Publications by authors named "Tolga Uz"

43 Publications

Single- and multiple-dose safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ASP0367, or bocidelpar sulfate, a novel modulator of peroxisome proliferator-activated receptor delta in healthy adults: Results from a phase 1 study.

Muscle Nerve 2021 Oct 12. Epub 2021 Oct 12.

Parexel International, Baltimore, MD, USA.

Introduction/aims: ASP0367, or bocidelpar sulfate, is an orally administered small molecule that potently and selectively modulates PPARδ to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. Objectives of this first-in-human trial were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of ASP0367 in healthy participants.

Methods: In this double-blind phase 1 study, adult participants were randomized to single or multiple ascending oral doses of ASP0367 or placebo; study duration was 1 and 14 days, respectively. Pharmacokinetic parameters under fed conditions were also evaluated.

Results: A total of 64 (single dose cohort) and 37 (multiple dose cohort) participants were included. Following single doses of 1-120 mg, ASP0367 was rapidly absorbed with median time to maximum plasma concentration (t ) of 1.50-2.24 hours under fasting conditions; ASP0367 concentrations declined in a multiphasic manner after reaching maximum plasma concentration. Under fed conditions, t was delayed 1.7 hours. Following multiple once-daily doses, mean half-life of ASP0367 10-75 mg ranged from 14.1-17.5 hours; steady state was reached after 4 days. Negligible accumulation was observed following repeated dosing. No participants receiving ASP0367 discontinued treatment, and all treatment-emergent adverse events were mild-to-moderate in severity; none were deemed drug-related. No clinically significant changes were observed on laboratory or electrocardiography evaluations. Treatment- and dose-dependent upregulation of six PPARδ target genes were observed with single and multiple doses of ASP0367.

Discussion: ASP0367, or bocidelpar sulfate, was well tolerated; rapid absorption, roughly dose-proportional bioavailability, and effects on PPARδ target genes were demonstrated in healthy adult participants.
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http://dx.doi.org/10.1002/mus.27436DOI Listing
October 2021

Phase 1 randomized study on the safety, tolerability, and pharmacodynamic cognitive and electrophysiological effects of a dopamine D receptor positive allosteric modulator in patients with schizophrenia.

Neuropsychopharmacology 2021 05 17;46(6):1145-1151. Epub 2020 Nov 17.

Astellas Pharma Global Development, Inc., Northbrook, IL, USA.

ASP4345, a novel dopamine D receptor positive allosteric modulator, is being evaluated for the treatment of cognitive impairment associated with schizophrenia (CIAS). This phase 1 multiple ascending-dose study (NCT02720263) assessed the safety, tolerability, and pharmacodynamics of ASP4345 in patients with schizophrenia/schizoaffective disorder. Pharmacodynamic assessments were Cogstate cognitive tests and electrophysiological biomarkers, including gamma-band power and phase synchronization in response to 40-Hz auditory steady-state stimulation, as well as mismatch negativity (MMN) and P3a event-related potentials. The sample size determination was based on standard practice in assessing safety and tolerability of a new chemical entity. Data were summarized by conversion of this data into effect sizes using descriptive and inferential statistics. A total of 36 randomized patients received ASP4345 (3, 15, 50, and 150 mg; n = 9 each dose) and 12 patients received placebo. Patients in the ASP4345 group experienced 73 treatment-emergent adverse events (TEAEs) and 34 TEAEs were reported for the placebo group. The most common TEAEs were headache and somnolence and nearly all TEAEs were mild in severity. No changes in mood or self-reports of suicidal ideation/behavior were observed. Improvements in performance on cognitive tests were noted, which suggests a potential improvement in psychomotor function and visual attention. Furthermore, positive changes in neurophysiological biomarkers (auditory steady-state response [ASSR] and MMN) suggest improvement in information processing. The findings need to be confirmed in studies with a larger patient population. Nonetheless, the trends in safety and pharmacodynamic data support further clinical development of ASP4345 for the treatment of CIAS.
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http://dx.doi.org/10.1038/s41386-020-00908-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182805PMC
May 2021

The effects of roflumilast, a phosphodiesterase type-4 inhibitor, on EEG biomarkers in schizophrenia: A randomised controlled trial.

J Psychopharmacol 2021 01 27;35(1):15-22. Epub 2020 Aug 27.

Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.

Background: Patients with schizophrenia have significant cognitive deficits, which may profoundly impair quality of life. These deficits are also evident at the neurophysiological level with patients demonstrating altered event-related potential in several stages of cognitive processing compared to healthy controls; within the auditory domain, for example, there are replicated alterations in Mismatch Negativity, P300 and Auditory Steady State Response. However, there are no approved pharmacological treatments for cognitive deficits in schizophrenia.

Aims: Here we examine whether the phosphodiesterase-4 inhibitor, roflumilast, can improve neurophysiological deficits in schizophrenia.

Methods: Using a randomised, double-blind, placebo-controlled, crossover design study in 18 patients with schizophrenia, the effect of the phosphodiesterase-4 inhibitor, roflumilast (100 µg and 250 µg) on auditory steady state response (early stage), mismatch negativity and theta (intermediate stage) and P300 (late stage) was examined using electroencephalogram. A total of 18 subjects were randomised and included in the analysis.

Results: Roflumilast 250 µg significantly enhanced the amplitude of both the mismatch negativity (=0.04) and working memory-related theta oscillations (=0.02) compared to placebo but not in the other (early- or late-stage) cognitive markers.

Conclusions: The results suggest that phosphodiesterase-4 inhibition, with roflumilast, can improve electroencephalogram cognitive markers, which are impaired in schizophrenia, and that phosphodiesterase-4 inhibition acts at an intermediate rather than early or late cognitive processing stage. This study also underlines the use of neurophysiological measures as cognitive biomarkers in experimental medicine.
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http://dx.doi.org/10.1177/0269881120946300DOI Listing
January 2021

Pharmacokinetics of ASP4345 from Single Ascending-Dose and Multiple Ascending-Dose Phase I Studies.

Clin Pharmacokinet 2021 01;60(1):79-88

Astellas Pharma Global Development, Inc., 1 Astellas Way, Northbrook, IL, 60062, USA.

