Lundbeck Research United States Inc.

Paramus, NJ, United States

Lundbeck Research United States Inc.

Paramus, NJ, United States
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Li Y.,Lundbeck Research United States Inc. | Pehrson A.L.,Lundbeck Research United States Inc. | Waller J.A.,Lundbeck Research United States Inc. | Dale E.,Lundbeck Research United States Inc. | And 2 more authors.
Frontiers in Neuroscience | Year: 2015

Major depressive disorder (MDD) is primarily conceptualized as a mood disorder but cognitive dysfunction is also prevalent, and may limit the daily function of MDD patients. Current theories on MDD highlight disturbances in dendritic plasticity in its pathophysiology, which could conceivably play a role in the production of both MDD-related mood and cognitive symptoms. This paper attempts to review the accumulated knowledge on the basic biology of the activity-regulated cytoskeleton-associated protein (Arc or Arg3.1), its effects on neural plasticity, and how these may be related to mood or cognitive dysfunction in animal models of MDD. On a cellular level, Arc plays an important role in modulating dendritic spine density and remodeling. Arc also has a close, bidirectional relationship with postsynaptic glutamate neurotransmission, since it is stimulated by multiple glutamatergic receptor mechanisms but also modulates a-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptor internalization. The effects on AMPA receptor trafficking are likely related to Arc's ability to modulate phenomena such as long-term potentiation, long-term depression, and synaptic scaling, each of which are important for maintaining proper cognitive function. Chronic stress models of MDD in animals show suppressed Arc expression in the frontal cortex but elevation in the amygdala. Interestingly, cognitive tasks depending on the frontal cortex are generally impaired by chronic stress, while those depending on the amygdala are enhanced, and antidepressant treatments stimulate cortical Arc expression with a timeline that is reminiscent of the treatment efficacy lag observed in the clinic or in preclinical models. However, pharmacological treatments that stimulate regional Arc expression do not universally improve relevant cognitive functions, and this highlights a need to further refine our understanding of Arc on a subcellular and network level. © 2015 Li, Pehrson, Waller, Dale, Sanchez and Gulinello.

Pehrson A.L.,University of Pittsburgh | Pehrson A.L.,Lundbeck Research United States Inc. | Bondi C.O.,University of Pittsburgh | Totah N.K.B.,University of Pittsburgh | And 2 more authors.
Psychopharmacology | Year: 2013

Rationale: Attention dysfunction is the hallmark of cognitive deficits associated with major psychiatric illnesses including schizophrenia. Cognitive deficits of schizophrenia have been attributed to reduced function of the N-methyl-d-aspartate (NMDA) receptor or reduced expression of the gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid decarboxylase-67, which presumably leads to attenuated neurotransmission at GABAA receptors. Objective: The present study used a rodent model to compare the inhibition of NMDA and GABAA receptors, and GAD activity on attention. We tested the impact of inhibiting these proteins brain wide or in the anterior cingulate cortex (ACC), a prefrontal cortex region critical for attentional processing. Methods: Rats were trained on the three choice serial reaction time task (3-CSRT), an attention test. The impact of systemic or intra-ACC injection of drugs on performance was measured in well-trained rats. Results: Reducing GABAA receptor function within the ACC with the direct antagonist SR95531 (1 or 3 ng/side) or brain wide using systemic injection of the benzodiazepine inverse agonist FG7142 (5 mg/kg) impaired accuracy and increased omissions. Systemic or intra-ACC inhibition of NMDA receptors using MK-801 (at 3 mg/kg or 3 μg, respectively) also impaired performance. Inhibition of GAD with 3-mercaptopropionic acid, even at high doses, had no effect on 3-CSRT accuracy or omissions when administered systemically or within the ACC. Conclusions: These data demonstrate that, while tonic stimulation of NMDA and GABAA receptors within the ACC are critical for attentional performance, reduction in GAD activity may have little functional significance and is not indicative of reduced GABA neurotransmission. © 2012 Springer-Verlag.

Nealey K.A.,Washington State University | Smith A.W.,Washington State University | Davis S.M.,Washington State University | Smith D.G.,Lundbeck Research United States Inc. | Walker B.M.,Washington State University
Neuropharmacology | Year: 2011

