for development of pharmacological strategies to treat deficits in motivation including anhedonia, a core and disabling symptom of depression well represented in multiple psychiatric disorders. Mechanisms include inflammation and cellular and systemic immunometabolism and alterations in dopamine, glutamate, and kynurenine metabolites, revealing a target-rich environment that nevertheless has yet to be fully exploited by current clinical trial designs and drugs employed.

Obesity and dietary fat influence dopamine neurotransmission: exploring the convergence of metabolic state, physiological stress, and inflammation on dopaminergic control of food intake

The aim of this review is to explore how metabolic changes induced by diets high in saturated fat (HFD) affect nucleus accumbens (NAc) dopamine neurotransmission and food intake, and to explore how stress and inflammation influence this process. Recent evidence linked diet-induced obesity and HFD with reduced dopamine release and reuptake. Altered dopamine neurotransmission could disrupt satiety circuits between NAc dopamine terminals and projections to the hypothalamus. The NAc directs learning and motivated behaviours based on homeostatic needs and psychological states. Therefore, impaired dopaminergic responses to palatable food could contribute to weight gain by disrupting responses to food cues or stress, which impacts type and quantity of food consumed. Specifically, saturated fat promotes neuronal resistance to anorectic hormones and activation of immune cells that release proinflammatory cytokines. Insulin has been shown to regulate dopamine neurotransmission by enhancing satiety, but less is known about effects of diet-induced stress. Therefore, changes to dopamine signalling due to HFD warrant further examination to characterise crosstalk of cytokines with endocrine and neurotransmitter signals. A HFD promotes a proinflammatory environment that may disrupt neuronal endocrine function and dopamine signalling that could be exacerbated by the hypothalamic-pituitary-adrenal and κ-opioid receptor stress systems. Together, these adaptive changes may dysregulate eating by changing NAc dopamine during hedonic versus homeostatic food intake. This could drive palatable food cravings during energy restriction and hinder weight loss. Understanding links between HFD and dopamine neurotransmission will inform treatment strategies for diet-induced obesity and identify molecular candidates for targeted therapeutics.

Effect of Methylphenidate on Resting-State Connectivity in Adolescents With a Disruptive Behavior Disorder: A Double-Blind Randomized Placebo-Controlled fMRI Study

Some studies suggest that methylphenidate (MPH) might be an effective treatment for antisocial and aggressive behavior in adolescence. However, little is known about the mechanism of action of MPH in adolescents with this kind of psychopathology. MPH is a dopamine and norepinephrine reuptake inhibitor and thus it is likely to affect dopaminergic mesocorticolimbic pathways. This is the first study to investigate the effect of MPH on resting-state connectivity of three mesolimbic seed regions with the rest of the brain in clinical referred male adolescents with a disruptive behavior disorder (DBD). Thirty-six male DBD adolescents and 31 male healthy controls (HCs) were included. DBD subjects were randomly allocated to a single dose of MPH (DBD-MPH, n = 20) or placebo (DBD-PCB, n = 16). Seed-based resting-state functional connectivity of the nucleus accumbens (NAcc), amygdala, and ventral tegmental area (VTA) with the rest of the brain was compared between groups. The NAcc seed showed increased connectivity in DBD-PCB compared to HC with the occipital cortex, posterior cingulate cortex (PCC), precuneus, and inferior parietal lobule (IPL) and increased connectivity in DBD-PCB compared to DBD-MPH with occipital cortex, IPL, and medial frontal gyrus. The amygdala seed showed increased connectivity in DBD-PCB compared to HC with the precuneus and PCC. The VTA seed showed increased connectivity in the DBD-MPH compared to the DBD-PCB group with a cluster in the postcentral gyrus and a cluster in the supplementary motor cortex/superior frontal gyrus. Both NAcc and amygdala seeds showed no connectivity differences in the DBD-MPH compared to the HC group, indicating that MPH normalizes the increased functional connectivity of mesolimbic seed regions with areas involved in moral decision making, visual processing, and attention.

Glutathione Deficiency during Early Postnatal Development Causes Schizophrenia-Like Symptoms and a Reduction in BDNF Levels in the Cortex and Hippocampus of Adult Sprague-Dawley Rats.