Background: Cognitive impairment is a core feature of schizophrenia. While first- and second-generation antipsychotic drugs treat psychotic exacerbations, no treatment is approved for the cognitive dysfunction. We have identified ASP4345, a positive allosteric modulator of the dopamine type 1 (D) receptor that selectively binds to, and enhances the activity of, D receptors. ASP4345 has the potential to be an effective and well-tolerated treatment option for cognitive impairment associated with schizophrenia.

Objective: The objective of this study was to determine the pharmacokinetics of ASP4345 in two phase I single ascending-dose and multiple ascending-dose studies.

Methods: Both phase I studies were randomized, double blind, and placebo controlled. The single dose-ascending study assessed pharmacokinetics of single oral doses of 3-900 mg of ASP4345 or placebo in the fasted state in healthy adult volunteers. This study also assessed cerebrospinal fluid pharmacokinetics, as well as the effects of food on pharmacokinetic parameters. The multiple ascending-dose study (NCT02720263) assessed the pharmacokinetics of multiple oral doses of 3-150 mg of ASP4345 in patients with schizophrenia or schizoaffective disorder receiving stable antipsychotic drug treatment. The pharmacokinetic data from both studies were summarized using descriptive statistics.

Results: The plasma concentration-time profile in both studies showed a rapid increase in concentrations of ASP4345. The median time to maximum concentration range was 1.00-2.26 h in the single ascending-dose study in the fasted state and 1.25-3.02 h in the multiple ascending-dose study at steady state. There were less than dose-proportional increases in maximum concentration and area under the curve in the single ascending-dose study, where doses had a range from 3 to 900 mg, and in the multiple ascending-dose study in patients with stabilized schizophrenia or schizoaffective disorder, where doses had a range from 3 to 150 mg. The mean terminal elimination half-life was dose independent and had a range from 9.12 to 14.3 h in the single ascending-dose study and from 11.1 to 26.8 h in the multiple ascending-dose study. Additionally, in the single ascending-dose study, absorption of 300 mg of ASP4345 was slightly delayed when administered in the fed state compared with the fasted state; median time to maximum concentration was 1.5 h under the fasting state and 4.0 h under fed states. All other pharmacokinetic parameters were comparable for both conditions. ASP4345 appeared in the cerebrospinal fluid with some delay; time to maximum concentration range was from 2.48 to 7.98 h in cerebrospinal fluid compared with 0.75 to 1.03 h in plasma (median cerebrospinal fluid/plasma = 0.188). The ratio of cerebrospinal fluid to total plasma for area under the curve from 0 to 24 h (0.157-0.573%) and maximum concentration (0.0899-0.311%) and the ratio of cerebrospinal fluid to unbound plasma for maximum concentration (25.0-86.4%) confirm the distribution of ASP4345 into the brain.

Conclusions: The pharmacokinetics of ASP4345 suggest that single daily dosing is appropriate for ASP4345. Furthermore, the concentration of ASP4345 in cerebrospinal fluid compared to free drug concentrations in plasma provides evidence of penetration of ASP4345 into the brain.
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http://dx.doi.org/10.1007/s40262-020-00911-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808976PMC
January 2021

A randomized, placebo-controlled, phase 1 study to evaluate the effects of TAK-063 on ketamine-induced changes in fMRI BOLD signal in healthy subjects.

Psychopharmacology (Berl) 2020 Feb 26;237(2):317-328. Epub 2019 Nov 26.

Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 60015, USA.

Rationale: Phosphodiesterase 10A inhibitor TAK-063 has shown effects that suggest efficacy in schizophrenia treatment.

Objective: This randomized, double-blind, placebo-controlled, incomplete-crossover study investigated effects of single oral administration of TAK-063 on ketamine-induced changes in blood oxygen level-dependent (BOLD) signal in healthy males.

Methods: Healthy men aged 18 to 45 years with normal magnetic resonance imaging (MRI) scans and electroencephalogram measurements at screening were eligible. Each subject was randomized to one of nine treatment schedules: all subjects received placebo and two of three doses of TAK-063 followed by ketamine. The primary endpoint was ketamine-induced brain activity in select regions of the brain during resting state. Secondary endpoints included pharmacokinetic parameters of TAK-063, proportion of subjects with treatment-emergent adverse events (AEs), and percentage of subjects meeting criteria for abnormal safety laboratory tests and vital sign measurements.

Results: The study comprised 27 subjects. Prior to ketamine infusion, TAK-063 exerted region-specific effects on resting state functional MRI (fMRI) BOLD signal. After ketamine administration, TAK-063 reduced the Cohen's effect size for resting-state fMRI BOLD signal in key brain regions examined, and exerted similar effects on BOLD signal during the working memory task across all doses. TAK-063 was safe and well tolerated.

Conclusions: Our results are consistent with non-clinical studies of ketamine and TAK-063 and clinical studies of ketamine and risperidone. It is unknown whether these data are predictive of potential antipsychotic efficacy, and further analyses are required.
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http://dx.doi.org/10.1007/s00213-019-05366-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018803PMC
February 2020

Acute treatment with the PDE4 inhibitor roflumilast improves verbal word memory in healthy old individuals: a double-blind placebo-controlled study.

Neurobiol Aging 2019 05 26;77:37-43. Epub 2019 Jan 26.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands. Electronic address:

There is ample evidence that phosphodiesterase 4 (PDE4) inhibition can improve memory performance in animal studies. In the present study, we examined the acute effects of the PDE4 inhibitor roflumilast on memory performance in healthy individuals (60-80 years of age). We tested the effects of acute roflumilast administration (100, 250, 1000 μg) in a double-blind, placebo-controlled, 4-way crossover design. Participants were first screened for their verbal word memory performance to ensure normal memory performance (within 0.5 standard deviation from norm score; n = 20) Drug effects on memory performance were tested in a verbal memory test and a spatial memory test. Reported side effects of drug treatment were registered. Roflumilast (100 μg) improved the delayed recall performance of the participants (Cohen's d, 0.69). No effects were observed in the spatial memory task. Roflumilast was well tolerated at this low dose. Although no clear adverse side effects were reported at the low dose, mild adverse events (including headache, dizziness, insomnia, and diarrhea) were reported after the 1000 μg dose. The present study provides first evidence that the PDE4 inhibitor roflumilast improves verbal memory performance in old participants. The current data encourage further development of PDE4 inhibitors for improving memory.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.01.014DOI Listing
May 2019

An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients.