Previously, it was shown that ethanol-dependent animals display increased sensitivity to the general opioid receptor antagonist nalmefene compared to naltrexone. It was hypothesized that the dissociable effects of the two antagonists were attributable to a κ-opioid receptor mechanism. Nucleus accumbens dynorphin is upregulated following chronic ethanol exposure and such neuroadaptations could contribute to nalmefene's increased potency in ethanol-dependent animals. To test this hypothesis, male Wistar rats were trained to self-administer ethanol using an operant conditioning procedure. Animals were then implanted with bilateral intra-accumbens shell guide cannulae and assigned to either a chronic intermittent ethanol vapor-exposure condition (to induce dependence) or an air-exposed control group. Following a one-month exposure period, nalmefene, nor-binaltorphimine (nor-BNI; selective for κ-opioid receptors) or a combination of the selective opioid receptor antagonists CTOP and naltrindole (selective for the μ- and δ-opioid receptors, respectively) were site-specifically infused into the nucleus accumbens shell prior to ethanol self-administration sessions during acute withdrawal. Nalmefene and CTOP/naltrindole dose-dependently reduced ethanol self-administration in nondependent and dependent animals, whereas nor-BNI selectively attenuated ethanol self-administration in ethanol-dependent animals without affecting the self-administration of nondependent animals. Further analysis indentified that intra-accumbens shell nalmefene was more potent in ethanol-dependent animals and that the increased potency was attributable to a κ-opioid receptor mechanism. These data support the concept that dysregulation of DYN/κ-opioid receptor systems contributes to the excessive self-administration observed in dependent animals and suggest that pharmacotherapeutics for ethanol dependence that target κ-opioid receptors, in addition to μ- and δ-opioid receptors, are preferable to those that target μ- and δ-opioid receptor mechanisms alone. © 2011 Elsevier Ltd. All rights reserved.

Sanchez C.,Lundbeck Research United States Inc. | Reines E.H.,Lundbeck | Montgomery S.A.,University of London
International Clinical Psychopharmacology | Year: 2014

It is known that newer antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), provide advantages in tolerability over antidepressants such as the tricyclics. However, even within the SSRI class, differences in efficacy or tolerability exist between the individual drugs. Among the three most widely prescribed SSRIs are paroxetine, sertraline, and escitalopram. Escitalopram is commonly referred to as an SSRI, but also has well-documented allosteric properties, and thus can be further classed as an allosteric serotonin reuptake inhibitor. All three antidepressants are efficacious compared with placebo, but there is evidence that escitalopram is more effective than a range of other antidepressants. There are no direct data to regard either paroxetine or sertraline as a superior antidepressant. Escitalopram is superior compared with paroxetine, which has a less favorable tolerability profile. Paroxetine is associated with cholinergic muscarinic antagonism and potent inhibition of CYP2D6, and sertraline has moderate drug interaction issues in comparison with escitalopram. Overall, as an allosteric serotonin reuptake inhibitor that is somewhat different from classical SSRIs, escitalopram is the first choice judged by combined efficacy and tolerability, and nonclinical data have offered possible mechanisms through which escitalopram could be more efficacious, based on its interaction with orthosteric and allosteric binding sites at the serotonin transporter. © 2014 Wolters Kluwer Health | Lippincott Williams &Wilkins.

Westrich L.,Lundbeck Research United States Inc. | Sprouse J.,Lundbeck Research United States Inc.
Current Opinion in Investigational Drugs | Year: 2010

When circadian rhythms - the daily oscillations of various physiological and behavioral events that are controlled by a central timekeeping mechanism - become desynchronized with the prevailing light:dark cycle, a maladaptative response can result. Animal data based primarily on genetic manipulations and clinical data from biomarker and gene expression studies support the notion that circadian abnormalities underlie certain psychiatric disorders. In particular, bipolar disorder has an interesting link to rhythm-related disease biology; other mood disturbances, such as major depressive disorder, seasonal affective disorder and the agitation and aggression accompanying severe dementia (sundowning), are also linked to changes in circadian rhythm function. Possibilities for pharmacological intervention derive most readily from the molecular oscillator, the cellular machinery that drives daily rhythms. © Thomson Reuters (Scientific) Ltd.

Nguyen H.,Texas A&M University | Ma G.,Texas A&M University | Ma G.,Lundbeck Research United States Inc. | Romo D.,Texas A&M University
Chemical Communications | Year: 2010

A concise, enantioselective synthesis of the Phase I anticancer agent, (-)-salinosporamide A, is described. The brevity of the described strategy stems from a key bis-cyclization of a β-keto tertiary amide, accomplished on gram scale, which retains optical purity enabled by A1,3-strain rendering epimerization slow relative to the rate of bis-cyclization. The versatility of the strategy for derivative synthesis is demonstrated by the synthesis of (-)-homosalinosporamide A. © 2010 The Royal Society of Chemistry.

Pehrson A.L.,Lundbeck Research United States Inc. | Sanchez C.,Lundbeck Research United States Inc.
CNS Spectrums | Year: 2014

Monoamine-based treatments for depression have evolved greatly over the past several years, but shortcomings such as suboptimal efficacy, treatment lag, and residual cognitive dysfunction are still significant. Preclinical and clinical studies using compounds directly targeting glutamatergic neurotransmission present new opportunities for antidepressant treatment, with ketamine having a surprisingly rapid and sustained antidepressant effect that is presumably mediated through glutamate-dependent mechanisms. While direct modulation of glutamate transmission for antidepressant and cognition-enhancing actions may be hampered by nonspecific effects, indirect modulation through the serotonin (5-HT) system may be a viable alternative approach. Based on localization and function, 5-HT can modulate glutamate neurotransmission at least through the 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 receptors, which presents a rational pharmacological opportunity for modulating glutamatergic transmission without the direct use of glutamatergic compounds. Combining one or more of these glutamate-modulating 5-HT targets with 5-HT transporter inhibition may offer new therapeutic opportunities. The multimodal compounds vortioxetine and vilazodone are examples of this approach with diverse mechanisms, and their different clinical effects will provide valuable insights into serotonergic modulation of glutamate transmission for the potential treatment of depression and associated cognitive dysfunction. © Cambridge University Press 2013.