Growing body of evidence points to dysregulation of redox status in the brain as an important factor in the pathogenesis of schizophrenia. The aim of our study was to evaluate the effects of l-buthionine-(S,R)-sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, and 1-[2-Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909), a dopamine reuptake inhibitor, given alone or in combination, to Sprague–Dawley pups during early postnatal development (p5–p16), on the time course of the onset of schizophrenia-like behaviors, and on the expression of brain-derived neurotrophic factor (BDNF) mRNA and its protein in the prefrontal cortex (PFC) and hippocampus (HIP) during adulthood. BSO administered alone decreased the levels of BDNF mRNA and its protein both in the PFC and HIP. Treatment with the combination of BSO + GBR 12909 also decreased BDNF mRNA and its protein in the PFC, but in the HIP, only the level of BDNF protein was decreased. Schizophrenia-like behaviors in rats were assessed at three time points of adolescence (p30, p42–p44, p60–p62) and in early adulthood (p90–p92) using the social interaction test, novel object recognition test, and open field test. Social and cognitive deficits first appeared in the middle adolescence stage and continued to occur into adulthood, both in rats treated with BSO alone or with the BSO + GBR 12909 combination. Behavior corresponding to positive symptoms in humans occurred in the middle adolescence period, only in rats treated with BSO + GBR 12909. Only in the latter group, amphetamine exacerbated the existing positive symptoms in adulthood. Our data show that rats receiving the BSO + GBR 12909 combination in the early postnatal life reproduced virtually all symptoms observed in patients with schizophrenia and, therefore, can be considered a valuable neurodevelopmental model of this disease.

(Nanocarbons Division SES Young Investigator Award) Nanomaterials Engineering to Probe and Control Living Systems

Unique physical, chemical, and optical phenomena arise when materials are confined to the nano-scale. We are accustomed to making observations and predictions for the behavior of living systems on a macroscopic scale that is intuitive for the time and size scales of our day-to-day lives. However, the building blocks of life: proteins, nucleic acids, and cells, occupy different spatiotemporal scales. Our lab focuses on understanding and exploiting tunable optical and mechanical properties of nanomaterials to access information about biological systems stored at the nano-scale. In the context of leveraging nanomaterial optical properties, we present recent work on developing and implementing dopamine nanosensors to image dopamine volume transmission in the extracellular space of the brain striatum. We validate our dopamine nanosensor in acute striatal slices with electrical and optogenetic stimulation of dopamine release, and show disrupted dopamine release or reuptake kinetics when brain tissue is exposed to dopamine agonist or antagonist drugs [1,2]. In the context of leveraging nanomaterial chemical properties, we also discuss how high aspect ratio nanomaterials can be synthesized to carry biomolecular cargo to living systems. In particular, genetic engineering of plants is at the core of environmental sustainability efforts, but the physical barrier presented by the cell wall has limited the ease and throughput with which exogenous biomolecules can be delivered to plants. We will describe how nanomaterials engineering principles can be leveraged to manipulate living plants [3, 4], in efforts to reconcile the benefits of crop genetic engineering with the demand for non-GMO foods [5]. Our work in the agricultural space provides a promising tool for species-independent, targeted, and passive delivery of genetic material, without transgene integration, into plant cells for rapid and parallelizable testing of plant genotype-phenotype relationships.1. Beyene, A.B., McFarlane, I.R., Pinals, R.L, Landry, M.P.‡ Stochastic Simulation of Dopamine Neuromodulation for Implementation of Fluorescent Neurochemical Probes in the Striatal Extracellular Space. ACS Chemical Neuroscience 8 (10), 2275-2289 (2017).2. Beyene, A. G., Delevich, K., O’Donnell, J.T.D., Piekarski, D.J., Lin, W.C., Thomas, A.W., Yang, S.J., Kosillo, P., Yang, D., Wilbrecht, L., Landry, M.P.‡ Imaging Striatal Dopamine Release Using a Non-Genetically Encoded Near-Infrared Fluorescent Catecholamine Nanosensor. Science Advances 5 (7), 1-11 (2019)3. Demirer, G.S., Zhang, H., Matos, J., Goh, N., Cunningham, F.J., Sung, Y., Chang, R., Aditham, A.J., , Chio, L., Cho, M.J., Staskawicz, B., Landry, M.P.‡ High Aspect Ratio Nanomaterials Enable Delivery of Functional Genetic Material Without DNA Integration in Mature Plants. Nature Nanotechnology (2019). DOI: 10.1038/s41565-019-0382-5NNANO-180816844. Demirer, G.S., Zhang, H., Goh, N.S., Grandio, E.G., Landry, M.P.‡ Carbon nanotube-mediated DNA delivery without transgene integration in intact plants. Nature Protocols (2019). DOI: 0.1038/s41596-019-0208-95. Landry, M.P.‡, Mitter, N.‡ How nanocarriers delivering cargoes in plants can change the GMO landscape. Nature Nanotechnology 2019, 14; 512–514

New generation antidepressants for depression in children and adolescents: a network meta-analysis.