Psychopharmacology (Berl) 2021 May 8;238(5):1279-1289. Epub 2018 Dec 8.

Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, SE5 8AF, UK.

Rationale: Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits.

Objectives: Based on animal models, we investigated the potential for roflumilast, a selective inhibitor of phosphodiesterase type 4 (PDE4), to improve cognition, which may act by increasing intracellular cyclic adenosine monophosphate in brain regions underlying cognitive deficits in schizophrenia.

Methods: This study consisted of a randomised, double-blind, placebo-controlled, crossover design involving 15 schizophrenia patients. In 3 treatment periods, patients were given 8 days of placebo or one of the two doses of roflumilast (100 and 250 μg daily) with 14 days of washout between treatments. The primary endpoints were dorsolateral prefrontal cortex (DLPFC) activation during a visuospatial working memory task measured with fMRI on dosing day 8 and verbal memory and working memory performance change from baseline to day 8. Least square mean change scores were calculated for behavioural outcomes; fMRI data were analysed in SPM12 with bilateral DLPFC as regions of interest.

Results: Verbal memory was significantly improved under 250 μg roflumilast (effect size (ES) = 0.77) compared to placebo. fMRI analyses revealed that increasing dose of roflumilast was associated with reduction of bilateral DLPFC activation during working memory compared to placebo, although this was not statistically significant (ES = 0.31 for the higher dose). Working memory was not improved (ES = 0.03).

Conclusions: Results support the mechanistic validation of potential novel strategies for improving cognitive dysfunction in schizophrenia and suggest that PDE4 inhibition may be beneficial for cognitive dysfunction in schizophrenia.

Trial Registration: NCT02079844 .
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http://dx.doi.org/10.1007/s00213-018-5134-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062361PMC
May 2021

A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[C]Rolipram.

Mol Imaging Biol 2018 08;20(4):615-622

Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.

Purpose: Phosphodiesterase 4 (PDE4) inhibition in the brain has been reported to improve cognitive function in animal models. Therefore, PDE4 inhibitors are one of key targets potential for drug development. Investigation of brain PDE4 occupancy would help to understand the effects of PDE4 inhibition to cognitive functions. Roflumilast is a selective phosphodiesterase type 4 (PDE4) inhibitor used clinically for severe chronic obstructive pulmonary disease, but the effects to the brain have not been well investigated. In this study, we aimed to investigate whether roflumilast entered the brain and occupied PDE4 in nonhuman primates.

Procedures: Positron emission tomography (PET) measurements with (R)-[C]rolipram were performed at baseline and after intravenous (i.v.) administration of roflumilast (3.6 to 200 μg/kg) in three female rhesus monkeys. Arterial blood samples were taken to obtain the input function. Protein binding was measured to obtain the free fraction (fp) of the radioligand. Total distribution volume (V) and V/fp were calculated as outcome measures from two tissue compartment model. Lassen plot approach was taken to estimate the target occupancy.

Results: The brain uptake of (R)-[C]rolipram decreased after roflumilast administration. PDE 4 occupancy by roflumilast showed dose- and plasma concentration-dependent increase, although PDE4 occupancy did not reach 50 % even after the administration of up to 200 μg/kg of roflumilast, regardless of outcome measures, V or V/fp.

Conclusions: This PET study showed that the brain PDE4 binding was blocked to a certain extent after i.v. administration of clinical relevant doses of roflumilast in nonhuman primates. Further clinical PET evaluation is needed to understand the relationship between PDE4 inhibition and potential improvement of cognitive function in human subjects.
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http://dx.doi.org/10.1007/s11307-018-1168-0DOI Listing
August 2018

Acute administration of roflumilast enhances sensory gating in healthy young humans in a randomized trial.

Psychopharmacology (Berl) 2018 01 3;235(1):301-308. Epub 2017 Nov 3.

Department of Neuropsychology and Psychopharmacology, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.

Introduction: Sensory gating is a process involved in early information processing which prevents overstimulation of higher cortical areas by filtering sensory information. Research has shown that the process of sensory gating is disrupted in patients suffering from clinical disorders including attention deficit hyper activity disorder, schizophrenia, and Alzheimer's disease. Phosphodiesterase (PDE) inhibitors have received an increased interest as a tool to improve cognitive performance in both animals and man, including sensory gating.

Methods: The current study investigated the effects of the PDE4 inhibitor roflumilast in a sensory gating paradigm in 20 healthy young human volunteers (age range 18-30 years). We applied a placebo-controlled randomized cross-over design and tested three doses (100, 300, 1000 μg).

Results: Results show that roflumilast improves sensory gating in healthy young human volunteers only at the 100-μg dose. The effective dose of 100 μg is five times lower than the clinically approved dose for the treatment of acute exacerbations in chronic obstructive pulmonary disease (COPD). No side-effects, such as nausea and emesis, were observed at this dose. This means roflumilast shows a beneficial effect on gating at a dose that had no adverse effects reported following single-dose administration in the present study.

Conclusion: The PDE4 inhibitor roflumilast has a favorable side-effect profile at a cognitively effective dose and could be considered as a treatment in disorders affected by disrupted sensory gating.
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http://dx.doi.org/10.1007/s00213-017-4770-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748397PMC
January 2018

A human [(11)C]T-773 PET study of PDE10A binding after oral administration of TAK-063, a PDE10A inhibitor.

Neuroimage 2016 Nov 15;141:10-17. Epub 2016 Jul 15.

Takeda Development Center Americas, Inc., Deerfield, IL, USA.