Leiser S.C.,Lundbeck Research United States Inc. | Dunlop J.,Pfizer | Bowlby M.R.,Merck And Co. | Devilbiss D.M.,University of Wisconsin - Madison
Biochemical Pharmacology | Year: 2011

Electroencephalography (EEG) and related methodologies offer the promise of predicting the likelihood that novel therapies and compounds will exhibit clinical efficacy early in preclinical development. These analyses, including quantitative EEG (e.g. brain mapping) and evoked/event-related potentials (EP/ERP), can provide a physiological endpoint that may be used to facilitate drug discovery, optimize lead or candidate compound selection, as well as afford patient stratification and Go/No-Go decisions in clinical trials. Currently, the degree to which these different methodologies hold promise for translatability between preclinical models and the clinic have not been well summarized. To address this need, we review well-established and emerging EEG analytic approaches that are currently being integrated into drug discovery programs throughout preclinical development and clinical research. Furthermore, we present the use of EEG in the drug development process in the context of a number of major central nervous system disorders including Alzheimer's disease, schizophrenia, depression, attention deficit hyperactivity disorder, and pain. Lastly, we discuss the requirements necessary to consider EEG technologies as a biomarker. Many of these analyses show considerable translatability between species and are used to predict clinical efficacy from preclinical data. Nonetheless, the next challenge faced is the selection and validation of EEG endpoints that provide a set of robust and translatable biomarkers bridging preclinical and clinical programs. © 2010 Elsevier Inc.

du Jardin K.G.,Lundbeck Research United States Inc. | Jensen J.B.,Lundbeck Research United States Inc. | Sanchez C.,Lundbeck Research United States Inc. | Pehrson A.L.,Lundbeck Research United States Inc.
European Neuropsychopharmacology | Year: 2014

We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT1A receptor agonist and 5-HT3 receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT3 receptor antagonist) or flesinoxan (5-HT1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1mg/kg (~80% 5-HT3 receptor occupancy; OR) and ≤3.0mg/kg (5-HT1A, 5-HT1B, 5-HT3 receptor occupancy: ~15%, 60%, 95%) in SA. Ondansetron exhibited a MED ≤3.0μg/kg (~25% 5-HT3 receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0mg/kg (~25% 5-HT1A receptor occupancy; SA); only 1.0mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT3, 5-HT1B, and 5-HT1A receptors, respectively. Vortioxetine's effects on SA performance may involve 5-HT1A receptor agonism, but not 5-HT3 receptor antagonism, whereas the effects on OR performance may involve 5-HT3 receptor antagonism and 5-HT1A receptor agonism. © 2013 Elsevier B.V. and ECNP.

Leiser S.C.,Lundbeck Research United States Inc. | Pehrson A.L.,Lundbeck Research United States Inc. | Robichaud P.J.,Lundbeck Research United States Inc. | Sanchez C.,Lundbeck Research United States Inc.
British Journal of Pharmacology | Year: 2014

Background and Purpose EEG studies show that 5-HT is involved in regulation of sleep-wake state and modulates cortical oscillations. Vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, 5-HT1B partial agonist, 5-HT1A agonist, and 5-HT transporter inhibitor. Preclinical (animal) and clinical studies with vortioxetine show positive impact on cognitive metrics involving cortical function. Here we assess vortioxetine's effect on cortical neuronal oscillations in actively awake rats. Experimental Approach Telemetric EEG recordings were obtained with the following treatments (mg·kg-1, s.c.): vehicle, vortioxetine (0.1, 1.0, 3.0, 10), 5-HT1A agonist flesinoxan (2.5), 5-HT3 antagonist ondansetron (0.30), 5-HT7 antagonist SB-269970-A (10), escitalopram (2.0), duloxetine (10) and vortioxetine plus flesinoxan. Target occupancies were determined by ex vivo autoradiography. Key Results Vortioxetine dose-dependently increased wakefulness. Flesinoxan, duloxetine, ondansetron, but not escitalopram or SB-269970-A increased wakefulness. Quantitative spectral analyses showed vortioxetine alone and with flesinoxan increased θ (4-8Hz), α (8-12Hz) and γ (30-50Hz) power. Duloxetine had no effect on θ and γ, but decreased α power, while escitalopram produced no changes. Ondansetron and SB-269970 (≈31-35% occupancy) increased θ power. Flesinoxan (≈41% occupancy) increased θ and γ power. Conclusions and Implications Vortioxetine increased wakefulness and increased frontal cortical activity, most likely because of its 5-HT7 and 5-HT 3 antagonism and 5-HT1A agonism. Vortioxetine differs from escitalopram and duloxetine by increasing cortical θ, α and γ oscillations. These preclinical findings suggest a role of vortioxetine in modulating cortical circuits known to be recruited during cognitive behaviours and warrant further investigation as to their clinical impact. © 2014 The British Pharmacological Society.

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