New generation antidepressants for depression in children and adolescents: a network meta-analysis.

Differential Influence of Amyloid-β on the Kinetics of Dopamine Release in the Dorsal and Ventral Striatum of Rats.

Dopaminergic dysfunction is a part of Alzheimer's disease pathology. The brain accumulation of amyloid-β of toxic form is a key link of the pathology, which, according to the literature, is also true for dopaminergic dysfunction. An increase in the amyloid-β level in the brain changes the maximum of the evoked dopamine release in the dorsal and ventralparts of the striatum of the experimental animals. Theoretically, this may be due to the change in the intensity of dopamine release from the nerve terminals or its reuptake. However, it has not been studied. To fill this gap, we examined the amyloid-β induced changes in the kinetics of the evoked dopamine release in the dorsal striatum and the nucleus accumbens core and shell. Amyloid-β solution (fragments 25-35) was injected into the ventricular system of the anesthetized male Wistar rats. Before and after injection, electrically evoked dopamine kinetics was registered with fast-scan cyclic voltammetry. The results had shown that the amount of dopamine release decreases in the dorsal striatum and increases in the nucleus accumbens shell. No changes were found in the intensity of dopamine reuptake.

Role of enteric dopaminergic neurons in regulating peristalsis of rat proximal colon.

Constipation is commonly seen in patients with Parkinson's disease associated with a loss of dopaminergic neurons in both central and enteric nervous systems. However, the roles of enteric dopaminergic neurons in developing constipation remain to be elucidated. Here, we investigated the roles of enteric dopaminergic neurons in the generation of colonic peristalsis. Cannulated segments of rat proximal colon were situated in the organ bath, abluminally perfused with physiological salt solution and luminally perfused with 0.9% saline. Drugs were applied in the abluminal solution. Changes in diameter along the length of the colonic segment were captured by a video camera and transformed into spatio-temporal maps. Fluorescence immunohistochemistry was also carried out. Blockade of nitrergic neurotransmission prevented oro-aboral propagation of peristaltic waves and caused a colonic constriction without affecting ripples, non-propagating myogenic contractions. Blockade of cholinergic neurotransmission also prevented peristaltic waves but suppressed ripples with a colonic dilatation. Tetrodotoxin (0.6μM) abolished peristaltic waves and increased ripples with a constriction. SCH 23390 (20μM), a D1 -like dopamine receptor antagonist, slowed the peristaltic waves and caused a constriction, while GBR 12909 (1μM), a dopamine reuptake inhibitor, diminished the peristaltic waves with a dilatation. Bath-applied dopamine (3μM) abolished the peristaltic waves associated with a colonic dilation in an SCH 23390 (5μM)-sensitive manner. D1 receptor immunoreactivity was co-localized to nitrergic and cholinergic neurons. Dopaminergic neurons appear to facilitate nitrergic neurons via D1 -like receptors to stabilize asynchronous contractile activity resulting in the generation of colonic peristalsis.

Effects of preoperative intravenous amantadine sulfate infusion on wake up test duration and postoperative opioid consumption in adolescents undergoing spine corrective surgery

BackgroundAmantadine sulfate is both a dopamine agonist and N-methyle-D-Aspartate (NMDA) antagonist which can augment the levels of dopamine in the striate body by triggering dopamine release and inhibiting dopamine reuptake. This study evaluated the effects of amantadine sulfate as a dopamine agonist on intraoperative wake up test duration and as a NMDA antagonist on cumulative opioid consumption 48 h after surgery. MethodsA randomized controlled double blind study, where 60 ASA class I and/or II patients of both sexes, planned for spine deformity corrective surgery were enrolled and divided into two groups (30 patients each): Group A received intravenous (IV) amantadine sulfate infusion (200 mg), and Group B received Ringer's lactate IV infusion. ResultsForty-eight hours after surgery, morphine consumption in group A was significantly lower than that in Group B (21.24 ± 1.1 vs. 30.41 ± 2.12 P < 0.001). Dynamic visual analog scale score was lower group A than that in group B (0.8 ± 0.71 vs. 2.7 ± 0.84 P < 0.001). Moreover, anesthetic consumption in group A was lower than that in group B; however, no statistical difference in wake-up test duration or recovery time from anesthesia was found between both groups. ConclusionsPreoperative administration of amantadine sulfate decreases postoperative morphine consumption and dynamic VAS score in patients undergoing corrective spine surgery. However, despite being a dopamine agonist, amantadine has no effect on wake- up test duration.