Phosphodiesterase 10A (PDE10A) is selectively expressed in the striatal regions in the brain and may play a role in modulating dopaminergic and glutamatergic second messenger pathways. PDE10A inhibitors are expected to be useful in treating neuropsychiatric disorders such as schizophrenia and Huntington's disease. In this study, the brain kinetics of [(11)C]T-773 in the human brain and test-retest reproducibility of the outcome measures were evaluated. Subsequently, the occupancy of a novel PDE10A inhibitor, TAK-063, was measured using [(11)C]T-773. Dynamic PET measurements were conducted three times for 12 healthy male subjects after intravenous bolus injection of [(11)C]T-773: two baseline PETs and one postdose PET (3hours) after oral administration of TAK-063 for four subjects, and one baseline PET and two postdose PET (3hours and 23hours) for eight subjects. Kinetic model analysis was performed with arterial input functions. PDE10A occupancy was calculated as the percent change of the binding specific to PDE10A (Vs) total distribution volume (VT), which was calculated as the VT of the putamen minus the VT of the cerebellum. Regional brain uptake was highest in the putamen. Time-activity curves of the brain regions were described with two tissue-compartment (2TC) models. The mean VT was 5.5±0.7 in the putamen and 2.3±0.5 in the cerebellum in the baseline PET. Absolute VT variability between the two baseline scans was less than 7%. Reproducibility of VT was excellent. PDE10A occupancy in the putamen ranged from 2.8% to 72.1% at 3hours after a single administration of 3 to 1000mg of TAK-063, and increased in a dose- and plasma concentration-dependent manner. At 23hours postdose, PDE10A occupancy in the putamen was 0 to 42.8% following administration of 3 to 100mg of TAK-063. In conclusion, [(11)C]T-773 showed good characteristics as a PET radioligand for PDE10A in the human brain.
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http://dx.doi.org/10.1016/j.neuroimage.2016.06.047DOI Listing
November 2016

The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses.

Behav Brain Res 2016 Apr 18;303:26-33. Epub 2016 Jan 18.

Dept. of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands. Electronic address:

Enhancement of central availability of the second messenger cAMP is a promising approach to improve cognitive function. Pharmacological inhibition of phosphodiesterase type 4 (PDE4), a group of cAMP hydrolyzing enzymes in the brain, has been shown to improve cognitive performances in rodents and monkeys. However, inhibition of PDE4 is generally associated with severe emetic side-effects. Roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), is yielding only mild emetic side effects. In the present study we investigate the potential of roflumilast as a cognition enhancer and to determine the potential coinciding emetic response in comparison to rolipram, a classic PDE4 inhibitor with pronounced emetic effects. Cognition enhancement was evaluated in mice and it was found that both roflumilast and rolipram enhanced memory in an object location task (0.03mg/kg), whereas only roflumilast was effective in a spatial Y-maze (0.1mg/kg). Emetic potential was measured using competition of PDE4 inhibition for α2-adrenergic receptor antagonism in which recovery from xylazine/ketamine-mediated anesthesia is used as a surrogate marker. While rolipram displayed emetic properties at a dose 10 times the memory-enhancing dose, roflumilast only showed increased emetic-like properties at a dose 100 times the memory-enhancing dose. Moreover, combining sub-efficacious doses of the approved cognition-enhancer donepezil and roflumilast, which did not improve memory when given alone, fully restored object recognition memory deficit in rats induced by the muscarinic receptor antagonist scopolamine. These findings suggest that roflumilast offers a more favorable window for treatment of cognitive deficits compared to rolipram.
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http://dx.doi.org/10.1016/j.bbr.2016.01.031DOI Listing
April 2016

Minocycline affects cocaine sensitization in mice.

Neurosci Lett 2009 Mar 4;452(3):258-61. Epub 2009 Feb 4.

Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.

Growing evidence has pointed to an interaction between the tetracycline antibiotic minocycline and drugs with abuse liability such as opioids and amphetamines. In this work, we tested the hypothesis that similar to its effects on methamphetamine-induced locomotor sensitization, minocycline may influence the behavioral effects of cocaine. Experiments were performed in male C57BL/6J mice using an automated system to measure locomotor activity. We found that 80 mg/kg minocycline significantly reduced locomotor activity when administered either alone or injected 30 min prior to cocaine, which increased locomotor activity. To investigate whether minocycline selectively affects the development of locomotor sensitization induced by four daily injections of 10mg/kg cocaine, we sought a schedule of minocycline administration that does not per se affect locomotor activity. Thus, we selected 40 mg/kg minocycline administered 3h prior to cocaine; minocycline did not affect cocaine-stimulated locomotor activity on the first day of administration but prevented the development of cocaine sensitization. We also tested whether minocycline would affect an already established cocaine sensitization. After establishing the sensitization effect by four daily injections, cocaine treatment was discontinued and mice were treated with minocycline daily (days 5-11) or on day 11 only. There was no effect of minocycline treatment on the response of cocaine-sensitized mice to the challenge dose of cocaine on day 11. The mechanisms by which minocycline interferes with the development of cocaine sensitization need to be characterized.
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http://dx.doi.org/10.1016/j.neulet.2009.01.078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680252PMC
March 2009

Minocycline increases phosphorylation and membrane insertion of neuronal GluR1 receptors.

Neurosci Lett 2008 Dec 7;447(2-3):134-7. Epub 2008 Oct 7.

The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA.

The tetracycline antibiotic minocycline beneficially affects neuronal functioning and also inhibits the enzyme 5-lipoxygenase (5-LOX). We hypothesized that similar to 5-LOX inhibitors, minocycline may increase phosphorylation and membrane insertion of the glutamate receptor GluR1. The experiments were performed in primary cultures of mouse striatal neurons and in the prefrontal cortex and striatum of minocycline-treated mice. In vitro, low micromolar minocycline concentrations increased GluR1 phosphorylation at Ser845 and Ser831 and increased the surface content of GluR1. Minocycline also increased GluR1 phosphorylation in vivo. Increased GluR1 phosphorylation and minocycline treatment have been associated with antidepressant and memory-enhancing activities. Direct consequences of minocycline-increased GluR1 phosphorylation are yet to be established.
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http://dx.doi.org/10.1016/j.neulet.2008.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2604812PMC
December 2008

The melatonin receptor MT1 is required for the differential regulatory actions of melatonin on neuronal 'clock' gene expression in striatal neurons in vitro.