Clinical Outcome and Striatal Dopaminergic Function After Shunt Surgery in Patients With Idiopathic Normal Pressure Hydrocephalus.

To determine changes in clinical features and striatal dopamine reuptake transporter (DAT) density after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). Participants with probable iNPH were assessed at baseline by means of clinical rating scales, brain MRI, and SPECT with [123I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (FP-CIT). Levodopa responsiveness was also evaluated. Patients who did or did not undergo lumboperitoneal shunt were clinically followed up and repeated SPECT after 2 years. We enrolled 115 patients with iNPH. Of 102 patients without significant levodopa response and no signs of atypical parkinsonism, 92 underwent FP-CIT SPECT (58 also at follow-up) and 59 underwent surgery. We identified a disequilibrium subtype (phenotype 1) and a locomotor subtype (phenotype 2) of higher-level gait disorder. Gait impairment correlated with caudate DAT density in both phenotypes, whereas parkinsonian signs correlated with putamen and caudate DAT binding in patients with phenotype 2, who showed more severe symptoms and lower striatal DAT density. Gait and caudate DAT binding improved in both phenotypes after surgery (p < 0.01). Parkinsonism and putamen DAT density improved in shunted patients with phenotype 2 (p < 0.001). Conversely, gait, parkinsonian signs, and striatal DAT binding worsened in patients who declined surgery (p < 0.01). This prospective interventional study highlights the pathophysiologic relevance of striatal dopaminergic dysfunction in the motor phenotypic expression of iNPH. Absence of levodopa responsiveness, shunt-responsive parkinsonism, and postsurgery improvement of striatal DAT density are findings that corroborate the notion of a reversible striatal dysfunction in a subset of patients with iNPH.

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.

Pathophysiological Mechanisms and Experimental Pharmacotherapy for L-Dopa-Induced Dyskinesia.

L-dopa-induced dyskinesia (LID) is the most frequent motor complication associated with chronic L-dopa treatment in Parkinson’s disease (PD). Recent advances in the understanding of the pathophysiological mechanisms underlying LID suggest that abnormalities in multiple neurotransmitter systems, in addition to dopaminergic nigrostriatal denervation and altered dopamine release and reuptake dynamics at the synaptic level, are involved in LID development. Increased knowledge of neurobiological LID substrates has led to the development of several drug candidates to alleviate this motor complication. However, with the exception of amantadine, none of the pharmacological therapies tested in humans have demonstrated clinically relevant beneficial effects. Therefore, LID management is still one of the most challenging problems in the treatment of PD patients. In this review, we first describe the known pathophysiological mechanisms of LID. We then provide an updated report of experimental pharmacotherapies tested in clinical trials of PD patients and drugs currently under study to alleviate LID. Finally, we discuss available pharmacological LID treatment approaches and offer our opinion of possible issues to be clarified and future therapeutic strategies.

Cocaine bugs: A brief case report of cocaine-induced delusion of parasitosis

IntroductionDelusional parasitosis (DP), also know as Ekbom syndrome and in some cases as Morgellons, was first described in the late 17th century in France. It is an obsessive phobic state in which the patient believes that the is infested by parasites. In the hallucinatory state, they frequently remove parts of the skin, identifying them as parasites. The cause of DP is unknown. Evidence supporting the dopamine theory defend that the inhibition of dopamine reuptake (for example cocaine and amphetamines) induce symptoms such as formication.ObjectivesThrough the description of the following clinical case, we emphasize its clinical features and complexities.MethodsReview of DP in light of a clinical caseResultsA 48-year-old woman was brought to the psychiatric emergency due to psychotic symptoms following cocaine use. She had a history of drug abuse. She was apparently asymptomatic until October 2019, when, in the background of vague sensation of something crawling under his skin, she developed a sudden onset belief that she had been infested by insects that crawled under his skin. Previous medical observation found no reason for a skin infection or infestation. Skin examination revealed itch marks and skin excoriations in the abdomen. Mental status examination revealed anxious and depressive affect, delusion of parasitosis, tactile hallucination and impaired insight. Routine hemogram and urinalysis was unremarkable, except for the detection of cocaine.ConclusionsDelusional parasitosis often presents to nonpsychiatric medical professionals. An awareness of such ilness, with an early recognition and timely referral are management cornerstones in order to successfully diagnose and treat patients.DisclosureNo significant relationships.