J Pineal Res 2009 Jan 16;46(1):87-94. Epub 2008 Sep 16.

Department of Psychiatry, The Psychiatric Institute, University of Illinois at Chicago, Chicago, IL, USA.

Through inhibitory G protein-coupled melatonin receptors, melatonin regulates intracellular signaling systems and also the transcriptional activity of certain genes. Clock genes are proposed as regulatory factors in forming dopamine-related behaviors and mood and melatonin has the ability to regulate these processes. Melatonin-mediated changes in clock gene expression have been reported in brain regions, including the striatum, that are crucial for the development of dopaminergic behaviors and mood. However, it is not known whether melatonin receptors present in striatum mediate these effects. Therefore, we investigated the role of the melatonin/melatonin receptor system on clock gene expression using a model of primary neuronal cultures prepared from striatum. We found that melatonin at the receptor affinity range (i.e., nm) affects the expression of the clock genes mPer1, mClock, mBmal1 and mNPAS2 (neuronal PAS domain protein 2) differentially in a pertussis toxin-sensitive manner: a decrease in Per1 and Clock, an increase in NPAS2 and no change in Bmal1 expression. Furthermore, mutating MT1 melatonin receptor (i.e., MT1 knockouts, MT1(-/-)) reversed melatonin-induced changes, indicating the involvement of MT1 receptor in the regulatory action of melatonin on neuronal clock gene expression. Therefore, by controlling clock gene expression we propose melatonin receptors (i.e., MT1) as novel therapeutic targets for the pathobiologies of dopamine-related behaviors and mood.
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http://dx.doi.org/10.1111/j.1600-079X.2008.00634.xDOI Listing
January 2009

Increased 5-lipoxygenase immunoreactivity in the hippocampus of patients with Alzheimer's disease.

J Histochem Cytochem 2008 Dec 4;56(12):1065-73. Epub 2008 Aug 4.

Department of Neurology, University of Pittsburgh School of Medicine, BSTWR S-521, Pittsburgh, PA 15261, USA.

The proinflammatory enzyme 5-lipoxygenase (5-LOX) is upregulated in Alzheimer's disease (AD), but its localization and association with the hallmark lesions of the disease, beta-amyloid (Abeta) plaques and neurofibrillary tangles (NFTs), is unknown. This study examined the distribution and cellular localization of 5-LOX in the medial temporal lobe from AD and control subjects. The spatial relationship between 5-LOX immunoreactive structures and AD lesions was also examined. We report that, in AD subjects, 5-LOX immunoreactivity is elevated relative to controls, and its localization is dependent on the antibody-targeted portion of the 5-LOX amino acid sequence. Carboxy terminus-directed antibodies detected 5-LOX in glial cells and neurons, but less frequently in neurons with dystrophic (NFT) morphology. In contrast, immunoreactivity observed using 5-LOX amino terminus-directed antibodies was virtually absent in neurons and abundant in NFTs, neuritic plaques, and glia. Double-labeling studies showed a close association of 5-LOX-immunoreactive processes and glial cells with Abeta immunoreactive plaques and vasculature and also detected 5-LOX in tau immunoreactive and amyloid containing NFTs. Different immunolabeling patterns with antibodies against carboxy vs amino terminus of 5-LOX may be caused by post-translational modifications of 5-LOX protein in Abeta plaques and NFTs. The relationship between elevated intracellular 5-LOX and hallmark AD pathological lesions provides further evidence that neuroinflammatory pathways contribute to the pathogenesis of AD.
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http://dx.doi.org/10.1369/jhc.2008.951855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583907PMC
December 2008

Melatonin signaling in mouse cerebellar granule cells with variable native MT1 and MT2 melatonin receptors.

Brain Res 2008 Aug 28;1227:19-25. Epub 2008 Jun 28.

Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, MC912, Chicago, IL 60612, USA.

Although G protein-coupled MT1 and MT2 melatonin receptors are expressed in neurons of the mammalian brain including in humans, relatively little is known about the influence of native MT1 and MT2 melatonin receptors on neuronal melatonin signaling. Whereas human cerebellar granule cells (CGC) express only MT1 receptors, mouse CGC express both MT1 and MT2. To study the effects of altered neuronal MT1/MT2 receptors, we used CGC cultures prepared from immature cerebella of wild-type mice (MT1/MT2 CGC) and MT1- and MT2-knockout mice (MT2 and MT1 CGC, respectively). Here we report that in MT1/MT2 cultures, physiological (low nanomolar) concentrations of melatonin decrease the activity (phosphorylation) of extracellular-signal-regulated kinase (ERK) whereas a micromolar concentration was ineffective. Both MT1 and MT2 deficiencies transformed the melatonin inhibition of ERK into melatonin-induced ERK activation. In MT1/MT2 CGC, 1 nM melatonin inhibited serine/threonine kinase Akt, whereas in MT1 and MT2 CGC, this concentration was ineffective. Under these conditions, both MT1 and MT2 deficiencies prevented melatonin from inhibiting forskolin-stimulated cAMP levels and cFos immunoreactivity. We demonstrated that selective removal of native neuronal MT1 and MT2 receptors has a profound effect on the intracellular actions of low/physiological concentrations of melatonin. Since the expression of MT1 and MT2 receptors is cell-type-specific and species-dependent, we postulate that the pattern of expression of neuronal melatonin receptor types in different brain areas and cells could determine the capabilities of endogenous melatonin in regulating neuronal functioning.
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http://dx.doi.org/10.1016/j.brainres.2008.06.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564848PMC
August 2008

Stimulatory effects of a melatonin receptor agonist, ramelteon, on BDNF in mouse cerebellar granule cells.

Neurosci Lett 2008 Jul 2;439(1):34-6. Epub 2008 May 2.

The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, MC912 Chicago, IL 60612, USA.

Melatonin receptor activation has been linked to the regulation of neurotrophic factors, including the brain-derived neurotrophic factor (BDNF). To further characterize the effects of melatonin receptor stimulation on neuronal BDNF, we used a clinically available novel agonist for MT1 and MT2 melatonin receptors, ramelteon. Primary cultures of cerebellar granule cells (CGC) have been established as an in vitro model for studying neuronal BDNF. We took advantage of the availability of MT1- and MT2-deficient (knockout; KO) mice to employ primary CGC prepared from wild type (WT), MT1 KO, and MT2 KO mice. We investigated the effects of ramelteon on BDNF protein and mRNA content. Administered in a low nanomolar range, ramelteon increased BDNF protein content in all three types of mouse CGC. This ramelteon-triggered BDNF protein elevation was not preceded by a BDNF mRNA increase. However, it was prevented by treatment of cultures with a protein synthesis inhibitor cycloheximide. These results demonstrated that the MT1/MT2 melatonin receptor agonist ramelteon is capable of increasing BDNF protein in neurons expressing either of the two melatonin receptor types and that this action of ramelteon involves translational mechanisms. Further research is needed to explore the putative influence of ramelteon on BDNF-associated neuroplasticity.
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http://dx.doi.org/10.1016/j.neulet.2008.04.099DOI Listing
July 2008

Role of melatonin receptors in the effects of melatonin on BDNF and neuroprotection in mouse cerebellar neurons.

J Neural Transm (Vienna) 2008 Nov 21;115(11):1495-9. Epub 2008 May 21.

Department of Psychiatry, The Psychiatric Institute, University of Illinois at Chicago, 1601 West Taylor Street, MC912, Chicago, IL 60612, USA.

Although melatonin affects developing neurons and is neuroprotective, a role of melatonin receptors termed MT1 and MT2 in these actions is unclear. We investigated the effects of melatonin on the levels of the brain derived neurotrophic factor (BDNF) in the developing cerebellum and cerebellar granule cells (CGC) of wild-type (WT), MT1- and MT2-knockout mice. A model of low-potassium CGC toxicity was used to evaluate neuroprotection. A 14-day-old pups and CGC cultures were treated with melatonin; 0.01 mg/kg intraperitoneally and 1 nM in vitro, respectively. Treatment of WT pups and CGC with melatonin did not alter BDNF levels. The absence of MT2 but not MT1 receptors enabled melatonin to increase cerebellar and CGC BDNF content. Nanomolar melatonin was neuroprotective in MT2-knockout but not WT CGC. We propose that CGC from MT2-knockout mice could serve as a model for studying the influence of melatonin on human CGC, which express MT1 but not MT2 receptors.
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http://dx.doi.org/10.1007/s00702-008-0066-zDOI Listing
November 2008

Effects of MK-886, a 5-lipoxygenase activating protein (FLAP) inhibitor, and 5-lipoxygenase deficiency on the forced swimming behavior of mice.

Neurosci Lett 2008 May 21;436(2):269-72. Epub 2008 Mar 21.

The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA.

A common biological pathway may contribute to the comorbidity of atherosclerosis and depression. Increased activity of the enzymatic 5-lipoxygenase (5-LOX, 5LO) pathway is a contributing factor in atherosclerosis and a 5-LOX inhibitor, MK-886, is beneficial in animal models of atherosclerosis. In the brain, MK-886 increases phosphorylation of the glutamate receptor subunit GluR1, and the increased phosphorylation of this receptor has been associated with antidepressant treatment. In this work, we evaluated the behavioral effects of MK-886 in an automated assay of mouse forced swimming, which identifies antidepressant activity as increased climbing behavior and/or decreased rest time. Whereas a single injection of MK-886 (3 and 10 mg/kg) did not affect forced swimming behaviors assayed 30 min later, six daily injections of 3 mg/kg MK-886 slightly increased climbing and significantly reduced rest time in wild-type mice but not in 5-LOX-deficient mice. A diet delivery of MK-886, 4 micro/(100 mg(body-weight)day), required 3 weeks to affect forced swimming; it increased climbing behavior. Climbing behavior was also increased in naive 5-LOX-deficient mice compared to naive wild-type controls. These results suggest that 5-LOX inhibition and deficiency may be associated with antidepressant activity. Increased climbing in a forced swimming assay is a typical outcome of antidepressants that increase noradrenergic and dopaminergic activity. Interestingly, 5-LOX deficiency and MK-886 treatment have been shown to be capable of increasing the behavioral effects of a noradrenaline/dopamine-potentiating drug, cocaine. Future research is needed to evaluate the clinical relevance of our findings.
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http://dx.doi.org/10.1016/j.neulet.2008.03.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423274PMC
May 2008

Drug- and region-specific effects of protracted antidepressant and cocaine treatment on the content of melatonin MT(1) and MT(2) receptor mRNA in the mouse brain.

Int J Neuroprot Neuroregener 2006 ;2:185-9

The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago Chicago, Illinois 60612, USA.

OBJECTIVES: In the mammalian brain, G protein-coupled MT(1) and MT(2) melatonin receptors may be involved in Alzheimer's pathology, long-term potentiation, depression, and in the behavioral effects of psychoactive drugs. These drugs; e.g. antidepressants and drugs of abuse, are typically used over long periods of time and may alter neuroplasticity and gene expression. We hypothesized that such antidepressant- and cocaine-altered expression of melatonin receptor mRNA may occur in the hippocampus and striatum. METHODOLOGY: Male C3H/HeJ mice were treated with the antidepressants fluoxetine, desipramine, and clomipramine, with the psychostimulant cocaine, and with a vehicle either a single time or once a day for 14 days. Brain samples were collected 24 h after the last injection and the content of MT(1) and MT(2) mRNA was assayed. RESULTS: A single drug injection did not alter the MT(1) and MT(2) mRNA content. In the hippocampus, protracted treatment with antidepressants increased the amount of MT(1) mRNA (with the exception of fluoxetine) but decreased MT(2) mRNA content; cocaine did not produce any alterations. In the striatum, antidepressants produced the opposite effect on MT(1) mRNA content; they decreased it. They did not significantly alter striatal MT(2) mRNA (we observed a nonsignificant trend to a decrease). Cocaine also decreased striatal MT(1) mRNA content without affecting MT(2) mRNA. CONCLUSION: These results suggest that drug- and region-specific alterations of MT(1)/MT(2) mRNA produced by protracted antidepressants and cocaine treatment may alter MT1/MT2 expression and contribute to long-term neuroplastic effects of these drugs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2286828PMC
January 2006

Caffeic acid attenuates the decrease of cortical BDNF transcript IV mRNA induced by swim stress in wild-type but not in 5-lipoxygenase-deficient mice.