A new player in the field: Methylphenidate in post-traumatic stress disorder treatment

IntroductionCurrently available psychotherapies and psychotropic drugs for post-traumatic stress disorder (PTSD) are poorly effective in a substantial proportion of patients. Dopaminergic dysfunction plays a prominent role in the pathophysiology of PTSD: intrusions, avoidance symptoms, anhedonia and emotional numbing. Dopamine reuptake inhibitors can be studied as novel drugs in PTSD treatment.ObjectivesExplore methylphenidate as a promising drug in PTSD treatment.MethodsCase report presentation based on the review of clinical notes and non-systematic review of the PTSD therapeutics state-of-the-art.ResultsA 72-year-old Portuguese male, a veteran of the Angolan War, sought medical attention four years ago after the death of his brother, which had happened three years before the consultation. The clinical picture consisted of re-experiencing the war and the loss of his brother, flash-backs, nightmares, irritability, a fear of losing control, inner dialogues with occasional intra-psychic voices, emotional numbing with the impossibility of developing loving relationships with his relatives, feelings of unreality, an episode of dissociative fugue and complaints of episodic forgetfulness and time warp. He was diagnosed with PTSD with dissociative symptoms, based on DSM 5 clinical criteria. He was initially treated with SNRIs and risperidone, with little improvement. A year ago, he suffered a flare-up, with suicidal ideation. He was prescribed methylphenidate 36 mg, with progressive improvement, persisting mild PTSD residual symptoms.ConclusionsThere is enough evidence of the dopamine involvement in PTSD, although research on dopaminergic drugs is scarce. Methylphenidate may be promising in the treatment of at least some individuals that haven’t responded to current psychological and medical interventions.

Sustained Release GLP-1 Agonist PT320 Delays Disease Progression in a Mouse Model of Parkinson's Disease.

GLP-1 agonists have become increasingly interesting as a new Parkinson's disease (PD) clinical treatment strategy. Additional preclinical studies are important to validate this approach and define the disease stage when they are most effective. We hence characterized the efficacy of PT320, a sustained release formulation of the long acting GLP-1 agonist, exenatide, in a progressive PD (MitoPark) mouse model. A clinically translatable biweekly PT320 dose was administered starting at 5 weeks of age and longitudinally evaluated to 24 weeks, and multiple behavioral/cellular parameters were measured. PT320 significantly improved spontaneous locomotor activity and rearing in MitoPark PD mice. "Motivated" behavior also improved, evaluated by accelerating rotarod performance. Behavioral improvement was correlated with enhanced cellular and molecular indices of dopamine (DA) midbrain function. Fast scan cyclic voltammetry demonstrated protection of striatal and nucleus accumbens DA release and reuptake in PT320 treated MitoPark mice. Positron emission tomography showed protection of striatal DA fibers and tyrosine hydroxylase protein expression was augmented by PT320 administration. Early PT320 treatment may hence provide an important neuroprotective therapeutic strategy in PD.

Amantadine Might be Used as a Drug for SARS-Cov-2 Treatment?

Coronavirus Disease 2019 (COVID-19) infection, the pandemics, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has no known effective radical pharmacotherapy and just supportive approach at present. Amantadine is a drug used in Parkinson’s disease and other parkinsonisms; and is known to increase indirectly dopamine by antagonistic effects at the N-methyl-Daspartate (NMDA) receptor by increasing the release and blocking the reuptake of dopamine. Initially, amantadine was approved as an antiviral drug. We hypothesize that if amantadine is considered its antiviral, immunological and neurostimulant effects might be useful in the supportive treatment of SARSCoV- 2 cases, especially those who developed acute respiratory failure with decreased vigilance and are being monitored in the intensive care unit. Further phase III clinical trials are needed.

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.

Anticholinergic symptoms in a patient with a bupropion overdose successfully managed with physostigmine: a case report

We report the case of anticholinergic poisoning in a patient suffering from an overdose of bupropion. The patient presented with bilateral mydriasis, involuntary movements and signs of agitation. Bupropion is commonly used as antidepressant and smoking cessation aid. It inhibits neuronal reuptake of dopamine and norepinephrine and also antagonizes acetylcholine at the level of the nicotinic receptor sites. So far bupropion overdose resulting in symptoms mimicking an anticholinergic syndrome has rarely been reported in literature. In this case, one milligram of intravenous physostigmine, an acetylcholinesterase inhibitor, rapidly resolved patient agitation and mydriasis. This case indicates that physostigmine might be used as an antidote to quickly reverse the central and peripheral anticholinergic symptoms in patients with an overdose of bupropion. Erratum This article is the corrected version of the article published in issue 2020/3, pages 137-140. Typos and order of authors have now been corrected. With apologies to the authors.

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.