J Neural Transm (Vienna) 2008 Jun 28;115(6):823-7. Epub 2008 Feb 28.

Department of Psychiatry, Psychiatric Institute, University of Illinois at Chicago, Chicago, IL 60612, USA.

Caffeic acid is a natural compound that inhibits 5-lipoxygenase (5-LOX). In mice, caffeic acid produces antidepressant-like effects and attenuates the decrease in cortical brain-derived neurotrophic factor (BDNF) mRNA induced by forced swimming. We used wild-type and 5-LOX-deficient mice and found that swimming reduced the cortical content of BDNF exon IV but not exon I mRNA. The BDNF transcript IV decrease was attenuated by caffeic acid in wild-type but not in 5-LOX-deficient mice, suggesting a role for 5-LOX in BDNF regulation.
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http://dx.doi.org/10.1007/s00702-008-0034-7DOI Listing
June 2008

Caffeic acid attenuates the decrease of cortical BDNF transcript IV mRNA induced by swim stress in wild-type but not in 5-lipoxygenase-deficient mice.

J Neural Transm (Vienna) 2008 Jun 28;115(6):823-7. Epub 2008 Feb 28.

Department of Psychiatry, Psychiatric Institute, University of Illinois at Chicago, Chicago, IL 60612, USA.

Caffeic acid is a natural compound that inhibits 5-lipoxygenase (5-LOX). In mice, caffeic acid produces antidepressant-like effects and attenuates the decrease in cortical brain-derived neurotrophic factor (BDNF) mRNA induced by forced swimming. We used wild-type and 5-LOX-deficient mice and found that swimming reduced the cortical content of BDNF exon IV but not exon I mRNA. The BDNF transcript IV decrease was attenuated by caffeic acid in wild-type but not in 5-LOX-deficient mice, suggesting a role for 5-LOX in BDNF regulation.
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http://dx.doi.org/10.1007/s00702-008-0034-7DOI Listing
June 2008

5-Lipoxygenase inhibitor MK-886 increases GluR1 phosphorylation in neuronal cultures in vitro and in the mouse cortex in vivo.

Brain Res 2007 May 14;1147:148-53. Epub 2007 Feb 14.

The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, MC912, Chicago, IL 60612, USA.

Modifications of AMPA glutamate receptor GluR1 phosphorylation are critical for neuroplastic mechanisms. Previous in vitro studies in brain slices employed MK-886, a functional inhibitor of the enzyme 5-lipoxygenase (5-LOX), and found increased GluR1 phosphorylation. Since slice preparations have accompanying postmortem phosphorylation changes, e.g., decreased GluR1 phosphorylation, it remains to be clarified whether MK-886 can affect GluR1 phosphorylation in intact neurons and in the brain in vivo. We used primary neuronal cultures prepared from embryonic mouse brain and in vivo drug administration to investigate the effects of MK-886 on GluR1 phosphorylation using quantitative Western immunoblotting assays. In vitro, MK-886 increased GluR1 phosphorylation at both serine 831 and serine 845. In vivo, repeated but not a single MK-886 injection increased GluR1 phosphorylation in the prefrontal cortex. These findings indicate that MK-886 has an intrinsic effect on neuronal phosphorylation both in vitro and in vivo and support the use of MK-886 as a pharmacological tool in studies of not only the 5-LOX pathway but also neuronal GluR1 functioning.
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http://dx.doi.org/10.1016/j.brainres.2007.02.012DOI Listing
May 2007

The pattern of melatonin receptor expression in the brain may influence antidepressant treatment.

Med Hypotheses 2007 2;69(1):120-4. Epub 2007 Jan 2.

Department of Psychiatry and the Psychiatric Institute, University of Illinois at Chicago, 1601 West Taylor Street, M/C912, Chicago, IL 60612, USA.

The pineal hormone melatonin produces most of its biological effects via G protein-coupled receptors MT1 and MT2. In mammals, these receptors are expressed in various tissues and organs including in the brain. Recent research points to a putative role of MT1/MT2 dimerization as a mechanism that could determine the receptor-mediated biological effects of melatonin. Brain content and the ratios between MT1 and MT2 receptors are affected by illness, e.g., Alzheimer's disease, and by prolonged drug treatment, e.g., antidepressants. New drugs with antidepressant properties that bind and activate melatonin receptors have been discovered. We hypothesize that endogenous, i.e., low, levels of melatonin could contribute to antidepressant effects depending on the expression pattern of melatonin receptors in the brain. Hence, we propose that a prolonged treatment with classical antidepressant drugs alters the brain ratio of MT1/MT2 receptors to enable the endogenous melatonin, which is secreted during the night, to further improve the antidepressant effects. A corollary of this hypothesis is that antidepressants would be less effective in conditions of pathologically altered brain melatonin receptors, e.g., in Alzheimer's patients or due to genetic polymorphisms. If our hypothesis is confirmed, supplementing classical antidepressant treatment with an appropriate dose of a melatonin receptor agonist might be used to improve antidepressant effects in subjects with a susceptible pattern of brain melatonin receptor expression.
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http://dx.doi.org/10.1016/j.mehy.2006.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1950672PMC
July 2007

Clock genes: influencing and being influenced by psychoactive drugs.

Authors:
Hari Manev Tolga Uz

Trends Pharmacol Sci 2006 Apr 2;27(4):186-9. Epub 2006 Mar 2.

Department of Psychiatry, The Psychiatric Institute, University of Illinois at Chicago, Chicago, IL 60612, USA.

Although clock genes are the hallmark of circadian rhythms, they are also currently considered as transcription factors that have a prominent role in the pharmacology of the CNS. The expression of these transcription factors in the mammalian brain is not only intrinsically rhythmic but is also modulated by external inputs and hormones. An altered expression of clock genes, as evidenced in transgenic mice, has a profound influence on the behavioral effects of psychoactive drugs. Focusing on clock genes expressed in the brain might lead to the discovery of novel drug-target pathways.
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http://dx.doi.org/10.1016/j.tips.2006.02.003DOI Listing
April 2006

Clock genes as a link between addiction and obesity.

Authors:
Hari Manev Tolga Uz

Eur J Hum Genet 2006 Jan;14(1)

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http://dx.doi.org/10.1038/sj.ejhg.5201524DOI Listing
January 2006

Impaired hippocampal long-term potentiation in melatonin MT2 receptor-deficient mice.

Neurosci Lett 2006 Jan 3;393(1):23-6. Epub 2005 Oct 3.

Department of Psychiatry, The Psychiatric Institute, University of Illinois at Chicago, 1601 West Taylor Street, MC912, 60612, USA.

The pineal product melatonin that acts on specific melatonin receptors has been implicated in pathobiological mechanisms of neuropsychiatric disorders including Alzheimer's disease. We used mice lacking melatonin MT(2) receptors (MT(2) knockouts) to investigate the role of these receptors in synaptic plasticity and learning-dependent behavior. In field CA1 of hippocampal slices from wild-type mice, theta burst stimulation induced robust and stable long-term potentiation that was smaller and decremental in slices from MT(2) knockouts. Tested in an elevated plus-maze on two consecutive days, wild-type mice showed shorter transfer latencies to enter a closed arm on the second day; this experience-dependent behavior did not occur in MT(2) knockouts. These results suggest that MT(2) receptors participate in hippocampal synaptic plasticity and in memory processes.
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http://dx.doi.org/10.1016/j.neulet.2005.09.040DOI Listing
January 2006

Reliability assessment of an automated forced swim test device using two mouse strains.

J Neurosci Methods 2005 Nov 20;149(1):26-30. Epub 2005 Jun 20.

The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, MC912, Chicago, IL 60612, USA.

The Porsolt forced swim test (FST) is one of the most widely used behavioral tests in the evaluation of the antidepressant effects of drugs. It is based on the fact that these drugs reduce the depression-related behaviors of learned helplessness. The model has been modified for use in mice. In contrast to rats, mice are exposed to forced swimming only once and their immobility behavior is measured and considered a "depression-like" phenotype. Like many other behavioral tests, FST can be affected by observer-related artifacts. In recent years, automated testing systems have been developed to decrease artifacts that may greatly influence the interpretation of results. In this work, we used two strains of mice, i.e., C3H/HeJ and C57BL/6J, which differ in their FST immobility times. We employed a new commercially available automated FST device and a blinded observer-based FST, and we examined their ability to measure behavioral differences between these two mouse strains. Our results suggest that the tested automated FST system generates reliable data comparable to results obtained by trained observers.
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http://dx.doi.org/10.1016/j.jneumeth.2005.04.010DOI Listing
November 2005

The regional and cellular expression profile of the melatonin receptor MT1 in the central dopaminergic system.

Brain Res Mol Brain Res 2005 May;136(1-2):45-53

Department of Psychiatry, Psychiatric Institute, University of Illinois at Chicago, 1601 West Taylor Street, M/C 912, Chicago, IL 60612, USA.

The physiological effects of pineal melatonin are primarily mediated by melatonin receptors located in the brain and periphery. Even though there are a number of studies demonstrating the regulatory role of melatonin in the development of dopaminergic behaviors, such as psychostimulant-induced diurnal locomotor sensitization or drug seeking, little is known about the contribution of melatonin receptors (i.e., MT1) to this role. Therefore, as a first step in understanding the functional role of melatonin receptors in dopaminergic behaviors, we focused on determining the expression pattern of MT1 receptors in the dopaminergic system of the human and rodent brain. Regional (e.g., nucleus accumbens shell) and cellular (e.g., tyrosine hydroxylase immunopositive cells) expression of MT1 mRNA was characterized by applying the immuno-laser capture microdissection (immuno-LCM) technique coupled with nested RT-PCR. Moreover, employing quantitative Western immunoblotting and RT-PCR, we found that the mouse MT1 receptor expression presents diurnal variations (i.e., low mRNA and high protein levels at night, ZT21). The dopaminergic system-based presence of MT1 receptor proteins was not limited to rodents; we found these receptors in postmortem human brain as well. Further research is needed to understand the regional/cellular functional role of melatonin receptors in the regulation of dopaminergic behaviors, using models such as melatonin receptor knockout mice.
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http://dx.doi.org/10.1016/j.molbrainres.2005.01.002DOI Listing
May 2005

Diurnal rhythms in quinpirole-induced locomotor behaviors and striatal D2/D3 receptor levels in mice.

Pharmacol Biochem Behav 2005 Mar 28;80(3):371-7. Epub 2005 Jan 28.

Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, M/C 912, Chicago, Illinois 60612, USA.

Dopaminergic drugs, including the D2/D3 agonist quinpirole, produce lasting changes in the brain that lead to altered behavioral responses. The action of these drugs is dosing time-dependent; in fruit flies, behavioral response to quinpirole shows a marked circadian variability. Here we demonstrate diurnal rhythm-dependent variations both in quinpirole-induced locomotor behaviors and in striatal D2 and D3 protein levels in mice. We found opposing diurnal rhythms in striatal D2 and D3 protein levels, resulting in a high D2/D3 ratio during the day and a low D2/D3 ratio at night. Protracted quinpirole treatment differentially altered striatal D2/D3 rhythms depending on the time of injection (i.e., day or night). When quinpirole-induced locomotor activity was analyzed for 90 min, we found hypomotility after the first day or nighttime drug injection. By the seventh injection, daytime quinpirole treatment produced clear hyperactivity while nighttime quinpirole treatment continued to induce a significant initial hypoactivity followed by a hyperactivity period. Our data indicate that quinpirole-induced long-term alterations in the brain include dosing time-dependent changes in dopamine receptor rhythms. Therefore, we propose that diurnal mechanisms, which participate in drug-induced long-term changes in the dopamine system, are important for the development of dopaminergic behaviors.
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http://dx.doi.org/10.1016/j.pbb.2004.11.016DOI Listing
March 2005
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